assignment on sympathetic nervous system

Sympathetic Nervous System: Functions & Examples

Olivia Guy-Evans, MSc

Associate Editor for Simply Psychology

BSc (Hons) Psychology, MSc Psychology of Education

Olivia Guy-Evans is a writer and associate editor for Simply Psychology. She has previously worked in healthcare and educational sectors.

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Karina Ascunce González

PhD Neuroscience Student, Yale University

Neuroscience B.A. (Hons), Harvard University

PhD Student at the Yale Biological & Biomedical Sciences' Interdepartmental Neuroscience Program interested in neurodegeneration, stem cell culture, and bioethics. AB in Neuroscience with a Secondary in Global Health & Health Policy from Harvard University. Karina has been published in peer reviewed journals.

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Editor-in-Chief for Simply Psychology

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The sympathetic nervous system (SNS) is a subdivision of the autonomic nervous system that regulates autonomic processes.

The sympathetic nervous system prepares the body for stress-related activities and slows bodily processes that are less important in emergencies, such as digestion.

These processes are not under direct conscious control, occurring automatically and without conscious thought.

The sympathetic nervous system is typically recruited in situations requiring quick responses.

• Increase heart rate
• Dilation of the pupils
• Secretion of sweat glands
• Dilated muscles
• Increase alertness
• Slowing down or stopping digestion
• Relaxation of the bladder

The SNS can maintain homeostasis through sweating to cool down the body or regulate heart rate. In contrast to the parasympathetic nervous system, which slows down physiological processes, the SNS typically stimulates organs.

The parasympathetic branch, however, stimulates digestion and the urinary system when relaxed, whereas the SNS slows them down as these processes are not required during heightened stress.

The SNS also works alongside the parasympathetic nervous system to maintain homeostasis – the balance of internal physiological mechanisms essential for all living organisms.

Essentially, the parasympathetic branch is the antagonist of the SNS. Also, the neurons of the SNS have shorter pathways than those of the parasympathetic nervous system.

This shorter distance allows for a quicker signal transmission; sometimes the responses happen before a person is consciously aware of them.

What does the sympathetic nervous system do?

1. fight-or-flight response.

The primary function of the SNS is to activate the fight-or-flight response in threatening situations.

For instance, if you are walking alone down a dark street at night and a stranger approaches you, your body responds in a way that enables you to either fight or run away from the situation.

In this situation, the SNS would trigger responses such as causing the eyes to dilate and the heart to beat faster.

These autonomic responses to a threatening situation are, therefore, essential for survival. In evolutionary terms, the SNS would have been used to fight or escape predators and for hunting to eat and survive.

More modern-day stressors can also stimulate the SNS, such as financial pressures, stresses at work, or anything that can cause high anxiety for individuals.

When a stressful or anxiety-provoking situation arises, the amygdala (an area of the brain associated with fear and emotions) sends a distress signal to the hypothalamus (a command structure of the brain associated with maintaining homeostasis).

Impulses are then transmitted through the SNS to the adrenal glands, which then pump adrenaline, and then cortisol (stress hormone), into the bloodstream.

This will then bring about the physiological changes needed to be prepared to either fight or flight.

The reactions brought about by the SNS result in heightened awareness and preparation for combat or running.

Fundamentally, the fight-or-flight response is mediated via impulses transmitted throughout the SNS to the adrenal glands.

The adrenal glands facilitate both short-term responses to stress as well as long-term responses.

Once the threat has been resolved, the parasympathetic nervous system takes over and returns bodily functions to a relaxed state.

2. Regulating Body Temperature

For homeostasis to be achieved, the SNS can control the body temperature of organisms through the use of fat reserves in the body.

The SNS uses these reserves to increase heat production and change blood flow to the skin.

The SNS is also able to stimulate the sweat glands to enable the body to cool down, as well as being able to stimulate fatty acid release to instigate long-term responses to persistent periods of cold.

3. Cardiovascular Effects

The SNS can have effects on the cardiovascular system within the body.

This comes into play when exercising (when heart rate needs to increase), changing posture (e.g., sitting to standing), and transitioning from sleep to wakefulness.

These changes via the SNS are necessary, especially when changing positions; otherwise, this can cause dizziness and fainting.

Nerves of the SNS

The SNS consists of neurons found within the peripheral nervous system and the central nervous system, which usually works in stimulating the body’s organs in response to fear or stress.

There are two types of neurons within the sympathetic nervous system: preganglionic and postganglionic neurons, or ganglion cells.

The word ‘ganglia’ refers to clusters of neurons outside the brain and spinal cord. Instead, they are part of the autonomic nervous system and run alongside the spinal cord.

The preganglionic neurons originate in the brain stem or spinal cord and will always leave the spinal cord through areas called the thoracic and lumbar regions.

The preganglionic neurons will then synapse with the postganglionic neurons at ganglia, which sit outside of the spinal cord.

The postganglionic neurons will then extend to target organs of the SNS (e.g., heart, sweat glands, and stomach) in order to trigger certain effects when activated.

Neurotransmitters within the SNS

Neurotransmitters are the chemical messengers which are transmitted through neurons. The preganglionic neuron’s primary neurotransmitter is acetylcholine.

Acetylcholine is a neurotransmitter found in both the central nervous system and the peripheral nervous system and plays a role in brain and muscle function.

The preganglionic neurons within the thoracic and lumbar regions in the spinal cord carry acetylcholine, making them cholinergic, and release it at synapses within the ganglia.

Acetylcholine is then taken up by the receptors on the postganglionic neurons. Activation of this process results in signals being extended to target areas of the sympathetic nervous system and the release of another neurotransmitter called norepinephrine.

Norepinephrine (also known as noradrenaline) is an excitatory neurotransmitter as it stimulates the body. This chemical helps in activating the body and brain to act during the fight-or-flight response, aiding in alertness.

Norepinephrine is released from the adrenal medulla after prolonged activation from postganglionic neurons. Epinephrine (also known as adrenaline) is also released from the adrenal medulla after increased levels of activation.

Epinephrine is also an excitatory neurotransmitter that is released into the bloodstream and enhances the neuronal effects of the SNS.

As a result, these neurotransmitters encourage the organs involved in the SNS to respond to a threat and cause blood vessels to dilate, or open up, to allow more blood flow in order for the muscles to fight or flight. This process is called vasodilation.

In other words, a perceived threat results in the secretion of epinephrine and norepinephrine from the adrenal medulla, which then acts on several organs and the cardiovascular system to mediate the fight-or-flight response.

Problems with the SNS

Although most modern-day stressors that trigger the SNS may appear small, they may be interpreted by our nervous system as a potential life threat.

If the SNS is activated too frequently, this can have long-lasting effects on the body, resulting in chronic stress.

Similarly, constant surges of epinephrine can damage blood vessels and arteries, which in turn can increase blood pressure and increase the risk of strokes and heart attacks.

Alternatively, if the SNS is under-functioning, this can also cause issues. If someone’s SNS is not functioning, they may not respond appropriately in times of stress.

They may not recognize that there is a danger, and they may take more risks as they are not being alerted by their SNS that they are in life-threatening situations.

As their organs are not receiving signals to fight-or-flight, they may be under-prepared in these situations, due to lack of blood being pumped around the body or other systems failing to be recruited.

Autonomic dysfunction is when the autonomic nervous system and its divisions do not work properly.

Depending on the condition, this may lead to altered functioning of the heart, sweat glands, pupils, and blood vessels. Autonomic dysfunction can develop when nerves of the autonomic nervous system are damaged and can range from mild to life-threatening.

The most common cause of autonomic dysfunction is diabetes, but there could be hereditary reasons, as well as aging, Parkinson’s disease, or chronic fatigue syndrome being some of the possible causes.

If someone believes they may be suffering from autonomic dysfunction, they may be experiencing one or more of the following symptoms:

Feeling dizziness or actually fainting. Inability to alter heart rate in response to exercise. Abnormally fast heart rate. Digestive issues. Visual problems, e.g. blurriness. Abnormal sweating – either too much sweating or not sweating enough. Lack of pupillary response.

Autonomic dysfunction can be treated depending on the symptoms being experienced. For instance, if the cause of dysfunction is due to diabetes, controlling blood sugar will be the primary treatment.

In many cases, treating the underlying disease (if applicable) can allow damaged nerves within the ANS to repair and regenerate.

Autonomic dysfunction can be diagnosed through a doctor, using measures such as blood pressure and heart rate, in order to understand what exactly the issue is.

How to calm an overactive sympathetic nervous system

If an individual has an overactive SNS in times that are not considered dangerous, there are quick methods that can somewhat aid in calming down the SNS.

Taking deep breaths at a slow and steady pace, as well as various breathing exercises, are ways to encourage our parasympathetic nervous system to antagonize the SNS. This can be a quick way to help manage stress responses and decrease anxiety.

Similarly, practicing mindfulness is another method to actively prompt the body to rest, rejuvenate and regenerate, allowing a return to homeostasis.

For more serious cases of chronic stress, deep breathing may not be useful, so it is recommended to seek a doctor’s advice, who may recommend medical treatment or therapies to be able to combat the cause of the stress.

Biology Dictionary. (October 4, 2019). Sympathetic Nervous System. https://biologydictionary.net/sympathetic-nervous-system/

Britannica, T. Editors of Encyclopaedia (2019, September 13). Sympathetic nervous system. Encyclopedia Britannica. https://www.britannica.com/science/sympathetic-nervous-system

Lumen. (n.d.). Functions of the Autonomic Nervous System. Retrieved May 5, 2021 from https://courses.lumenlearning.com/boundless-ap/chapter/functions-of-the-autonomic-nervous-system/

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Sympathetic vs. Parasympathetic Nervous System

Reviewed by: BD Editors

The human nervous system is a sprawling network of nerves and cells which, together, regulate all of the vital functions that take place in our bodies. The sympathetic nervous system (SNS) and the parasympathetic nervous system (PSNS) are both components of the autonomic nervous system (ANS). Together, they regulate the involuntary and reflexive functions of the human body.

The PSNS controls the ‘rest and digest’ functions of the body and maintains the body’s internal environment. It is responsible for regulating digestive and sexual function while keeping heart rate and blood pressure steady. The SNS is the driving force behind the ‘fight or flight’ response and triggers a number of physiological changes that prepare the body to confront or flee a perceived threat.

What Does the Parasympathetic Nervous System Do?

The PSNS regulates the functions of your organs and glands at rest, otherwise known as the ‘rest and digest’ or ‘feed and breed’ activities. Put simply, the PSNS keeps your bodily functions working as they should. It keeps your heart rate and blood pressure steady while stimulating activities related to digestive and sexual function. These include the production of saliva, tears, and urine, digestion, defecation, and sexual arousal.

Key Effects of the Parasympathetic Nervous System

• Saliva production increases
• Mucus production increases
• Motility of the large and small intestines increases
• Activity in the stomach increases
• Urine secretion increases
• Bronchial muscles are contraction
• Pupils are constricted
• Heart rate is decreased

What Does the Sympathetic Nervous System Do?

The SNS is, arguably, even more important than the PSNS because it controls our ‘fight or flight’ response. If we find ourselves in a dangerous situation, it is the SNS that prepares us to save ourselves by either fighting the threat or running away from it. When confronted with a potential threat, the SNS directs energy away from non-essential functions (like the digestive system) and towards functions that are essential to survival.

First, the hormone adrenaline is released from the adrenal gland. As adrenaline flows through your bloodstream, it causes several physiological changes in the body that prepare it to fight or flee.

Heart rate and blood pressure are both increased. This boosts the flow of oxygenated blood to the muscles, which contract, ready for action. At the same time, the bronchial tubes dilate, increasing airflow in and out of the lungs and sending extra oxygen to the brain to improve alertness. The pupils also dilate, which allows more light to enter your eyes so you can see your surroundings more clearly.

All of these responses happen quickly and involuntarily, allowing you to react rapidly to the perceived threat. For example, if you see a car speeding towards you, you may leap out of the way before you have even fully registered what is happening, all thanks to the actions of the SNS.

Key Effects of the Sympathetic Nervous System

• Adrenaline is released
• Heart rate increases
• Blood pressure increases
• Bronchial tubes dilate
• Glycogen is converted to glucose at an increased rate
• Pupils dilate
• Muscles contract
• Saliva production decreases
• Mucus production decreases
• Urine Secretion decreases
• Activity in the stomach decreases
• Motility of the large and small intestine decreases

What is the Autonomic Nervous System?

The SNS and PSNS are the two main parts of the autonomic nervous system (ANS), which controls the functions of our internal organs. All of the functions of the ANS are involuntary and reflexive , so we don’t always notice its effects on our bodies.

When the PSNS branch of the ANS is activated, the body is focused on ‘rest and digest’ or ‘feed and breed’ activities. The SNS stimulates the ‘fight or flight’ response and directs energy away from ‘rest and digest’ functions and towards those essential for survival. Together, both branches of the ANS regulate the vital activities of the internal organs when at rest and when under threat.

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Sympathetic Nervous System

The Sympathetic nervous system is part of the autonomic nervous system . It becomes more active when you are stressed. It directs the body’s rapid involuntary response to dangerous or stressful situations. It is a part of the “fight or flight” response. It controls aspects of the body related to the flight-or-fight response, such as mobilizing fat reserves, increasing the heart rate, and releasing adrenaline. It is part of the autonomic nervous system (ANS), which also includes the parasympathetic nervous system (PNS). It is a major effector of thermoregulatory responses. This can include actions of running, fighting, hiding, and generally, actions used to escape predators.

The sympathetic nervous system can increase heart rate; make bronchial passages wider; decrease motility (movement) of the large intestine; make blood vessels narrower; increase peristalsis in the esophagus; cause pupil dilation, piloerection (goosebumps) and perspiration (sweating); and raise blood pressure. The actions of the sympathetic nervous system occur in concert with other neural or hormonal responses to stress, including increases in corticotropin and cortisol secretion. This is important because a slow or ineffective response can lead to the death of an organism. Their role in the short-term regulation of blood pressure, especially in responses to transient changes in arterial pressure, via baroreflex mechanisms is well known.

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What Is the Sympathetic Nervous System?

Fight, Flight, Freeze, Fawn Responses

• How it Works

The sympathetic nervous system (SNS) is responsible for the body's stress response and is activated when you perceive danger. The brain sends messages to the rest of the body to prepare for and respond to danger, initiating a fight, flight, freeze, or fawn stress response. If the SNS is chronically activated, it can impact your health.

Learn about the sympathetic nervous system function and your body's response to perceived danger.

Lourdes Balduque / Getty Images

Function of the Sympathetic Nervous System

The primary function of the sympathetic nervous system is to keep your body safe from danger. When you perceive a threat, your sympathetic nervous system helps prepare your body and mind for impending danger. This is known as a stress response.

Types of Stress Responses

Scientists initially categorized the stress response as a fight or flight response. More recently, two more reactions have been identified: Freeze or fawn. Sympathetic nervous system stress responses include:

• Fight response : This response involves aggression directed toward the danger or perceived danger. For example, someone threatened by another person may become physically defensive and attack or punch that person.
• Flight response : This response may also be called the flee response. It involves avoiding danger or perceived danger by running, driving, or moving in a different direction. For example, a person may run out of a burning building and keep running until they are far away from it.
• Freeze response : This response involves holding as still as possible while the danger or perceived danger is present. For example, opossums and other animals are known for "playing dead" when threatened.
• Fawn response : This response involves acting to prevent or decrease conflict. For example, someone being robbed may willingly hand over valuable or cherished belongings to remain physically safe.

Sympathetic Nervous System Anatomy

The two main parts of the sympathetic nervous system are the brain and the spinal cord .

• The brain is responsible for processing the threat.
• The spinal cord communicates the threat to other parts of the body.

Once the brain is alerted to a threat, it sends messages via neurons (chemical messengers) to clusters of nerve cells called ganglia , which are responsible for sensory and motor responses. Then, the ganglia send those neurons to the body parts that respond to danger, such as muscles needed to run away or fight.

Sympathetic vs. Parasympathetic Nervous System (PNS)

The sympathetic and parasympathetic nervous systems (PNS) comprise the autonomic nervous system . They work together to shift the mind and body between alertness and calmness. The PNS response is sometimes called "rest and digest" because when the PNS is activated, the body responds by increasing digestion, sleep, the tendency toward social interactions, and repairing injuries.

How the Sympathetic Nervous System Works

When the brain senses danger, the amygdala , responsible for interpreting external stimuli, sends a message to the hypothalamus , which is responsible for maintaining our body's baseline state. Then the brain releases hormones that cause the body to react.

For example, adrenaline ( epinephrine ) helps get oxygen to the muscles by opening the airways and telling the blood vessels to send more blood to the heart and lungs.

What Happens When the Sympathetic Nervous System Is Activated?

The sympathetic nervous system causes physical changes all over the body. When you experience a fight, flight, freeze, or fawn reaction, your brain sends messages to the rest of your body to prepare for danger. Your body responds by increasing blood sugar levels and releasing fat for energy to protect against danger.

Some other parts of your body that respond when the sympathetic nervous system is activated include:

• Eyes : The pupils of the eyes get bigger to let in more light so the threat can be seen more easily.
• Lungs : The lungs open up to provide more oxygen to muscles, and the brain, which helps muscles work better and the brain becomes more alert.
• Heart : The heart beats faster to pump more blood to organs needing more blood flow.
• Digestive system : The digestive system slows so more energy can be used to respond to the threat or danger.

Sometimes the sympathetic nervous system becomes activated when there is no real danger or remains activated after the threat is gone. Long-term activation of the sympathetic nervous system has been linked to health concerns such as:

• Autoimmune disease
• Chronic stress
• High blood pressure

It can also lead to physical effects such as fatigue .

The sympathetic nervous system helps to protect you from danger. When you perceive danger, your brain and spinal cord release chemicals and send messages to other body parts to respond. Physical changes take place to make the body and mind more able to respond to the threat. The parasympathetic nervous system creates an opposite response after the threat is gone, which allows the body and mind to rest and recover.

American Psychological Association. Sympathetic nervous system .

American Psychological Association. Stress effects on the body .

Encyclopedia Britannica. Sympathetic nervous system .

Simple Psychology. Fight, flight, freeze, or fawn: what this response means .

Encyclopedia Britannica. Fight-or-flight response .

Zingela Z, Stroud L, Cronje J, Fink M, van Wyk S. The psychological and subjective experience of catatonia: a qualitative study .  BMC Psychol . 2022;10(1):173. doi:10.1186/s40359-022-00885-7

American Psychological Association. Fight-or-flight response .

American Psychological Association. Autonomic nervous system (ANS) .

Hospital for Special Surgery. How the parasympathetic nervous system can lower stress .

American Psychological Association. Parasympathetic nervous system .

Harvard Medical School. Understanding the stress response .

Endocrine Society. Adrenal hormones .

The American Institute of Stress. How stress affects your vision .

DeLalio LJ, Sved AF, Stocker SD. Sympathetic nervous system contributions to hypertension: updates and therapeutic relevance .  Canadian Journal of Cardiology . 2020;36(5):712-720. doi:10.1016/j.cjca.2020.03.003

Harvard Medical School. Stress and the sensitive gut .

Won E, Kim YK. Stress, the autonomic nervous system, and the immune-kynurenine pathway in the etiology of depression .  Curr Neuropharmacol . 2016;14(7):665-673. doi:10.2174/1570159X14666151208113006

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Neuroanatomy, sympathetic nervous system.

Mark N. Alshak ; Joe M. Das .

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• Introduction

The sympathetic autonomic nervous system (SANS) is one of the two divisions of the autonomic nervous system (ANS), along with the parasympathetic nervous system (PANS), These systems primarily work unconsciously in opposite ways to regulate many functions and parts of the body. Colloquially, the SANS governs the "fight or flight" response while the PANS controls the "rest and digest" response. The main overall end effect of the SANS is to prepare the body for physical activity, a whole-body reaction affecting many organ systems throughout the body to redirect oxygen-rich blood to areas of the body needed during intense physical demand. [1]

• Structure and Function

The sympathetic nervous system is composed of many pathways that perform a variety of functions on various organ systems. The preganglionic neurons of the SANS arise from the thoracic and lumbar regions of the spinal cord (T1 to L2) with the cell bodies distributed in four regions of the gray matter in the spinal cord bilaterally and symmetrically. [1] [2]  As opposed to the parasympathetic nervous system, the first-order neurons of the SANS are short before synapsing on postsynaptic neurons found within sympathetic ganglia. Similar to the PANS, the neurotransmitter used at this junction is acetylcholine. This acetylcholine activates nicotinic receptors. These postganglionic neurons then travel to their effector sites and release the neurotransmitters epinephrine or norepinephrine, except for sympathetic innervation of sweat glands and the arrectores pili muscles, the small muscles attached to hair follicles, which use acetylcholine as their postganglionic neurotransmitter. [3]  These neurotransmitters act on adrenergic receptors. Among the adrenergic receptors are alpha-1 (coupled to a Gq and works through the IP3/Ca2+ pathway), alpha-2 (coupled to Gi and works through decreasing the cAMP pathway), and beta-1 and beta-2 (coupled to Gs and works through increasing the cAMP pathway). [4]  Whether beta-1 and beta-2 are excitatory or inhibitory depends on the tissue on which it is located. These receptors are located on various parts of the body and regulate the actions of the SANS.

The functions of the sympathetic nervous system are expansive and involve many organ systems and various types of adrenergic receptors.

The effects in which SANS acts in direct contrast to the PANS function include the following:

• In the eye, sympathetic activation causes the radial muscle of the iris (alpha-1) to contract, which leads to mydriasis, allowing more light to enter. Furthermore, the ciliary muscle (beta-2) relaxes, allowing for far vision to improve.
• In the heart (beta-1, beta-2), sympathetic activation causes an increased heart rate, the force of contraction, and rate of conduction, allowing for increased cardiac output to supply the body with oxygenated blood.
• In the lungs, bronchodilation (beta-2) and decreased pulmonary secretions (alpha-1, beta-2) occur to allow more airflow through the lungs.
• In the stomach and intestines, decreased motility (alpha-1, beta-2) and sphincter contraction (alpha-1), as well as contraction of the gallbladder (beta-2), occur to slow down digestion to divert energy to other parts of the body.
• The exocrine and endocrine pancreas (alpha-1, alpha-2) decreases both enzyme and insulin secretion.
• In the urinary bladder, there is relaxation of the detrusor muscle and contraction of the urethral sphincter (beta-22) to help stop urine output during sympathetic activation.
• The kidney (beta-1) increases renin secretion to increase intravascular volume.
• The salivary glands (alpha-1, beta-2) work through small volumes of potassium and water secretion. 

Actions of SANS which do not oppose those of the PANS include the following:

• There is strong constriction through the alpha-1 receptor in arterioles of the skin, abdominal viscera, and kidney, and weak constriction through the alpha-1 and beta-2 receptors in the skeletal muscle.
• In the liver, increased glycogenolysis and gluconeogenesis (alpha-1, beta-2) occur to allow for glucose to be available for energy throughout the body.
• In the spleen, there is a contraction (alpha-1).
• Sweat glands and arrector pili muscles (muscarinic) work to increase sweating and erection of hair to help cool down the body.
• Lastly, the adrenal medulla (nicotinic receptor) increases the release of epinephrine and norepinephrine to act elsewhere in the body. [1]

Neurons of the peripheral autonomic nervous system, which includes both the sympathetic nervous system and parasympathetic nervous system, arise from neural crest cells that originate between the neural and non-neural ectoderm. They form the dorsal neural folds as the folds themselves form the neural tube. [5]

• Physiologic Variants

Aging has various effects on the sympathetic nervous system. Research has demonstrated that with increased age that baroreceptors of the heart decrease and become less sensitive; there is a compensatory increase in cardiovascular SANS activity and a reduction in PANS activity. However, both sympathetic and parasympathetic nervous activity to the iris decreases with aging, which is consistent with the general decline of peripheral somatic nerve function. [6]  Research has also shown that baseline levels of noradrenaline levels increase with age resulting in an elevated basal SANS activation, while the reactivity becomes reduced with aging. [7]  This increase in activation plays a role, among other disease processes, in both age-related hypertension and heart failure. [8]

• Surgical Considerations

Horner syndrome is a complication born from interruption of the sympathetic innervation to the eye and adnexa at varying levels, most commonly of the neck, resulting in increased parasympathetic input. It presents with the classic triad of ipsilateral ptosis, pupillary miosis, and facial anhidrosis. It can be a complication of neck surgeries that damage the sympathetic input. [9] There are even reports after minimally invasive thyroidectomy. [10]  For more information on Horner syndrome, please refer to our accompanying article. [11]

Hyperhidrosis, otherwise known as excessive sweating, is a common indication for minimally invasive thoracic sympathectomy. Hyperhidrosis is excessive sweating beyond the organism’s physiological need to sweat to have a temperature within an adequate range. Removing the sympathetic input to the part of the body affected by hyperhidrosis is an acceptable and well-tolerated treatment. [12]  Thorascoposic sympathectomy can also be useful to treat severe Raynaud syndrome, defined as episodic vascular spasms and digital ischemia secondary to cold or emotional stimuli. [13]

• Clinical Significance

The clinical significance of the sympathetic nervous system is vast as it affects many organ systems. Of the many physiological and pathological processes, pheochromocytoma, erections and priapism, diabetic neuropathy, and orthostatic hypotension are described below.

Pheochromocytomas are tumors that arise from chromaffin cells present in the adrenal medulla or paraganglion cells that secrete excess amounts of catecholamines (norepinephrine, epinephrine). Because of this catecholamine release, the symptoms are largely that of sympathetic activation, such as hypertension, tachycardia/palpitations, hyperglycemia, and diaphoresis. [14]

Erections are a product of parasympathetic activity. In the resting state, the SANS predominates, and the penis remains flaccid. However, if the sympathetic fibers to the penis are damaged or compromised, a sustained erection of over 4 hours, called priapism, can occur and result in devastating consequences to the penis. This condition can result from spinal cord or cauda equina injury as the sympathetic input is damaged, and the parasympathetic tone dominates. [15]  Nevertheless, SANS also contributes to the normal sexual function of a man. Sympathetic stimulation of the male genitals causes sperm emission, which is sensed by the hypogastric nerve. [16]

Diabetic autonomic neuropathy is one of the most common causes of sympathetic nerve neuropathy. This sympathetic denervation can lead to impaired myocardial coronary blood flow and reduced myocardial contractility. [17]  Diabetic neuropathy plays a crucial role in morbidity and mortality in patients with both type 1 and type 2 diabetes mellitus and causes dysfunction of many systems, including the heart, the Gastroenterol tract, the genitourinary system, and sexuality. As it is well established that hyperglycemia is the primary driver of this diabetic complication, the clinician must establish early and sustained intensive glycemic control to prevent or delay the onset and slow the progression of autonomic dysfunction. However, this strategy seems to be more effective in type 1 versus type 2 diabetic patients. [18]  

Lastly, orthostatic hypotension is a common problem caused by the failure of noradrenergic neurotransmission. It is defined as a drop of systolic blood pressure by at least 20 mmHg or diastolic by 10 mmHg. [19]  It is caused by a wide variety of disease processes, including but not limited to pure autonomic failure, multiple system atrophy, and autonomic neuropathies that damage the SANS. [20]

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12.1 Basic Structure and Function of the Nervous System

Learning objectives.

By the end of this section, you will be able to:

• Identify the anatomical and functional divisions of the nervous system
• Relate the functional and structural differences between gray matter and white matter structures of the nervous system to the structure of neurons
• List the basic functions of the nervous system

The picture you have in your mind of the nervous system probably includes the brain , the nervous tissue contained within the cranium, and the spinal cord , the extension of nervous tissue within the vertebral column. That suggests it is made of two organs—and you may not even think of the spinal cord as an organ—but the nervous system is a very complex structure. Within the brain, many different and separate regions are responsible for many different and separate functions. It is as if the nervous system is composed of many organs that all look similar and can only be differentiated using tools such as the microscope or electrophysiology. In comparison, it is easy to see that the stomach is different than the esophagus or the liver, so you can imagine the digestive system as a collection of specific organs.

The Central and Peripheral Nervous Systems

The nervous system can be divided into two major regions: the central and peripheral nervous systems. The central nervous system (CNS) is the brain and spinal cord, and the peripheral nervous system (PNS) is everything else ( Figure 12.2 ). The brain is contained within the cranial cavity of the skull, and the spinal cord is contained within the vertebral cavity of the vertebral column. It is a bit of an oversimplification to say that the CNS is what is inside these two cavities and the peripheral nervous system is outside of them, but that is one way to start to think about it. In actuality, there are some elements of the peripheral nervous system that are within the cranial or vertebral cavities. The peripheral nervous system is so named because it is on the periphery—meaning beyond the brain and spinal cord. Depending on different aspects of the nervous system, the dividing line between central and peripheral is not necessarily universal.

Nervous tissue, present in both the CNS and PNS, contains two basic types of cells: neurons and glial cells. A glial cell is one of a variety of cells that provide a framework of tissue that supports the neurons and their activities. The neuron is the more functionally important of the two, in terms of the communicative function of the nervous system. To describe the functional divisions of the nervous system, it is important to understand the structure of a neuron. Neurons are cells and therefore have a soma , or cell body, but they also have extensions of the cell; each extension is generally referred to as a process . There is one important process that every neuron has called an axon , which is the fiber that connects a neuron with its target. Another type of process that branches off from the soma is the dendrite . Dendrites are responsible for receiving most of the input from other neurons. Looking at nervous tissue, there are regions that predominantly contain cell bodies and regions that are largely composed of just axons. These two regions within nervous system structures are often referred to as gray matter (the regions with many cell bodies and dendrites) or white matter (the regions with many axons). Figure 12.3 demonstrates the appearance of these regions in the brain and spinal cord. The colors ascribed to these regions are what would be seen in “fresh,” or unstained, nervous tissue. Gray matter is not necessarily gray. It can be pinkish because of blood content, or even slightly tan, depending on how long the tissue has been preserved. But white matter is white because axons are insulated by a lipid-rich substance called myelin . Lipids can appear as white (“fatty”) material, much like the fat on a raw piece of chicken or beef. Actually, gray matter may have that color ascribed to it because next to the white matter, it is just darker—hence, gray.

The distinction between gray matter and white matter is most often applied to central nervous tissue, which has large regions that can be seen with the unaided eye. When looking at peripheral structures, often a microscope is used and the tissue is stained with artificial colors. That is not to say that central nervous tissue cannot be stained and viewed under a microscope, but unstained tissue is most likely from the CNS—for example, a frontal section of the brain or cross section of the spinal cord.

Regardless of the appearance of stained or unstained tissue, the cell bodies of neurons or axons can be located in discrete anatomical structures that need to be named. Those names are specific to whether the structure is central or peripheral. A localized collection of neuron cell bodies in the CNS is referred to as a nucleus . In the PNS, a cluster of neuron cell bodies is referred to as a ganglion . Figure 12.4 indicates how the term nucleus has a few different meanings within anatomy and physiology. It is the center of an atom, where protons and neutrons are found; it is the center of a cell, where the DNA is found; and it is a center of some function in the CNS. There is also a potentially confusing use of the word ganglion (plural = ganglia) that has a historical explanation. In the central nervous system, there is a group of nuclei that are connected together and were once called the basal ganglia before “ganglion” became accepted as a description for a peripheral structure. Some sources refer to this group of nuclei as the “basal nuclei” to avoid confusion.

Terminology applied to bundles of axons also differs depending on location. A bundle of axons, or fibers, found in the CNS is called a tract whereas the same thing in the PNS would be called a nerve . There is an important point to make about these terms, which is that they can both be used to refer to the same bundle of axons. When those axons are in the PNS, the term is nerve, but if they are CNS, the term is tract. The most obvious example of this is the axons that project from the retina into the brain. Those axons are called the optic nerve as they leave the eye, but when they are inside the cranium, they are referred to as the optic tract. There is a specific place where the name changes, which is the optic chiasm, but they are still the same axons ( Figure 12.5 ). A similar situation outside of science can be described for some roads. Imagine a road called “Broad Street” in a town called “Anyville.” The road leaves Anyville and goes to the next town over, called “Hometown.” When the road crosses the line between the two towns and is in Hometown, its name changes to “Main Street.” That is the idea behind the naming of the retinal axons. In the PNS, they are called the optic nerve, and in the CNS, they are the optic tract. Table 12.1 helps to clarify which of these terms apply to the central or peripheral nervous systems.

Interactive Link

In 2003, the Nobel Prize in Physiology or Medicine was awarded to Paul C. Lauterbur and Sir Peter Mansfield for discoveries related to magnetic resonance imaging (MRI). This is a tool to see the structures of the body (not just the nervous system) that depends on magnetic fields associated with certain atomic nuclei. The utility of this technique in the nervous system is that fat tissue and water appear as different shades between black and white. Because white matter is fatty (from myelin) and gray matter is not, they can be easily distinguished in MRI images. Try this PhET simulation that demonstrates the use of this technology and compares it with other types of imaging technologies. Also, the results from an MRI session are compared with images obtained from X-ray or computed tomography. How do the imaging techniques shown in this game indicate the separation of white and gray matter compared with the freshly dissected tissue shown earlier?

Functional Divisions of the Nervous System

The nervous system can also be divided on the basis of its functions, but anatomical divisions and functional divisions are different. The CNS and the PNS both contribute to the same functions, but those functions can be attributed to different regions of the brain (such as the cerebral cortex or the hypothalamus) or to different ganglia in the periphery. The problem with trying to fit functional differences into anatomical divisions is that sometimes the same structure can be part of several functions. For example, the optic nerve carries signals from the retina that are either used for the conscious perception of visual stimuli, which takes place in the cerebral cortex, or for the reflexive responses of smooth muscle tissue that are processed through the hypothalamus.

There are two ways to consider how the nervous system is divided functionally. First, the basic functions of the nervous system are sensation, integration, and response. Secondly, control of the body can be somatic or autonomic—divisions that are largely defined by the structures that are involved in the response. There is also a region of the peripheral nervous system that is called the enteric nervous system that is responsible for a specific set of the functions within the realm of autonomic control related to gastrointestinal functions.

Basic Functions

The nervous system is involved in receiving information about the environment around us (sensation) and generating responses to that information (motor responses). The nervous system can be divided into regions that are responsible for sensation (sensory functions) and for the response (motor functions). But there is a third function that needs to be included. Sensory input needs to be integrated with other sensations, as well as with memories, emotional state, or learning (cognition). Some regions of the nervous system are termed integration or association areas. The process of integration combines sensory perceptions and higher cognitive functions such as memories, learning, and emotion to produce a response.

Sensation. The first major function of the nervous system is sensation—receiving information about the environment to gain input about what is happening outside the body (or, sometimes, within the body). The sensory functions of the nervous system register the presence of a change from homeostasis or a particular event in the environment, known as a stimulus . The senses we think of most are the “big five”: taste, smell, touch, sight, and hearing. The stimuli for taste and smell are both chemical substances (molecules, compounds, ions, etc.), touch is physical or mechanical stimuli that interact with the skin, sight is light stimuli, and hearing is the perception of sound, which is a physical stimulus similar to some aspects of touch. There are actually more senses than just those, but that list represents the major senses. Those five are all senses that receive stimuli from the outside world, and of which there is conscious perception. Additional sensory stimuli might be from the internal environment (inside the body), such as the stretch of an organ wall or the concentration of certain ions in the blood.

Response. The nervous system produces a response on the basis of the stimuli perceived by sensory structures. An obvious response would be the movement of muscles, such as withdrawing a hand from a hot stove, but there are broader uses of the term. The nervous system can cause the contraction of all three types of muscle tissue. For example, skeletal muscle contracts to move the skeleton, cardiac muscle is influenced as heart rate increases during exercise, and smooth muscle contracts as the digestive system moves food along the digestive tract. Responses also include the neural control of glands in the body as well, such as the production and secretion of sweat by the eccrine and merocrine sweat glands found in the skin to lower body temperature.

Responses can be divided into those that are voluntary or conscious (contraction of skeletal muscle) and those that are involuntary (contraction of smooth muscles, regulation of cardiac muscle, activation of glands). Voluntary responses are governed by the somatic nervous system and involuntary responses are governed by the autonomic nervous system, which are discussed in the next section.

Integration. Stimuli that are received by sensory structures are communicated to the nervous system where that information is processed. This is called integration. Stimuli are compared with, or integrated with, other stimuli, memories of previous stimuli, or the state of a person at a particular time. This leads to the specific response that will be generated. Seeing a baseball pitched to a batter will not automatically cause the batter to swing. The trajectory of the ball and its speed will need to be considered. Maybe the count is three balls and one strike, and the batter wants to let this pitch go by in the hope of getting a walk to first base. Or maybe the batter’s team is so far ahead, it would be fun to just swing away.

Controlling the Body

The nervous system can be divided into two parts mostly on the basis of a functional difference in responses. The somatic nervous system (SNS) is responsible for conscious perception and voluntary motor responses. Voluntary motor response means the contraction of skeletal muscle, but those contractions are not always voluntary in the sense that you have to want to perform them. Some somatic motor responses are reflexes, and often happen without a conscious decision to perform them. If your friend jumps out from behind a corner and yells “Boo!” you will be startled and you might scream or leap back. You didn’t decide to do that, and you may not have wanted to give your friend a reason to laugh at your expense, but it is a reflex involving skeletal muscle contractions. Other motor responses become automatic (in other words, unconscious) as a person learns motor skills (referred to as “habit learning” or “procedural memory”).

The autonomic nervous system (ANS) is responsible for involuntary control of the body, usually for the sake of homeostasis (regulation of the internal environment). Sensory input for autonomic functions can be from sensory structures tuned to external or internal environmental stimuli. The motor output extends to smooth and cardiac muscle as well as glandular tissue. The role of the autonomic system is to regulate the organ systems of the body, which usually means to control homeostasis. Sweat glands, for example, are controlled by the autonomic system. When you are hot, sweating helps cool your body down. That is a homeostatic mechanism. But when you are nervous, you might start sweating also. That is not homeostatic, it is the physiological response to an emotional state.

There is another division of the nervous system that describes functional responses. The enteric nervous system (ENS) is responsible for controlling the smooth muscle and glandular tissue in your digestive system. It is a large part of the PNS, and is not dependent on the CNS. It is sometimes valid, however, to consider the enteric system to be a part of the autonomic system because the neural structures that make up the enteric system are a component of the autonomic output that regulates digestion. There are some differences between the two, but for our purposes here there will be a good bit of overlap. See Figure 12.6 for examples of where these divisions of the nervous system can be found.

Visit this site to read about a woman that notices that her daughter is having trouble walking up the stairs. This leads to the discovery of a hereditary condition that affects the brain and spinal cord. The electromyography and MRI tests indicated deficiencies in the spinal cord and cerebellum, both of which are responsible for controlling coordinated movements. To what functional division of the nervous system would these structures belong?

Everyday Connection

How much of your brain do you use.

Have you ever heard the claim that humans only use 10 percent of their brains? Maybe you have seen an advertisement on a website saying that there is a secret to unlocking the full potential of your mind—as if there were 90 percent of your brain sitting idle, just waiting for you to use it. If you see an ad like that, don’t click. It isn’t true.

An easy way to see how much of the brain a person uses is to take measurements of brain activity while performing a task. An example of this kind of measurement is functional magnetic resonance imaging (fMRI), which generates a map of the most active areas and can be generated and presented in three dimensions ( Figure 12.7 ). This procedure is different from the standard MRI technique because it is measuring changes in the tissue in time with an experimental condition or event.

The underlying assumption is that active nervous tissue will have greater blood flow. By having the subject perform a visual task, activity all over the brain can be measured. Consider this possible experiment: the subject is told to look at a screen with a black dot in the middle (a fixation point). A photograph of a face is projected on the screen away from the center. The subject has to look at the photograph and decipher what it is. The subject has been instructed to push a button if the photograph is of someone they recognize. The photograph might be of a celebrity, so the subject would press the button, or it might be of a random person unknown to the subject, so the subject would not press the button.

In this task, visual sensory areas would be active, integrating areas would be active, motor areas responsible for moving the eyes would be active, and motor areas for pressing the button with a finger would be active. Those areas are distributed all around the brain and the fMRI images would show activity in more than just 10 percent of the brain (some evidence suggests that about 80 percent of the brain is using energy—based on blood flow to the tissue—during well-defined tasks similar to the one suggested above). This task does not even include all of the functions the brain performs. There is no language response, the body is mostly lying still in the MRI machine, and it does not consider the autonomic functions that would be ongoing in the background.

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Nervous system

Author: Jana Vasković, MD • Reviewer: Nicola McLaren, MSc Last reviewed: November 03, 2023 Reading time: 20 minutes

The nervous system is a network of neurons whose main feature is to generate, modulate and transmit information between all the different parts of the human body . This property enables many important functions of the nervous system, such as regulation of vital body functions ( heartbeat , breathing , digestion), sensation and body movements . Ultimately, the nervous system structures preside over everything that makes us human; our consciousness, cognition, behaviour and memories.

The nervous system consists of two divisions; 

• Central nervous system (CNS) is the integration and command center of the body
• Peripheral nervous system (PNS) represents the conduit between the CNS and the body. It is further subdivided into the somatic nervous system (SNS) and the autonomic nervous system (ANS) . 

Understanding the nervous system requires knowledge of its various parts, so in this article you will learn about the nervous system breakdown and all its various divisions.

How do neurons function?

Glial cells, white and gray matter, nervous system divisions, central nervous system, cranial nerves, spinal nerves, somatic nervous system, sympathetic nervous system, parasympathetic nervous system, enteric nervous system, cranial nerve palsies, affected taste in the anterior 2/3 of the tongue, limb nerve lesions, hirschsprung’s disease, spina bifida, parkinson’s disease.

Cells of the nervous system 

Two basic types of cells are present in the nervous system; 

Neurons , or nerve cell, are the main structural and functional units of the nervous system. Every neuron consists of a body (soma) and a number of processes (neurites). The nerve cell body contains the cellular organelles and is where neural impulses ( action potentials ) are generated. The processes stem from the body, they connect neurons with each other and with other body cells , enabling the flow of neural impulses. There are two types of neural processes that differ in structure and function; 

• Axons are long and conduct impulses away from the neuronal body. 
• Dendrites are short and act to receive impulses from other neurons, conducting the electrical signal towards the nerve cell body.

Every neuron has a single axon, while the number of dendrites varies. Based on that number, there are four structural types of neurons ; multipolar, bipolar, pseudounipolar and unipolar. 

Learn more about the neurons in our study unit:

The morphology of neurons makes them highly specialized to work with neural impulses; they generate, receive and send these impulses onto other neurons and non-neural tissues. 

There are two types of neurons, named according to whether they send an electrical signal towards or away from the CNS;

• Efferent neurons (motor or descending) send neural impulses from the CNS to the peripheral tissues , instructing them how to function. 
• Afferent neurons (sensory or ascending) conduct impulses from the peripheral tissues to the CNS. These impulses contain sensory information, describing the tissue's environment.

The site where an axon connects to another cell to pass the neural impulse is called a synapse . The synapse doesn't connect to the next cell directly. Instead, the impulse triggers the release of chemicals called neurotransmitters from the very end of an axon. These neurotransmitters bind to the effector cell’s membrane, causing biochemical events to occur within that cell according to the orders sent by the CNS.

Ready to reinforce your knowledge about the neurons? Try out our quiz below:

Glial cells , also called neuroglia or simply glia, are smaller non-excitatory cells that act to support neurons. They do not propagate action potentials. Instead, they myelinate neurons, maintain homeostatic balance, provide structural support, protection and nutrition for neurons throughout the nervous system. 

This set of functions is provided for by four different types of glial cells;

• Myelinating glia produce the axon-insulating myelin sheath. These are called oligodendrocytes in the CNS and Schwann cells in the PNS. Remember these easily with the mnemonic "COPS" ( C entral - O ligodendrocytes; P eripheral - S chwann)
• Astrocytes (CNS) and satellite glial cells (PNS) both share the function of supporting and protecting neurons. 
• Other two glial cell types are found in CNS exclusively; microglia are the phagocytes of the CNS and ependymal cells which line the ventricular system of the CNS. The PNS doesn’t have a glial equivalent to microglia as the phagocytic role is performed by macrophages.

Most axons are wrapped by a white insulating substance known as a  myelin sheath , which is produced by oligodendrocytes and Schwann cells. Myelin encloses an axon segmentally, leaving interruptions between the segments known as myelin sheath gaps (a.ka.  nodes of Ranvier) . The neural impulses propagate through the myelin sheath gaps only, skipping the myelin sheath. This significantly increases the speed of neural impulse propagation. 

The white color of myelinated axons is distinguished from the gray colored neuronal bodies and dendrites. Based on this, nervous tissue is divided into white matter and gray matter, both of which has a specific distribution; 

• White matter comprises the outermost layer of the spinal cord and the inner part of the brain .
• Gray matter is located in the central part of the spinal cord, outermost layer of the brain ( cerebral cortex ), and in several subcortical nuclei of the brain deep to the cerebral cortex.

Master the histology of nervous tissue with our customizable quiz: We got you covered with neurons, nerves and ganglia!

So nervous tissue, comprised of neurons and neuroglia, forms our nervous organs (e.g. the brain, nerves). These organs unite according to their common function, forming the evolutionary perfection that is our nervous system. 

The nervous system (NS) is structurally broken down into two divisions; 

• Central nervous system (CNS) - consists of the brain and spinal cord
• Peripheral nervous system (PNS) - gathers all neural tissue outside the CNS

Functionally , the PNS is further subdivided into two functional divisions; 

• Somatic nervous system (SNS) -  informally described as the voluntary system
• Autonomic nervous system (ANS) - described as the involuntary system. 

They say that the nervous system is one of the hardest anatomy topic. But you're in luck, as we've got a learning strategy for you to master neuroanatomy in a lot shorter time than you though you'll need. Check out our quizzes and more for the nervous system anatomy practice !

Although divided structurally into central and peripheral parts, the nervous system divisions are actually interconnected with each other. Axon bundles pass impulses between the brain and spinal cord. These bundles within the CNS are called afferent and efferent neural pathways or tracts . Axons that extend from the CNS to connect with peripheral tissues belong to the PNS. Axons bundles within the PNS are called afferent and efferent peripheral nerves .

Learn more about the functional divisions of the nervous system in the video below:

The central nervous system (CNS) consists of the brain and spinal cord. These are found housed within the skull and vertebral column respectively.

The brain is made of four parts; cerebrum , diencephalon , cerebellum and brainstem . Together these parts process the incoming information from peripheral tissues and generate commands; telling the tissues how to respond and function. These commands tackle the most complex voluntary and involuntary human body functions, from breathing to thinking.

The spinal cord continues from the brainstem. It also has the ability to generate commands but for involuntary processes only, i.e. reflexes . However, its main function is to pass information between the CNS and periphery. 

Learn more about the CNS anatomy here:

Peripheral nervous system

The PNS consists of 12 pairs of cranial nerves, 31 pairs of spinal nerves and a number of small neuronal clusters throughout the body called ganglia. Peripheral nerves can be sensory (afferent), motor (efferent) or mixed (both). Depending on what structures they innervate, peripheral nerves can have the following modalities;

• Special - innervating special senses (e.g. eye ) and is found only in afferent fibers
• General - supplying everything except special senses
• Somatic - innervates the skin and skeletal muscles (e.g. biceps brachii )
• Visceral - supplies internal organs . 

Cranial nerves are peripheral nerves that emerge from the cranial nerve nuclei of the brainstem and spinal cord. They innervate the head and neck . Cranial nerves are numbered one to twelve according to their order of exit through the skull fissures . Namely, they are: olfactory nerve (CN I), optic nerve (CN II), oculomotor nerve (CN III), trochlear nerve (CN IV), trigeminal nerve (CN V), abducens nerve (VI), facial nerve (VII), vestibulocochlear nerve (VIII), glossopharyngeal nerve (IX), vagus nerve (X), accessory nerve (XI), and hypoglossal nerve (XII). These nerves are motor (III, IV, VI, XI, and XII), sensory (I, II and VIII) or mixed (V, VII, IX, and X).

Among many strategies for learning cranial nerves anatomy, our experts have determined that one of the most efficient is through interactive learning. Check out Kenhub’s interactive cranial nerves quizzes and labeling exercises to cut your studying time in half.

Jump right into our cranial nerves quiz in multiple difficulty levels:

Or learn more about the cranial nerves in this study unit.

Spinal nerves  emerge from the segments of the spinal cord . They are numbered according to their specific segment of origin. Hence, the 31 pairs of spinal nerves are divided into 8 cervical pairs, 12 thoracic pairs, 5 lumbar pairs, 5 sacral pairs, and 1 coccygeal spinal nerve. All spinal nerves are mixed, containing both sensory and motor fibers.

Spinal nerves innervate the entire body, with the exception of the head. They do so by either directly synapsing with their target organs or by interlacing with each other and forming plexuses. There are four major plexuses that supply the body regions ; 

• Cervical plexus (C1-C4) - innervates the neck 
• Brachial plexus (C5-T1) - innervates the upper limb  
• Lumbar plexus (L1-L4) - innervates the lower abdominal wall , anterior hip and thigh  
• Sacral plexus (L4-S4) - innervates the pelvis and the lower limb

Want to learn more about the spinal nerves and plexuses? Check out our resources.

Ganglia (sing. ganglion) are clusters of neuronal cell bodies outside of the CNS, meaning that they are the PNS equivalents to subcortical nuclei of the CNS. Ganglia can be sensory or visceral motor (autonomic) and their distribution in the body is clearly defined.

Dorsal root ganglia are clusters of sensory nerve cell bodies located adjacent to the spinal cord. They are a component of the posterior root of a spinal nerve.

Autonomic ganglia are either sympathetic or parasympathetic. Sympathetic ganglia are found in the thorax and abdomen , grouped into paravertebral and prevertebral ganglia. Paravertebral ganglia lie on either side of vertebral column ( para- means beside), comprising two ganglionic chains that extend from the base of the skull to the coccyx, called sympathetic trunks. Prevertebral ganglia (collateral ganglia, preaortic ganglia) are found anterior to the vertebral column ( pre- means in front of), closer to their target organ. They are further grouped according to which branch of abdominal aorta they surround; celiac, aorticorenal, superior and inferior mesenteric ganglia.

Parasympathetic ganglia are found in the head and pelvis. Ganglia in the head are associated with relevant cranial nerves and are the ciliary, pterygopalatine , otic and submandibular ganglia. Pelvic ganglia lie close to the reproductive organs comprising autonomic plexuses for innervation of pelvic viscera, such as prostatic and uterovaginal plexuses.

Find everything about ganglia needed for your neuroanatomy exam here.

The somatic nervous system is the voluntary component of the peripheral nervous system. It consists of all the fibers within cranial and spinal nerves that enable us to perform voluntary body movements (efferent nerves) and feel sensation from the skin, muscles and joints (afferent nerves). Somatic sensation relates to touch, pressure, vibration, pain, temperature, stretch and position sense from these three types of structures. 

Sensation from the glands, smooth and cardiac muscles is conveyed by the autonomic nerves.

Autonomic nervous system

The autonomic nervous system is the involuntary part of the peripheral nervous system. Further divided into the sympathetic (SANS), parasympathetic (PANS) systems, it is comprised exclusively of visceral motor fibers. Nerves from both these divisions innervate all involuntary structures of the body; 

• Cardiac muscle
• Glandular cells
• Smooth muscles present in the walls of the blood vessels and hollow organs. 

Balanced functioning of these two systems plays a crucial role in maintaining homeostasis, meaning that the SANS and PANS do not oppose each other but rather, they complement each other. They do so by potentiating the activity of different organs under various circumstances; for example, the PSNS will stimulate higher intestine activity after food intake, while SANS will stimulate the heart to increase the output during exercise.

Autonomic nerves synapse within autonomic ganglia before reaching their target organ, thus all of them have presynaptic and postsynaptic parts. Presynaptic fibers originate from CNS and end by synapsing with neurons of the peripheral autonomic ganglia. Postsynaptic fibers are the axons of ganglion neurons, extending from the ganglion to peripheral tissues. In sympathetic nerves, the presynaptic fiber is short as the ganglia are located very close to the spinal cord, while the postsynaptic fiber is much longer in order to reach the target organ. In parasympathetic nerves it’s the opposite; the presynaptic fiber is longer than the postsynaptic.

The autonomic nervous system seems to be the only thing that can act without your free will. Learn about how it does that here.

The sympathetic system (SANS) adjusts our bodies for situations of increased physical activity. Its actions are commonly described as the “fight-or-flight” response as it stimulates responses such as faster breathing, increased heart rate, elevated blood pressure, dilated pupils and redirection of blood flow from the skin, kidneys , stomach and intestines to the heart and muscles, where it’s needed. 

Sympathetic nerve fibers have a thoracolumbar origin, meaning that they stem from the T1-L2/L3 spinal cord segments. They synapse with prevertebral and paravertebral ganglia, from which the postsynaptic fibers travel to supply the target viscera.

The parasympathetic nervous system (PSNS) adjusts our bodies for energy conservation, activating “rest and digest” or “feed and breed” activities. The nerves of the PSNS slow down the actions of cardiovascular system , divert blood away from muscles and increase peristalsis and gland secretion. 

Parasympathetic fibers have craniosacral outflow, meaning that they originate from the brainstem (cranio-) and S2-S4 spinal cord segments (-sacral). These fibers travel to thoracic and abdominal organs, where they synapse in ganglia located close to or within the target organ.

Enteric nervous system comprises the SANS and PANS fibers that regulate the activity of the gastrointestinal tract . This system is made of parasympathetic fibers of the vagus nerve (CN X) and sympathetic fibers of the thoracic splanchnic nerves . These fibers form two plexuses within the wall of the intestinal tube which are responsible for modulating intestinal peristalsis, i.e. propagation of consumed food from esophagus to rectum ;

• Submucosal plexus (of Meissner) found in the submucosa of the intestines and contains only parasympathetic fibers
• Myenteric plexus (of Auerbach) located in the muscularis externa of intestines, containing both sympathetic and parasympathetic nerve fibers

You can easily remember these two plexuses using a simple mnemonic! ' SMP & MAPS ', which stands for:

• S ubmucosal
• M eissner's
• P arasympathetic
• A uerbach's
• S ympathetic

Clinical notes

Vagotomy for gastric ulcers is an old procedure which is used as surgical management in patients with recurrent gastric ulcers when there is no effect of diet alterations or antiulcer drugs. The vagus nerve stimulates the secretion of gastric acid. Three types of vagotomy can be performed which would greatly diminish this effect.

The 12 cranial nerves all leave/enter the skull through various foramina. Narrowing of these foramina or any constriction along the nerves course results in nerve palsy. For example, Bell’s palsy affects the facial nerve. On the affected side of the face, the patient has:

• dry eyesan absent corneal reflex, overloud hearing and affected taste in the anterior 2/3 of the tongue.
• an absent corneal reflex
• overloud hearing

Limb nerve palsies often result from fracture, constriction or overuse. For example, carpal tunnel syndrome affects the median nerve, and occurs when the nerve is compressed within the tunnel. This is due to enlargement of the flexor tendons within the tunnel or swelling due to oedema. It often occurs in pregnancy and acromegaly.

This is colonic atony secondary to a failure of the ganglion cells (described in the enteric nervous system section) to migrate into the enteric nervous system. This results in a severely constipated and malnourished child, which is in desperate need of corrective surgery.

Failure of normal development of the meninges and/or vertebral neural arch results in a defect usually in the lumbar spine, where part of the spinal cord is covered only by meninges and therefore sits outside the body. Both environmental and genetic factors contribute to its cause. Folate supplements are now given to all pregnant mothers in early pregnancy for its prevention.

Dopamine is essential for the correct functioning of the basal ganglia, structures in the brain that control our cognition and movement. Parkinson’s patients suffer degradation of these dopaminergic neurons in the substantia nigra, resulting in:

• difficulty initiating movement
• shuffling gait
• masked facies
• cog-wheel/lead-pipe rigidity in the limbs

References:

• Blumenfeld, H. (2018). Neuroanatomy through clinical cases. Sunderland, MA: Sinauer.
• Goodfellow, J., Collins, D., Silva, D., Dardis, R., & Nagaraya, S. (2016). Neurology & neurosurgery. New Delhi, India: Jp medical pub.
• Patestas, M. A., & Gartner, L. P. (2016). A textbook of neuroanatomy. Hoboken: Wiley Blackwell
• Waxman, S. G. (2010). Clinical neuroanatomy. New York: McGraw-Hill Medical.

Author, review and layout:

Illustrators:

• Nervous system (anterior view) - Begoña Rodriguez
• 12 cranial nerves (diagram) - Paul Kim

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Nervous System Anatomy and Physiology

Illuminate the complex pathways of the nervous system with our definitive guide. Nursing students, unlock the secrets of the intricate web that dictates our every thought, action, and feeling.

Table of Contents

Functions of the nervous system, structural classification, functional classification, supporting cells, central nervous system, cerebral hemispheres, diencephalon, cerebrospinal fluid, the blood-brain barrier, gray matter of the spinal cord and spinal roots, white matter of the spinal cord, peripheral nervous system, structure of a nerve, cranial nerves, spinal nerves and nerve plexuses, autonomic nervous system, anatomy of the parasympathetic division, anatomy of the sympathetic division, nerve impulse, the nerve impulse pathway, communication of neurons at synapses, autonomic functioning, sympathetic division, parasympathetic division.

To carry out its normal role, the nervous system has three overlapping functions.

• Monitoring changes. Much like a sentry, it uses its millions of sensory receptors to monitor changes occurring both inside and outside the body; these changes are called stimuli, and the gathered information is called sensory input.
• Interpretation of sensory input. It processes and interprets the sensory input and decides what should be done at each moment, a process called integration .
• Effects responses. It then effects a response by activating muscles or glands (effectors) via motor output.
• Mental activity. The brain is the center of mental activity, including consciousness, thinking, and memory .
• Homeostasis . This function depends on the ability of the nervous system to detect, interpret, and respond to changes in internal and external conditions. It can help stimulate or inhibit the activities of other systems to help maintain a constant internal environment.

Anatomy of the Nervous System

The nervous system does not work alone to regulate and maintain body homeostasis; the endocrine system is a second important regulating system.

Organization of the Nervous System

We only have one nervous system, but, because of its complexity, it is difficult to consider all of its parts at the same time; so, to simplify its study, we divide it in terms of its structures (structural classification) or in terms of its activities (functional classification).

The structural classification, which includes all of the nervous system organs, has two subdivisions- the central nervous system and the peripheral nervous system.

• Central nervous system (CNS). The CNS consists of the brain and spinal cord , which occupy the dorsal body cavity and act as the integrating and command centers of the nervous system
• Peripheral nervous system (PNS). The PNS, the part of the nervous system outside the CNS, consists mainly of the nerves that extend from the brain and spinal cord.

The functional classification scheme is concerned only with PNS structures.

• Sensory division . The sensory, or afferent division, consists of nerves (composed of nerve fibers) that convey impulses to the central nervous system from sensory receptors located in various parts of the body.
• Somatic sensory fibers. Sensory fibers delivering impulses from the skin, skeletal muscles, and joints are called somatic sensory fibers.
• Visceral sensory fibers. Those that transmit impulses from the visceral organs are called visceral sensory fibers.
• Motor division. The motor, or efferent division carries impulses from the CNS to effector organs, the muscles, and glands; the motor division has two subdivisions: the somatic nervous system and the autonomic nervous system .
• Somatic nervous system. The somatic nervous system allows us to consciously, or voluntarily , control our skeletal muscles.
• Autonomic nervous system. The autonomic nervous system regulates events that are automatic, or involuntary ; this subdivision, commonly called the involuntary nervous system, has two parts: the sympathetic and parasympathetic, which typically bring about opposite effects.

Nervous Tissue: Structure and Function

Even though it is complex, nervous tissue is made up of just two principal types of cells- supporting cells and neurons.

Supporting cells in the CNS are “lumped together” as neuroglia, which literally means “nerve glue”.

• Neuroglia. Neuroglia includes many types of cells that generally support, insulate, and protect the delicate neurons; in addition, each of the different types of neuroglia, also simply called either glia or glial cells, has special functions.
• Astrocytes. These are abundant, star-shaped cells that account for nearly half of the neural tissue; astrocytes form a living barrier between the capillaries and neurons and play a role in making exchanges between the two so they could help protect neurons from harmful substances that might be in the blood .
• Microglia. These are spiderlike phagocytes that dispose of debris, including dead brain cells and bacteria.
• Ependymal cells. Ependymal cells are glial cells that line the central cavities of the brain and the spinal cord; the beating of their cilia helps to circulate the cerebrospinal fluid that fills those cavities and forms a protective cushion around the CNS.
• Oligodendrocytes. These are glia that wraps their flat extensions tightly around the nerve fibers, producing fatty insulating coverings called myelin sheaths.
• Schwann cells. Schwann cells form the myelin sheaths around nerve fibers that are found in the PNS.
• Satellite cells. Satellite cells act as protective, cushioning cells.

Neurons, also called nerve cells, are highly specialized to transmit messages (nerve impulses) from one part of the body to another.

• Cell body. The cell body is the metabolic center of the neuron; it has a transparent nucleus with a conspicuous nucleolus; the rough ER, called Nissl substance , and neurofibrils are particularly abundant in the cell body.
• Processes. The armlike processes, or fibers, vary in length from microscopic to 3 to 4 feet; dendrons convey incoming messages toward the cell body, while axons generate nerve impulses and typically conduct them away from the cell body.
• Axon hillock. Neurons may have hundreds of branching dendrites, depending on the neuron type, but each neuron has only one axon, which arises from a conelike region of the cell body called the axon hillock.
• Axon terminals. These terminals contain hundreds of tiny vesicles, or membranous sacs that contain neurotransmitters.
• Synaptic cleft. Each axon terminal is separated from the next neuron by a tiny gap called the synaptic cleft.
• Myelin sheaths. Most long nerve fibers are covered with a whitish, fatty material called myelin , which has a waxy appearance; myelin protects and insulates the fibers and increases the transmission rate of nerve impulses.
• Nodes of Ranvier. Because the myelin sheath is formed by many individual Schwann cells, it has gaps, or indentations, called nodes of Ranvier.

Classification

Neurons may be classified either according to how they function or according to their structure.

• Functional classification. Functional classification groups neurons according to the direction the nerve impulse is traveling relative to the CNS; on this basis, there are sensory , motor , and association neurons.
• Sensory neurons. Neurons carrying impulses from sensory receptors to the CNS are sensory, or afferent , neurons; sensory neurons keep us informed about what is happening both inside and outside the body.
• Motor neurons. Neurons carrying impulses from the CNS to the viscera and/or muscles and glands are motor, or efferent , neurons.
• Interneurons. The third category of neurons is known as the interneurons or association neurons; they connect the motor and sensory neurons in neural pathways.
• Structural classification. Structural classification is based on the number of processes extending from the cell body.
• Multipolar neuron. If there are several processes, the neuron is a multipolar neuron; because all motor and association neurons are multipolar, this is the most common structural type.
• Bipolar neurons. Neurons with two processes- an axon and a dendrite- are called bipolar neurons; these are rare in adults, found only in some special sense organs, where they act in sensory processing as receptor cells.
• Unipolar neurons. Unipolar neurons have a single process emerging from the cell’s body, however, it is very short and divides almost immediately into proximal (central) and distal (peripheral) processes.

During embryonic development, the CNS first appears as a simple tube, the neural tube, which extends down the dorsal median plan of the developing embryo’s body.

Because the brain is the largest and most complex mass of nervous tissue in the body, it is commonly discussed in terms of its four major regions – cerebral hemispheres, diencephalon, brain stem, and cerebellum.

The paired cerebral hemispheres, collectively called the cerebrum, are the most superior part of the brain, and together are a good deal larger than the other three brain regions combined.

• Gyri. The entire surface of the cerebral hemispheres exhibits elevated ridges of tissue called gyri, separated by shallow grooves called sulci .
• Fissures. Less numerous are the deeper grooves of tissue called fissures, which separate large regions of the brain; the cerebral hemispheres are separated by a single deep fissure, the longitudinal fissure .
• Lobes. Other fissures or sulci divide each hemisphere into a number of lobes, named for the cranial bones that lie over them.
• Regions of the cerebral hemisphere. Each cerebral hemisphere has three basic regions: a superficial cortex of gray matter, an internal white matter , and the basal nuclei .
• Cerebral cortex. Speech, memory, logical and emotional response, as well as consciousness, interpretation of sensation, and voluntary movement , are all functions of neurons of the cerebral cortex.
• Parietal lobe. The primary somatic sensory area is located in the parietal lobe posterior to the central sulcus; impulses traveling from the body’s sensory receptors are localized and interpreted in this area.
• Occipital lobe. The visual area is located in the posterior part of the occipital lobe.
• Temporal lobe. The auditory area is in the temporal lobe bordering the lateral sulcus, and the olfactory area is found deep inside the temporal lobe.
• Frontal lobe. The primary motor area , which allows us to consciously move our skeletal muscles, is anterior to the central sulcus in the front lobe.
• Pyramidal tract. The axons of these motor neurons form the major voluntary motor tract- the corticospinal or pyramidal tract, which descends to the cord.
• Broca’s area. A specialized cortical area that is very involved in our ability to speak, Broca’s area, is found at the base of the precentral gyrus (the gyrus anterior to the central sulcus).
• Speech area. The speech area is located at the junction of the temporal, parietal, and occipital lobes; the speech area allows one to sound out words.
• Cerebral white matter. The deeper cerebral white matter is composed of fiber tracts carrying impulses to, from, and within the cortex.
• Corpus callosum. One very large fiber tract, the corpus callosum, connects the cerebral hemispheres; such fiber tracts are called commissures .
• Fiber tracts. Association fiber tracts connect areas within a hemisphere, and projection fiber tracts connect the cerebrum with lower CNS centers.
• Basal nuclei. There are several islands of gray matter, called the basal nuclei, or basal ganglia , buried deep within the white matter of the cerebral hemispheres; it helps regulate voluntary motor activities by modifying instructions sent to the skeletal muscles by the primary motor cortex.

The diencephalon, or interbrain, sits atop the brain stem and is enclosed by the cerebral hemispheres.

• Thalamus. The thalamus, which encloses the shallow third ventricle of the brain, is a relay station for sensory impulses passing upward to the sensory cortex.
• Hypothalamus. The hypothalamus makes up the floor of the diencephalon; it is an important autonomic nervous system center because it plays a role in the regulation of body temperature, water balance, and metabolism; it is also the center for many drives and emotions, and as such, it is an important part of the so-called limbic system or “emotional-visceral brain”; the hypothalamus also regulates the pituitary gland and produces two hormones of its own.
• Mammillary bodies. The mammillary bodies, reflex centers involved in olfaction (the sense of smell ), bulge from the floor of the hypothalamus posterior to the pituitary gland.
• Epithalamus. The epithalamus forms the roof of the third ventricle; important parts of the epithalamus are the pineal body (part of the endocrine system) and the choroid plexus of the third ventricle, which forms the cerebrospinal fluid .

The brain stem is about the size of a thumb in diameter and approximately 3 inches long.

• Structures. Its structures are the midbrain , pons , and medulla oblongata .
• Midbrain. The midbrain extends from the mammillary bodies to the pons inferiorly; it is composed of two bulging fiber tracts, the cerebral peduncles , which convey descending and ascending impulses.
• Corpora quadrigemina. Dorsally located are four rounded protrusions called the corpora quadrigemina because they remind some anatomists of two pairs of twins; these bulging nuclei are reflex centers involved in vision and hearing.
• Pons. The pons is a rounded structure that protrudes just below the midbrain, and this area of the brain stem is mostly fiber tracts; however, it does have important nuclei involved in the control of breathing.
• Medulla oblongata. The medulla oblongata is the most inferior part of the brain stem; it contains nuclei that regulate vital visceral activities; it contains centers that control heart rate , blood pressure , breathing, swallowing, and vomiting among others.
• Reticular formation. Extending the entire length of the brain stem is a diffuse mass of gray matter, the reticular formation; the neurons of the reticular formation are involved in motor control of the visceral organs; a special group of reticular formation neurons, the reticular activating system (RAS) , plays a role in consciousness and the awake/ sleep cycles.

The large, cauliflower-like cerebellum projects dorsally from under the occipital lobe of the cerebrum.

• Structure. Like the cerebrum. the cerebellum has two hemispheres and a convoluted surface; it also has an outer cortex made up of gray matter and an inner region of white matter.
• Function. The cerebellum provides precise timing for skeletal muscle activity and controls our balance and equilibrium.
• Coverage. Fibers reach the cerebellum from the equilibrium apparatus of the inner ear, the eye, the proprioceptors of the skeletal muscles and tendons, and many other areas.

Protection of the Central Nervous System

Nervous tissue is very soft and delicate, and the irreplaceable neurons are injured by even the slightest pressure, so nature has tried to protect the brain and the spinal cord by enclosing them within the bone (the skull and vertebral column ), membranes (the meninges), and a watery cushion (cerebrospinal fluid).

The three connective tissue membranes covering and protecting the CNS structures are the meninges.

• Dura mater. The outermost layer, the leathery dura mater, is a double-layered membrane where it surrounds the brain; one of its layers is attached to the inner surface of the skull, forming the periosteum (periosteal layer) ; the other, called the meningeal layer , forms the outermost covering of the brain and continues as the dura mater of the spinal cord.
• Falx cerebri.  In several places, the inner dural membrane extends inward to form a fold that attaches the brain to the cranial cavity, and one of these folds is the falx cerebri.
• Tentorium cerebelli. The tentorium cereberi separates the cerebellum from the cerebrum.
• Arachnoid mater. The middle layer is the weblike arachnoid mater; its threadlike extensions span the subarachnoid space to attach it to the innermost membrane.
• Pia mater. The delicate pia mater, the innermost meningeal layer, clings tightly to the surface of the brain and spinal cord, following every fold.

Cerebrospinal fluid (CSF) is a watery “broth” similar in its makeup to blood plasma , from which it forms.

• Contents. The CSF contains less protein and more vitamin C, and glucose .
• Choroid plexus. CSF is continually formed from the blood by the choroid plexuses; choroid plexuses are clusters of capillaries hanging from the “roof” in each of the brain’s ventricles.
• Function. The CSF in and around the brain and cord forms a watery cushion that protects the fragile nervous tissue from blows and other trauma .
• Normal volume. CSF forms and drains at a constant rate so that its normal pressure and volume (150 ml-about half a cup) are maintained.
• Lumbar tap. The CSF sample for testing is obtained by a procedure called lumbar or spinal tap ; because the withdrawal of fluid for testing decreases CSF fluid pressure, the patient must remain in a horizontal position (lying down) for 6 to 12 hours after the procedure to prevent an agonizingly painful “spinal headache”.

No other body organ is so absolutely dependent on a constant internal environment as is the brain, and so the blood-brain barrier is there to protect it.

• Function. The neurons are kept separated from bloodborne substances by the so-called blood-brain barrier, composed of the least permeable capillaries in the whole body.
• Substances allowed. Of water-soluble substances, only water, glucose , and essential amino acids pass easily through the walls of these capillaries.
• Prohibited substances. Metabolic wastes, such as toxins, urea, proteins, and most drugs are prevented from entering the brain tissue.
• Fat-soluble substances. The blood-brain barrier is virtually useless against fats, respiratory gases, and other fat-soluble molecules that diffuse easily through all plasma membranes.

Spinal Cord

The cylindrical spinal cord is a glistening white continuation of the brain stem.

• Length. The spinal cord is approximately 17 inches (42 cm) long.
• Major function. The spinal cord provides a two-way conduction pathway to and from the brain, and it is a major reflex center (spinal reflexes are completed at this level).
• Location. Enclosed within the vertebral column, the spinal cord extends from the foramen magnum of the skull to the first or second lumbar vertebra, where it ends just below the ribs.
• Meninges. Like the brain, the spinal cord is cushioned and protected by the meninges; meningeal coverings do not end at the second lumbar vertebra but instead, extend well beyond the end of the spinal cord in the vertebral canal.
• Spinal nerves. In humans, 31 pairs of spinal nerves arise from the cord and exit from the vertebral column to serve the body area close by.
• Cauda equina. The collection of spinal nerves at the inferior end of the vertebral canal is called cauda equina because it looks so much like a horse’s tail.

The gray matter of the spinal cord looks like a butterfly or a letter H in cross-section.

• Projections. The two posterior projections are the dorsal , or posterior , horns ; the two anterior projections are the ventral , or anterior , horns .
• Central canal. The gray matter surrounds the central canal of the cord, which contains CSF.
• Dorsal root ganglion. The cell bodies of sensory neurons, whose fibers enter the cord by the dorsal root , are found in an enlarged area called dorsal root ganglion; if the dorsal root or its ganglion is damaged, the sensation from the body area served will be lost.
• Dorsal horns. The dorsal horns contain interneurons.
• Ventral horns. The ventral horns of gray matter contain cell bodies of motor neurons of the somatic nervous system, which send their axons out the ventral root of the cord.
• Spinal nerves. The dorsal and ventral roots fuse to form the spinal nerves.

The white matter of the spinal cord is composed of myelinated fiber tracts- some running to higher centers, some traveling from the brain to the cord, and some conducting impulses from one side of the spinal cord to the other.

• Regions. Because of the irregular shape of the gray matter, the white matter on each side of the cord is divided into three regions- the dorsal, lateral , and ventra l columns; each of the columns contains a number of fiber tracts made up of axon with the same destination and function.
• Sensory tracts. Tracts conducting sensory impulses to the brain are sensory, or afferent , tracts.
• Motor tracts. Those carrying impulses from the brain to skeletal muscles are motor, or efferent , tracts.

The peripheral nervous system consists of nerves and scattered groups of neuronal cell bodies (ganglia) found outside the CNS.

A nerve is a bundle of neuron fibers found outside the CNS.

• Endoneurium. Each fiber is surrounded by a delicate connective tissue sheath, an endoneurium.
• Perimeurium. Groups of fibers are bound by a coarser connective tissue wrapping, the perineurium, to form fiber bundles, or fascicles .
• Epineurium. Finally, all the fascicles are bound together by a tough fibrous sheath, the epineurium, to form the cordlike nerve.
• Mixed nerves. Nerves carrying both sensory and motor fibers are called mixed nerves.
• Sensory nerves. Nerves that carry impulses toward the CNS only are called sensory, or afferent, nerves.
• Motor nerves. Those that carry only motor fibers are motor, or efferent, nerves.

The 12 pairs of cranial nerves primarily serve the head and the neck.

• Olfactory. Fibers arise from the olfactory receptors in the nasal mucosa and synapse with the olfactory bulbs; its function is purely sensory, and it carries impulses for the sense of smell.
• Optic. Fibers arise from the retina of the eye and form the optic nerve; its function is purely sensory and carries impulses for vision.
• Oculomotor. Fibers run from the midbrain to the eye; it supplies motor fibers to four of the six muscles (superior, inferior, medial rectus, and inferior oblique) that direct the eyeball; to the eyelid; and to the internal eye muscles controlling lens shape and pupil size.
• Trochlear. Fibers run from the midbrain to the eye; it supplies motor fibers for one external eye muscle ( superior oblique).
• Trigeminal. Fibers emerge from the pons and form three divisions that run to the face; it conducts sensory impulses from the skin of the face and mucosa of the nose and mouth ; also contains motor fibers that activate the chewing muscles.
• Abducens. Fibers leave the pons and run to the eye; it supplies motor fibers to the lateral rectus muscle, which rolls the eye laterally.
• Facial. Fibers leave the pons and run to the face; it activates the muscles of facial expression and the lacrimal and salivary glands ; which carry sensory impulses from the taste buds of the anterior tongue.
• Vestibulocochlear. fibers run from the equilibrium and hearing receptors of the inner ear to the brain stem; its function is purely sensory; vestibular branch transmits impulses for the sense of balance, and cochlear branch transmits impulses for the sense of hearing.
• Glossopharyngeal. Fibers emerge from the medulla and run to the throat; it supplies motor fibers to the pharynx (throat) that promote swallowing and saliva production; it carries sensory impulses from the taste buds of the posterior tongue and from pressure receptors of the carotid artery.
• Vagus. Fibers emerge from the medulla and descend into the thorax and abdominal cavity; the fibers carry sensory impulses from and motor impulses to the pharynx, larynx , and the abdominal and thoracic viscera; most motor fibers are parasympathetic fibers that promote digestive activity and help regulate heart activity.
• Accessory. Fiber arise from the medulla and superior spinal cord and travel to muscles of the neck and back; mostly motor fiber that activate the sternocleidomastoid and trapezius muscles.
• Hypoglossal. Fibers run from the medulla to the tongue; motor fibers control tongue movements; sensory fibers carry impulses from the tongue.

The 31 pairs of human spinal nerves are formed by the combination of the ventral and dorsal roots of the spinal cord.

• Rami. Almost immediately after being formed, each spinal nerve divides into dorsal and ventral rami, making each spinal nerve only about 1/2 inch long; the rami contains both sensory and motor fibers.
• Dorsal rami. The smaller dorsal rami serve the skin and muscles of the posterior body trunk.
• Ventral rami. The ventral rami of spinal nerves T1 through T12 form the intercostal nerves, which supply the muscles between the ribs and the skin and muscles of the anterior and lateral trunk.
• Cervical plexus. The cervical plexus originates from the C1-C5, and the phrenic nerve is an important nerve; it serves the diaphragm , skin, and muscles of the shoulder and neck.
• Brachial plexus. The axillary nerve serves the deltoid muscles and skin of the shoulder, muscles, and skin of the superior thorax; the radial nerve serves the triceps and extensor muscles of the forearm , and the skin of the posterior upper limb; the median nerve serves the flexor muscles and skin of the forearm and some muscles of the hand; the musculocutaneous nerve serves the flexor muscles of the arm and the skin of the lateral forearm; and the ulnar nerve serves some flexor muscles of forearm; wrist and many hand muscles, and the skin of the hand.
• Lumbar plexus. The femoral nerve serves the lower abdomen, anterior and medial thigh muscles, and the skin of the anteromedial leg and thigh; the obturator nerve serves the adductor muscles of the medial thigh and small hip muscles, and the skin of the medial thigh and hip joint.
• Sacral plexus. The sciatic nerve (the largest nerve in the body) serves the lower trunk and posterior surface of the thigh, and it splits into the common fibular and tibial nerves; the common fibular nerve serves the lateral aspect of the leg and foot, while the tibial nerve serves the posterior aspect of leg and foot; the superior and inferior gluteal nerves serve the gluteal muscles of the hip.

The autonomic nervous system (ANS) is the motor subdivision of the PNS that controls body activities automatically.

• Composition. It is composed of a specialized group of neurons that regulate cardiac muscle, smooth muscles, and glands.
• Function. At every moment, signals flood from the visceral organs into the CNS, and the automatic nerves make adjustments as necessary to best support body activities.
• Divisions. The ANS has two arms: the sympathetic division and the parasympathetic division.

The parasympathetic division allows us to “unwind” and conserve energy.

• Preganglionic neurons. The preganglionic neurons of the parasympathetic division are located in brain nuclei of several cranial nerves- III, VII, IX, and X (the vagus being the most important of these) and in the S2 through S4 levels of the spinal cord.
• Craniosacral division. The parasympathetic division is also called the craniosacral division; the neurons of the cranial region send their axons out in cranial nerves to serve the head and neck organs.
• Pelvic splanchnic nerves. In the sacral region, the preganglionic axons leave the spinal cord and form the pelvic splanchnic nerves, also called the pelvic nerves, which travel to the pelvic cavity.

The sympathetic division mobilizes the body during extreme situations and is also called the thoracolumbar division because its preganglionic neurons are in the gray matter of the spinal cord from T1 through L2.

• Ramus communicans. The preganglionic axons leave the cord in the ventral root, enter the spinal nerve, and then pass through a ramus communicans, or small communicating branch, to enter a sympathetic chain ganglion.
• Sympathetic chain. The sympathetic trunk, or chain, lies along the vertebral column on each side.
• Splanchnic nerves. After it reaches the ganglion, the axon may synapse with the second neuron in the sympathetic chain at the same or a different level, or the axon may through the ganglion without synapsing and form part of the splanchnic nerves.
• Collateral ganglion. The splanchnic nerves travel to the viscera to synapse with the ganglionic neuron, found in a collateral ganglion anterior to the vertebral column.

Physiology of the Nervous System

The physiology of the nervous system involves a complex journey of impulses.

Neurons have two major functional properties: irritability, the ability to respond to a stimulus and convert it into a nerve impulse, and conductivity, the ability to transmit the impulse to other neurons, muscles, or glands.

• Electrical conditions of a resting neuron’s membrane. The plasma membrane of a resting, or inactive, neuron is polarized, which means that there are fewer positive ions sitting on the inner face of the neuron’s plasma membrane than there are on its outer surface; as long as the inside remains more negative than the outside, the neuron will stay inactive.
• Action potential initiation and generation. Most neurons in the body are excited by neurotransmitters released by other neurons; regardless of what the stimulus is, the result is always the same- the permeability properties of the cell’s plasma membrane change for a very brief period.
• Depolarization. The inward rush of sodium ions changes the polarity of the neuron’s membrane at that site, an event called depolarization.
• Graded potential. Locally, the inside is now more positive, and the outside is less positive, a situation called graded potential.
• Nerve impulse. If the stimulus is strong enough, the local depolarization activates the neuron to initiate and transmit a long-distance signal called an action potential, also called a nerve impulse; the nerve impulse is an all-or-none response; it is either propagated over the entire axon, or it doesn’t happen at all; it never goes partway along an axon’s length, nor does it die out with distance as do graded potential.
• Repolarization. The outflow of positive ions from the cell restores the electrical conditions at the membrane to the polarized or resting, state, an event called repolarization; until a repolarization occurs, a neuron cannot conduct another impulse.
• Saltatory conduction. Fibers that have myelin sheaths conduct impulses much faster because the nerve impulse literally jumps, or leaps, from node to node along the length of the fiber; this occurs because no electrical current can flow across the axon membrane where there is fatty myelin insulation.

How the nerve impulse actually works is detailed below.

• Resting membrane electrical conditions. The external face of the membrane is slightly positive; its internal face is slightly negative; the chief extracellular ion is sodium , whereas the chief intracellular ion is potassium ; the membrane is relatively permeable to both ions.
• Stimulus initiates local depolarization. A stimulus changes the permeability of a “ patch ” of the membrane, and sodium ions diffuse rapidly into the cell; this changes the polarity of the membrane (the inside becomes more positive; the outside becomes more negative) at that site.
• Depolarization and generation of an action potential. If the stimulus is strong enough, depolarization causes membrane polarity to be completely reversed and an action potential is initiated.
• Propagation of the action potential. Depolarization of the first membrane patch causes permeability changes in the adjacent membrane, and the events described in (b) are repeated; thus, the action potential propagates rapidly along the entire length of the membrane.
• Repolarization. Potassium ions diffuse out of the cell as the membrane permeability changes again, restoring the negative charge on the inside of the membrane and the positive charge on the outside surface; repolarization occurs in the same direction as depolarization.

The events occurring at the synapse are arranged below.

• Arrival. The action potential arrives at the axon terminal.
• Fusion. The vesicle fuses with the plasma membrane.
• Release. Neurotransmitter is released into the synaptic cleft.
• Binding. The neurotransmitter binds to a receptor on receiving neuron’s end.
• Opening. The ion channel opens.
• Closing. Once the neurotransmitter is broken down and released, the ion channel close.

Body organs served by the autonomic nervous system receive fibers from both divisions.

• Antagonistic effect. When both divisions serve the same organ, they cause antagonistic effects, mainly because their post ganglionic axons release different transmitters.
• Cholinergic fibers. The parasympathetic fibers called cholinergic fibers, release acetylcholine.
• Adrenergic fibers. The sympathetic postganglionic fibers, called adrenergic fibers, release norepinephrine .
• Preganglionic axons. The preganglionic axons of both divisions release acetylcholine.

The sympathetic division is often referred to as the “fight-or-flight” system.

• Signs of sympathetic nervous system activities. A pounding heart; rapid, deep breathing ; cold, sweaty skin; a prickly scalp, and dilated pupils are sure signs sympathetic nervous system activities.
• Effects. Under such conditions, the sympathetic nervous system increases heart rate , blood pressure , and blood glucose levels; dilates the bronchioles of the lungs ; and brings about many other effects that help the individual cope with the stressor.
• Duration of the effect. The effects of sympathetic nervous system activation continue for several minutes until its hormones are destroyed by the liver .
• Function. Its function is to provide the best conditions for responding to some threat, whether the best response is to run, to see better, or to think more clearly.

The parasympathetic division is most active when the body is at rest and not threatened in any way.

• Function. This division, sometimes called the “resting-and-digesting” system, is chiefly concerned with promoting normal digestion, with elimination of feces and urine , and with conserving body energy, particularly by decreasing demands on the cardiovascular system .
• Relaxed state. Blood pressure and heart and respiratory rates rate being regulated at normal levels, the digestive tract is actively digesting food, and the skin is warm (indicating that there is no need to divert blood to skeletal muscles or vital organs.
• Optical state. The eye pupils are constricted to protect the retinas from excessive damaging light, and the lenses of the eye are “set” for close vision.

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Human Nervous System

Living organisms adapt to their moves and positions in response to the environmental changes for their protection or to their advantage. When an entity reacts to the changes in its surroundings, it is referred to as stimulus while the reaction to the stimulus is referred to as a response. Common stimuli are sound, light, air, heat, smell, taste, water and gravity.

Think of burning your finger of fracturing your bone without any pain sensation. It may certainly sound like a superpower or an ideal situation, however, when it comes to the standpoint of survival, it can be disastrous.

The characteristic behaviour of living entities is to respond to stimuli with the intervention of the nervous system. It is an organ system ascribed to send signals from the spinal cord and the brain throughout the body and then back from all the body parts to the brain. The neuron acts as the mediator and is the basic signalling unit of the nervous system.

Pain is the body’s way of letting us know that something is not right. It can prevent further injuries or push us to seek medical attention. Moreover, all of this is possible because humans can respond and react to stimuli due to control and coordination among the various organs and organ systems.

Control and Coordination in simple multicellular organisms take place through only the Nervous system which coordinates activities of our body. It is the control system for all our actions, thinking, and behaviour.

Refer more:  Control and Coordination

Let us have a detailed look at the nervous system notes to explore what is the nervous system, and the different functions of the nervous system with the help of diagrams. Table of Contents

What is the Nervous System?

Human nervous system diagram, central nervous system, peripheral nervous system, recommended video:.

The nervous system or the neural system is a complex network of neurons specialized to carry messages .  The complexity of the nervous system increases as we move towards higher animals.

For instance, cnidarians such as jellyfish have relatively simple nerve nets spread throughout their body. Crabs have a more complicated nervous system in the form of 2 nerve centers called dorsal ganglion and ventral ganglion.

As we move further up the ladder, higher organisms such as vertebrates have a developed brain. Moreover, it is one of the most complicated structures in the animal kingdom, containing billions of neurons, all intricately connected.

In the human body, the neural system integrates the activities of organs based on the stimuli, which the neurons detect and transmit. They transmit messages in the form of electrical impulses and convey messages to and from the sense organs. Thus, the nervous coordination involves the participation of the sense organs, nerves, spinal cord, and brain.

Also Read:  Creutzfeldt-Jakob Disease

Diagram of the Human Nervous System

One of the most complex organ system to ever evolve, the human nervous system consists of two parts, namely:

• Central Nervous System (consists of the brain and spinal cord)
• Peripheral Nervous System (includes all the nerves of the body)

Central Nervous System (CNS) is often called the central processing unit of the body. It consists of the brain and the spinal cord.

The brain is one of the important, largest and central organ of the human nervous system. It is the control unit of the nervous system, which helps us in discovering new things, remembering and understanding, making decisions, and a lot more. It is enclosed within the skull, which provides frontal, lateral and dorsal protection. The human brain is composed of three major parts:

Forebrain : The anterior part of the brain, consists of Cerebrum, Hypothalamus and Thalamus.

Midbrain : The smaller and central part of the brainstem, consists of Tectum and Tegmentum.

Hindbrain : The central region of the brain, composed of Cerebellum, Medulla and Pons.

Also read: Human Brain

Spinal Cord

The spinal cord is a cylindrical bundle of nerve fibers and associated tissues enclosed within the spine and connect all parts of the body to the brain. It begins in continuation with the medulla and extends downwards. It is enclosed in a bony cage called vertebral column and surrounded by membranes called meninges. The spinal cord is concerned with spinal reflex actions and the conduction of nerve impulses to and from the brain.

Peripheral Nervous System (PNS) is the lateral part of the nervous system that develops from the central nervous system which connects different parts of the body with the CNS. We carry out both voluntary and involuntary actions with the help of peripheral nerves.

Also refer:  Peripheral Nervous System

PNS includes two types of nerve fibers:

• Afferent nerve fibers – These are responsible for transmitting messages from tissues and organs to the CNS.
• Efferent nerve-fibers – These are responsible for conveying messages from CNS to the corresponding peripheral organ.

Classification of the peripheral nervous system:

Somatic neural system (SNS): It is the neural system that controls the voluntary actions in the body by transmitting impulses from CNS to skeletal muscle cells. It consists of the somatic nerves.

Autonomic neural system (ANS): The autonomic neural system is involved in involuntary actions like regulation of physiological functions (digestion, respiration, salivation, etc.). It is a self-regulating system which conveys the impulses from the CNS to the smooth muscles and involuntary organs (heart, bladder and pupil). The autonomic neural system can be further divided into:

• Sympathetic nervous system
• Parasympathetic nervous system

A Neuron is a structured and functional unit of the nervous system and unlike other cells, neurons are irregular in shape and able to conduct electrochemical signals. The different parts of a neuron are discussed below.

• Dendrite stretches out from the cell body of a neuron, and it is the shortest fibre in the cell body.
• Axon is the longest thread on the cell body of a neuron and has an insulating and protective sheath of myelin around it.
• Cell body consists of cytoplasm and nucleus.
• Synapse is the microscopic gap between a pair of adjacent neurons over which nerve impulses pass, when moving from one neuron to the other.

Explore more:  Placebo Effect

Nerves are thread-like structures that emerge from the brain and spinal cord. It is responsible for carrying messages to all the parts of the body. There are three types of nerves. Some of these neurons can fire signals at speeds of over 119 m/s or above 428 km/h.

• Sensory nerves send messages from all the senses to the brain.
• Motor nerves carry messages from the brain to all the muscles.
• Mixed nerves carry both sensory and motor nerves.

Also read: Nerves

Cranial nerves begin from the brain as these nerves carry impulses to start from the central nervous system. Certain cranial nerves belong to the group of mixed nerves while certain ones fall under sensory nerves. Spinal nerves originate from the spinal cord. All the spinal nerves carry impulses to and from the central nervous system and these are part of mixed nerves. The above nervous system diagram depicts the various nerves arising from various parts of the body.

Learn more in detail about the  Human Nervous System with diagrams or any  other related topics by referring to the nervous system notes provided at BYJU’S website. Download BYJU’S app for further reference.

Frequently Asked Questions

What are the two divisions of the nervous system.

The human nervous system controls all activities of the body in a quicker fashion. It can be divided into the central nervous system and peripheral nervous system. The central nervous system includes spinal cord and brain and the peripheral covers the nerves branching from spinal cord and brain.

What are nerves and neurons?

Nerves are thread-like structures that emerge from the spinal cord and brain. These nerves are actual projections of neurons. A neuron is a basic structural and functional unit of a nervous system that conducts electrochemical signals.

What are cranial nerves?

The nerves that extend throughout the body on both sides and emerges directly from the brain stem and brain are called cranial nerves. They carry information from the brain to other parts, primarily to the neck and head.

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• Published: 16 August 2024

Motor innervation directs the correct development of the mouse sympathetic nervous system

• Alek G. Erickson   ORCID: orcid.org/0000-0001-7110-9386 1   na1 ,
• Alessia Motta   ORCID: orcid.org/0000-0002-1008-8347 2   na1 ,
• Maria Eleni Kastriti   ORCID: orcid.org/0000-0002-0563-7399 1 , 3 ,
• Steven Edwards 4 ,
• Fanny Coulpier 5 ,
• Emy Théoulle 6 ,
• Aliia Murtazina   ORCID: orcid.org/0000-0003-1630-1855 7 ,
• Irina Poverennaya   ORCID: orcid.org/0000-0003-2562-5632 3 ,
• Daniel Wies 1 ,
• Jeremy Ganofsky   ORCID: orcid.org/0000-0002-2361-7869 6 ,
• Giovanni Canu   ORCID: orcid.org/0000-0002-3349-4479 8 ,
• Francois Lallemend   ORCID: orcid.org/0000-0001-5484-0011 7 ,
• Piotr Topilko 5 ,
• Saida Hadjab   ORCID: orcid.org/0000-0001-7953-8396 7 ,
• Kaj Fried   ORCID: orcid.org/0000-0002-9997-7078 7 ,
• Christiana Ruhrberg   ORCID: orcid.org/0000-0002-3212-9381 8 ,
• Quenten Schwarz   ORCID: orcid.org/0000-0002-5958-4181 9 ,
• Valerie Castellani   ORCID: orcid.org/0000-0001-9623-9312 6 ,
• Dario Bonanomi   ORCID: orcid.org/0000-0003-4517-1244 2 &
• Igor Adameyko   ORCID: orcid.org/0000-0001-5471-0356 1 , 3  

Nature Communications volume  15 , Article number:  7065 ( 2024 ) Cite this article

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• Developmental neurogenesis
• Neuronal development

The sympathetic nervous system controls bodily functions including vascular tone, cardiac rhythm, and the “fight-or-flight response”. Sympathetic chain ganglia develop in parallel with preganglionic motor nerves extending from the neural tube, raising the question of whether axon targeting contributes to sympathetic chain formation. Using nerve-selective genetic ablations and lineage tracing in mouse, we reveal that motor nerve-associated Schwann cell precursors (SCPs) contribute sympathetic neurons and satellite glia after the initial seeding of sympathetic ganglia by neural crest. Motor nerve ablation causes mispositioning of SCP-derived sympathoblasts as well as sympathetic chain hypoplasia and fragmentation. Sympathetic neurons in motor-ablated embryos project precociously and abnormally towards dorsal root ganglia, eventually resulting in fusion of sympathetic and sensory ganglia. Cell interaction analysis identifies semaphorins as potential motor nerve-derived signaling molecules regulating sympathoblast positioning and outgrowth. Overall, central innervation functions both as infrastructure and regulatory niche to ensure the integrity of peripheral ganglia morphogenesis.

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Introduction.

The autonomic nervous system (ANS), a crucial component of the peripheral nervous system (PNS), orchestrates a variety of physiological functions including heart rate, gut motility, and stress responses 1 . The sympathetic branch of the ANS controls the “fight or flight” response and is typically counteracted by the parasympathetic branch that mediates the “rest and digest” response 2 . The coordinated development of these two systems is vital for mammalian survival and homeostasis, yet the mechanisms underlying their patterning remain enigmatic.

The sympathetic system consists of paired ganglia arranged along the spinal axis, adjacent to the dorsal aorta, which receive inputs from pre-ganglionic fibers extending from cholinergic visceral motor neurons within the ventral neural tube 3 . As most of the neuronal and all glial elements of the PNS, sympathetic ganglia originate from neural crest cells (NCC), a transient migratory population that leaves the dorsal neural tube around embryonic day (E)9 in mice 4 , 5 . Early waves move ventrally towards the dorsal aorta where they differentiate into sympathetic neurons and glia 6 , 7 . Ventrolateral waves give rise to sensory cells of the dorsal root ganglia (DRGs) and the boundary cap cells (BCCs) lining the dorsal and ventral roots, while late dorsolateral waves generate the pigment-producing melanocytes. Some NCCs eventually become Schwann cell precursors (SCPs), which characteristically migrate along developing nerves 8 . SCPs contribute to various structures including parasympathetic ganglia 9 , 10 , chromaffin cells of the adrenal medulla 11 , 12 , and parts of the enteric nervous system 13 , suggesting that peripheral nerves play a crucial role in ANS development.

Various aspects of PNS development depend on the correct positioning and growth of pre-existing nerve tracts 14 , 15 , 16 . A general wiring strategy, where an initial outgrowth of pioneer neurons establishes a template to guide subsequent axon growth, is evident in the pathfinding of some sympathetic and sensory fibers that depend on pre-extended motor axons 17 . Similarly, SCPs and multipotent glial progenitors of the boundary cap utilize the infrastructure provided by peripheral nerves to reach target organs. However, innervation is thought to be dispensable for the formation of sympathetic ganglia, as their initial assembly relies on early free-migrating NCC coalescing near the dorsal aorta 18 . Notwithstanding, it has been recently discovered that some sympathetic neurons in the paraganglia, as well as intra-adrenal sympathetic neurons, are derived from SCPs 12 , 19 , pointing to the possibility that the sympathetic chain might also receive a contribution from SCPs to boost later growth. However, the extent to which motor nerves and motor nerve-associated SCPs contribute to the formation of the sympathetic chain remains undetermined.

In this study, we took advantage of genetic motor nerve ablation, in vivo tracing of boundary cap and glial lineages, and single-cell transcriptomics, to investigate the role of motor nerves in sympathetic chain formation. We discovered that genetic ablation of motor nerves impairs the development of sympathetic ganglia, as motor nerve-guided SCPs are unavailable. Simultaneously, aberrant clusters of sympathetic neurons are generated from sensory nerve-associated SCPs and become ectopically neurogenic in the absence of motor fibers. Finally, motor nerves control the navigation of sympathetic fibers, preventing them from innervating inappropriate targets, such as sensory ganglia. Thus, by controlling progenitor cell placement and axonal outgrowth, motor neurons act as “insulators” that maintain the separation between distinct elements of the PNS.

Early-recruited SCPs are primed toward sympathetic fate while arriving on motor nerves

Sympathetic chain development begins with ventrally migrating waves of SOX10 + NCCs that coalesce in the vicinity of the dorsal aorta from where they receive inductive signals, such as Bone Morphogenetic Protein (BMP) 7 . These precursor cells, known as “sympathoblasts”, express early autonomic markers ( Phox2b ) and later differentiate into bona fide sympathetic neurons (labeled by Tyrosine Hydroxylase, Th ) (Fig.  1a ) 2 . Soon after the initial assembly of sympathetic chain ganglia, preganglionic motor nerves start to arrive from the developing neural tube. To track the dynamics of motor axons during neural crest migration and subsequent steps of sympathetic ganglia development, we utilized Hb9-GFP transgenic mice in which motor neurons are labeled with green fluorescent protein (GFP) (Fig.  1b ). We observed that outgrowing motor axons partly interrupted the neural crest wave, and freely migrating NCCs became associated with the nerve as SCPs. This transition is evidenced by a gradual shift in the migratory stream angle (Fig.  1c ), widening gap between SCPs and free-migrating NCCs (Fig.  1d ), and consolidation of the SOX10 + stream as the nerve grows towards the sympathetic anlagen, showing that SCPs do not leave the nerve once attached (Fig.  1e ). These relationships suggest that during early axon growth, motor nerves influence migratory patterns of SCPs.

a Current model of sympathetic ganglia development from early stream of free neural crest migration. Free-NCCs (yellow) become primed toward autonomic fate (yellow-blue hybrid cells) as they approach the dorsal aorta region, where they differentiate into sympathetic neurons (blue) and coalesce to form the sympathetic ganglia chain. b Transverse sections of the same E10.5 Hb9-GFP embryo (representative of 3 embryos) from sacral to thoracic levels reveal the developmental progression of motor axons ( Hb9-GFP labeling) exiting the ventral neural tube (outlined) and intersecting the stream of free NCCs (SOX10 + ). NCCs are recruited on motor nerves as SCPs (arrowheads) leaving a “gap” with freely migrating cells. Scatterplots of measurement of ( c ) the angle created by intersecting the line bisecting the NCC migratory stream, with the dorsoventral axis bisecting the neural tube ( d ) gap between nerve-associated SCP and the nearest free NCC, ( e ) mediolateral thickness of the NCC/SCP streams (distance between most medial and lateral SOX10 + cells just ventrolateral to the neural tube), perpendicular to ( c ). The red, blue, and green colors in ( c – e ) represent measurements from individual E10.5 embryos (n = 3). Linear regression assessed correlation coefficients and p-values. f E10.5 transverse optical sections (representative of 3 embryos) show ITGA4 + /SOX10 + SCP associated with axons (2H3, Neurofilament) at thoracic level, and free migrating ITGA4 - /SOX10 + NCCs at sacral level. Single channels are magnified from the boxed regions in the merge image. The nerve bundle is outlined. g , h Transverse sections of Hb9-GFP embryos. At E10.5 ( g ), SCPs (SOX10 + , gray) migrate along GFP + /TUJ1 + motor axons that form the ventral root before sensory axons (GFP - /TUJ1 + ) have begun to extend from the DRG (representative of 3 embryos). At E11.5 ( h ), SCPs are associated with both motor and sensory fascicles in the main nerve bundle (blue arrowheads). Along the white ramus connecting to sympathetic ganglia (PHOX2B + , blue), SCPs are largely associated with motor axons (red arrows), which form the bulk of the nerve (white arrowheads). The boxed regions are magnified in the right panels. Representative of 6 embryos. i Transverse sections representative of n = 5 E12.5 Hb9-GFP embryos with TRKA staining of sensory projections (red) co-extending with motor axons (GFP + , green). Individual channels are shown in the right panels. The boxed area, magnified in the bottom panel, shows the white ramus (arrowhead) formed predominantly by preganglionic motor axons, with minimal contribution from viscerosensory fibers. PHOX2B (blue) marks sympathetic ganglia. j Schematic showing equal distribution of SCPs (yellow) on motor (green) and sensory (red) fibers in axial and intercostal nerves, while SCPs migrating toward sympathetic chain ganglia (blue) are almost exclusively recruited on motor axons of the white ramus. DA dorsal aorta, DRG dorsal root ganglia, MN motor neurons, NCCs neural crest cells, NT neural tube, SCPs Schwann cell precursors, SG sympathetic chain ganglia, WR white ramus communicans. Scale bars: b : 100 μm; f : 50 μm; g – i : 100 μm.

While SCPs were previously distinguished from NCCs and ganglia-residing satellite glia solely on the basis of their association with nerves, a SCP-specific gene signature referred to as a “hub state” marked by Itga4 expression has been recently described 20 . Indeed, at E10.5 ITGA4 levels were greater in SOX10 + cells that were associated to neurofilament-positive (2H3 + ) peripheral nerves of the ventral root, compared to NCCs that were still freely migrating in the caudal region (Fig.  1f ), suggesting that nerve association coincided with the adoption of the SCP hub state. The conversion of NCCs into SCPs proceeded according to the axial maturation gradient (Fig.  1b and Suppl Fig.  1a ), with anterior structures developing earlier than their posterior counterparts. This was also reflected in the gradients of motor innervation and induction/compaction of the PHOX2B + sympathetic anlagen (Suppl Fig.  1b ). Consequently, TH + sympathetic neurons appeared first in the brachial and cervical regions at E10.5, while nearly all migrating SOX10 + cells in the trunk were already associated with growing peripheral nerves (Suppl Fig.  1c ). During the early recruitment of SCPs, between E10.5 and E11.5, the ventral root is dominated by motor axons, as most TUJ1 + nerve fibers were also Hb9-GFP + (Fig.  1g , h ). By E12.5, the outgrowing spinal nerves carried both motor (efferent) and sensory (afferent) fibers that could be distinguished by Hb9-GFP and TRKA (NTRK1) labeling, respectively (Fig.  1i ). Notably, the majority of the white ramus communicans , connecting to sympathetic ganglia, was composed of Hb9-GFP + preganglionic visceral motor axons branching off the common nerve bundle, while TRKA + viscerosensory axons extending from the DRGs were present in small numbers (Fig.  1i ). Therefore, SCPs predominantly migrate along developing motor axons to reach the sympathetic anlagen (Fig.  1j ).

Next, we reconstructed the development of the white ramus in Hb9-GFP embryos, seeking to identify SCPs transitioning towards the autonomic neuroblast fate, as indicated by the co-occurrence of SOX10 and PHOX2B expression. From E10.5 onwards, most NCCs that had migrated to the sympathetic chain expressed the autonomic marker PHOX2B (Fig.  2a ). At this stage, some SCPs expressed PHOX2B at the extending tips of visceral motor nerves near the coalescing sympathetic ganglia (Fig.  2a , arrowheads), suggesting these cells were primed for the autonomic fate. At all later stages, this autonomic primed subpopulation of SCPs was detected exclusively along the white ramus or its fine branches (Fig.  2b , c ). None of the observed SCP cell populations expressed TH along the ventral root, indicating that terminal sympathetic neuron maturation occurs only within the sympathetic ganglia (Fig.  2d ). Together, these data are consistent with a model in which motor nerves recruit nearby freely migrating NCCs into SCPs, and that some of these motor nerve-associated SCPs become primed to an autonomic neurogenic fate en route as they approach the sympathetic ganglia, while others remain gliogenic (Fig.  2e ).

Transverse sections from E10.5 ( a ), E11.5 ( b ), and E12.5 ( c ) Hb9-GFP embryos immunostained for the NCC/SCP marker SOX10 (blue) and the sympathetic marker PHOX2B (red). Boxed regions are magnified in the corresponding bottom panels. Arrowheads point to committed PHOX2B + SCPs associated with motor axons. Arrows point to PHOX2B - SCPs that may acquire glial fate within the ganglia. Representative of at least n = 4 embryos per stage. d Transverse view of E10.5 (upper panel) and E12.5 (bottom panel) Hb9-GFP embryo trunks immunostained for the early sympathetic marker PHOX2B (red) and differentiated sympathetic neuron marker TH (blue). The boxed regions are magnified to show individual PHOX2B (middle) and TH (right) staining. Arrowheads point to PHOX2B + /TH - SCPs associated with motor axons. The images are representative of at least 3 embryos per stage. e Schematic of motor nerves (green) assisting the late wave of SCP migration (yellow) towards sympathetic ganglia (blue). Motor axons represent a permissive substrate for autonomic priming (yellow-blue hybrid cells; PHOX2B + /TH - ) but not for neuronal maturation (blue, TH + ). SCPs that do not acquire PHOX2B expression might differentiate into satellite glial cells within sympathetic ganglia. DA dorsal aorta, DRG dorsal root ganglia, MN motor neurons, NCCs neural crest cells, NT neural tube, SCPs Schwann cell precursors, SG sympathetic chain ganglia, WR white ramus communicans. Scale bars: a – c : 100 μm, 50 μm, 25 μm (from top to bottom panels); d : 100 µm.

SCPs give rise to sympathetic chain neurons

The induction of autonomic markers observed in visceral motor nerve-associated SCPs in the dorsal aorta region suggests that they may give rise to a portion of the sympathetic chain neurons. Since NCCs in all rostral segments of the trunk have already become nerve-associated SCPs by E10.5 (Suppl Fig.  1 ) 21 , we conducted SCP-specific lineage tracing with Plp1-Cre ERT2 ; R26R-YFP , inducing the reporter by tamoxifen injection at E10.5. In such an experimental setup, recombination occurs around E11, as SCPs presumably begin to contribute to the sympathetic fate. Embryos were collected at E13.5, and traced sympathetic neurons were quantified across the body axis (Fig.  3a ). Approximately 10% of sympathetic neurons were labeled at the cervical level, while this proportion increased to around 40% in the posterior thoracolumbar region (Fig.  3b , c ). The actual contribution of SCPs to sympathoblasts is likely higher since we have previously estimated the recombination efficiency of Plp1-Cre ERT2 in SOX10 + cells to be around 80% 11 . This data is consistent with a model in which a significant portion of sympathetic chain neurons are derived from nerve-associated SCPs rather than free-migrating NCCs, contrary to the traditional view of development. However, we note that this lineage tracing does not distinguish the neurogenic contribution of nerve-delivered SCPs from that of intra-ganglionic satellite glia derived from earlier-migrating NCCs.

a Plp1-Cre ERT2 ; R26-YFP embryos traced by tamoxifen injection at E10.5 and harvested at E13.5. Immunostaining for TH and YFP on sagittal sections through sympathetic ganglia at different anatomical locations of the traced Plp1-Cre ERT2 ; R26-YFP embryos. b Quantifications of YFP + /TH + cells traced at different levels of the sympathetic chain along the body axis. Colors represent individual embryos (n = 4). Mean ± SEM, one-way ANOVA and post hoc Tukey’s Multiple Comparison Test, (***) p = 0.001, (*) p = 0.0343, (ns) p = 0.6829. c Schematic of lineage tracing experiment. Induction of YFP expression in Plp1 + cells (yellow) at E10.5 results in differential contribution to sympathetic ganglia along different body segments. At brachial levels (left), in E10.5 embryos all YFP-labeled NCC derivatives are associated with nerves, revealing the extent of SCP contribution to sympathetic ganglia neurons (green cells in the ganglia at E13.5). At lumbar levels (right), YFP is induced in both nerve-associated SCPs and residual free-migrating NCCs at E10.5, resulting in mixed NCC/SCP contribution to sympathetic neurons (larger fraction of green cells in the ganglia at E13.5). d Transverse sections of Prss56-Cre; R26-Tomato E13.5 embryos immunostained for TH (red) and SOX10 (green) visualized alongside endogenous Tomato fluorescence (TOM, gray). Nuclei are in blue. (Top) TOM + boundary caps adjacent to the neural tube (outlined). (Middle) BCC-derived SCPs (TOM + /SOX10 + , arrowheads) in the ventral root (outlined). (Bottom) TH + /TOM + traced cells (arrowheads) in sympathetic chain ganglia from the lower lumbar region (observed in n = 5/5 embryos). e Schematic showing the restricted expression of BCC markers, Prss56 and Egr2 in the boundary caps at E10.5 (upper panel) and tracing of BCC derivatives (purple) along nerves and sympathetic ganglia (bottom panel). f Combined UMAP embedding with color-coded scRNAseq clusters (top) and sample origin (bottom). Arrows show RNA velocity-determined transcriptional flows. g Feature plots showing expression of selected cell type marker genes. SG sympathetic ganglia, BCCs boundary cap cells, NCCs neural crest cells, NT neural tube, SCPs Schwann cell precursors. Scale bars: a : 50 μm; d : 100 μm (top), 50 μm (middle), 25 μm (bottom).

To address this issue, we performed lineage tracing of boundary cap cells (BCCs), a multipotent neural crest derivative localized exclusively at CNS nerve exit/entry points 22 . BCCs are highly proliferative and differentiate into various neural crest-derived cell types, including nerve-associated SCPs 23 . BCCs markers ( Prss56 and Egr2/Krox20 ) are expressed at CNS entry/exit points but are absent along spinal nerves and in the sympathetic chain 22 . Hence, Cre alleles based on these cell-specific markers are useful to determine whether BCC-derived SCPs contribute to the sympathetic chain via the nerve. In line with this possibility, we observed Prss56-Cre -traced cells primarily at the expected boundary cap location at E13.5, with a few dispersing along ventral root nerves, and some within posterior sympathetic chain ganglia, where they expressed TH (Fig.  3d , e ). These results suggest that BCC-derived SCPs travel along the white ramus and are recruited in the ganglia where they give rise to sympathetic neurons.

As a complementary approach to identify BCC-derived nerve-associated SCPs, we undertook single-cell transcriptomics to profile Prss56-Cre and Krox20-Cre -traced cells dissected from the dorsal and ventral roots at E11.5 and E12.5 (Fig.  3f and Suppl Fig.  2 ). We detected Krox20 / Prss56 -traced BCC derivatives expressing the hub state markers Sox8 and Itga4 (Fig.  3g ). RNA velocity analysis revealed multiple trajectories including BCC-to-SCP and neuronal differentiation (Fig. 3f ), which is primarily dominated by sensory neurogenesis (Fig. 3g ). As expected from our analysis of lineage-traced cells on tissue sections, some BCC-traced cells were found to express the pro-autonomic neuronal markers Ascl1 and Gata2 , as well as Maoa , Mapt , Cartpt , and Th (Fig.  3g ).

From these studies, we conclude that Plp1 + SCPs and satellite glia contribute to late sympathetic neurogenesis (after E10.5), and that BCCs can give rise to sympathetic chain neurons via a nerve-associated SCP state.

Motor ablation leads to misplacement of sympathoblasts associating with sensory fibers

To directly assess the requirement of motor nerves in sympathetic ganglia development, we analyzed Olig2-Cre; R26-DTA (referred to as Olig2-Cre; DTA ) embryos in which motor neurons are selectively ablated following expression of diphtheria toxin (DTA) in Olig2 + motor neuron progenitors. Olig2-Cre; DTA embryos displayed a near total loss of HB9 + motor neurons by E10.5 (Suppl Fig.  3a, b, c ), resulting in complete depletion of motor axons in the ventral root (Fig.  4a , Suppl Fig.  3d ) 24 . Therefore, the Olig2-Cre; DTA model effectively and selectively eliminates motor neurons and their associated axons from early embryonic stages. In these embryos, the pelvic ganglion, which forms independently from motor nerves 18 , developed normally (Suppl Fig.  3e , f ), whereas chromaffin cells in the adrenal medulla, largely originating from nerve-associated SCPs 11 , were severely reduced (Suppl Fig.  3g ). In addition, the genetic ablation of motor neurons affected the projection of DRG-derived sensory axons (Suppl Fig.  3h ), in agreement with previous studies 17 . Lacking the motor component, peripheral nerves of the ventral root were shorter (Suppl Fig.  3i ) and significantly thinner (Suppl Fig.  3j ) than control embryos.

a Transverse sections showing complete loss of motor neuron cell bodies and axons (asterisks) in E11.5 Olig2-Cre; DTA embryos (right, n = 3) compared to control littermates (left, n = 2). Motor neurons are labeled with the cell-specific transgenic reporter MN (218-2) -GFP . In mutants, SCPs (SOX10 + , red) migrate exclusively along sensory nerves (GFP - /TUJ1 + ). Individual labeling from the boxed regions are shown separately in the right panels. b Transverse sections at E12.5 showing mispatterning of viscerosensory projections (TRKA + /TUJ1 + ; arrowheads) in Olig2-Cre; DTA (bottom, n = 3) compared to controls (top, n = 3). PHOX2B (blue) identifies sympathetic ganglia. The boxed regions are magnified in middle and right panels. TRKA (gray) is shown separately in the right panels. c Transverse view of SCPs (SOX10, red) migrating on motor nerves (arrowheads) in E12.5 controls (left). SCP delivery to sympathetic ganglia (PHOX2B, TH) along the white ramus is interrupted (asterisks) in Olig2-Cre; DTA (right). SOX10 (gray) is shown separately in the right panels. d Area of glial cells (SOX10 + pixels) in sympathetic ganglia from E12.5 controls (black dots) and Olig2-Cre; DTA (blue dots). Mean (normalized to control) ± SEM, Unpaired two-sided t test (**) p = 0.0017; controls n = 4, mutants n = 4. e Sympathetic chain ganglia area (PHOX2B+ px) measured in transverse sections from E12.5 controls and Olig2-Cre; DTA . Mean (normalized to control) ± SEM, Unpaired two-sided t test (*) p = 0.0226; controls n = 7, mutants n = 7. f Time course of autonomic priming identified by PHOX2B + cells associated with peripheral nerves (TUJ1 + ) outside sympathetic ganglia (arrowheads) in E10.5, E11.5, and E12.5 Olig2-Cre; DTA (bottom) and control (top) embryos. PHOX2B is shown separately in gray. Images are representative of at least 3 embryos per genotype, per stage. g Ectopic autonomic priming (PHOX2B + cells) along sensory nerves (TRKA + /TUJ1 + ) away from the ganglia chain in E12.5 Olig2-Cre; DTA (bottom), but not in controls (top). The merged channels in the boxed regions are shown separately in the right panels. Average number of nerve-associated primed SCPs (PHOX2B + cells outside the ganglia) ( h ) and distance from ganglia ( i ) in controls and Olig2-Cre; DTA . Mean ± SEM, Unpaired two-sided t test (*) p = 0.0136; (**) p = 0.0027; controls n = 3, mutants n = 3. j Schematics of autonomic priming (yellow-blue hybrid cells) on motor axons of the white ramus in the vicinity of the dorsal aorta in controls (left) compared to uncontrolled aberrant priming along sensory nerves far away from the sympathetic chain in motor nerve-ablated mutants (right). DA dorsal aorta, DRG dorsal root ganglia, MN motor neurons, NT neural tube, SCPs Schwann cell precursors, SG sympathetic chain ganglia, WR white ramus communicans. Scale bars: 100 µm.

Notably, in line with the predominance of motor fibers, the white ramus was entirely absent in Olig2-Cre; DTA embryos, leaving only occasional mis-patterned viscerosensory axons reaching the sympathetic ganglia (Fig.  4b ). This was accompanied by a marked decrease in SOX10 + glial cells delivered to the ganglia at E12.5 (Fig.  4c , d , Suppl Fig.  4a ), as well as a 20% reduction in PHOX2B + sympathoblasts inside the ganglia at this stage (Fig.  4e ). These alterations were not caused by an overall developmental delay since mutant embryos did not exhibit defects in body length at E12.5 (Suppl Fig.  4b ). Moreover, early placement/induction of the sympathetic chain was unaffected in Olig2-Cre; DTA (Suppl Fig.  4c–f ) and the size of TH + sympathoblasts was normal (Suppl Fig.  4g ), although the ganglia appeared aberrantly aggregated (Suppl Fig.  4a ).

We hypothesized that loss of the white ramus would prevent SCPs from reaching the sympathetic anlagen. Indeed, in Olig2-Cre; DTA embryos between E10.5 and E12.5, PHOX2B + cells accumulated along the spared sensory nerves at the prospective branching point of visceral motor axons (Fig.  4f ). These ectopically primed sympathoblasts spread aberrantly along the entire sensory nerve, from the DRG to the nerve endings (Fig.  4f–h ) and were detected hundreds of micrometers away from the usual location near the sympathetic chain ganglia (Fig.  4i ).

Overall, these results indicate that motor nerves influence the position of sympathetic progenitor cells. In the absence of motor axons, nerve-associated SCPs engage in a PHOX2B + state, and these primed cells disperse along sensory fibers to distant locations away from their normal induction site near the dorsal aorta (Fig.  4j ), at the expense of satellite glia and autonomic progenitor cells in the forming ganglia. These results distinguish sympathetic neurons and glia into two separate categories: an early population derived directly from free-migrating NCC, and a late population derived from nerve-associated SCPs. Whether these cell waves become functionally identical or not remains the subject of future investigation.

Motor axons influence the timing and position of sympathetic differentiation and axonal projection

We noticed that many misplaced PHOX2B + sympathoblasts associated with sensory nerves in motor-ablated embryos differentiated into TH + neurons even at abnormal positions far from the dorsal aorta (Fig.  5a , Suppl Fig.  4h ). This phenotype, in which sympathetic neurons mature and project along sensory nerves, worsened from E11.5 to E13.5, leading to the formation of several independent TH + neuronal clusters of misplaced sympathoblasts and the concomitant “fragmentation” of the sympathetic chain (Fig.  5a, b ).

Transverse sections at E11.5 ( a ) and E13.5 ( b ) showing misplaced sympathoblasts differentiating into sympathetic neurons (TH + , yellow) along sensory nerves (TUJ1 + , cyan) and forming ectopic mini-ganglia in Olig2-Cre; DTA (arrowheads) but not in controls. SOX10 labels SCPs (magenta). TH staining is shown separately in the bottom panels (gray). Arrows point to fragmented sympathetic chain ganglia. Representative images of 6 embryos per genotype at E11.5 and 4 embryos per genotype at E13.5. c Dorsal view of a whole mount immunostaining for TH, Neurofilament (2H3), and vascular marker CD31 of E12.5 control embryo. The region encompassing the sympathetic chain visualized in (d) is outlined. d Dorsal view of a whole mount immunostaining for TH in control (left) and Olig2-Cre; DTA (right) E11.5 (top), E12.5 (middle), and E13.5 (bottom) embryos. Arrowheads point to sensory fiber-associated TH + sympathetic neurons distant from the chain ganglia. Premature and aberrant extension of sympathetic fibers is visible in mutants. Representative images of at least n = 5 embryos per genotype at each stage. e Quantification of misplaced sensory nerve-attached sympathetic neurons per DRG between brachial and lumbar levels, averaged per embryo. Mean ± SEM, Unpaired two-sided t test (****) p < 0.0001; controls n = 3, mutants n = 3. f Quantification of misplaced TH + cells outside the chain ganglia at E12.5, per embryo. Mean ± SEM, Unpaired two-sided t test (**) p = 0.0066; controls n = 3, mutants n = 4. g Distribution of the distances between misplaced TH + cells and the borders of the chain ganglia. Each color of dot represents a different embryo (n = 3 controls, n = 4 mutants). Sagittal view of thoracic ( h ) and lumbar ( i ) regions from whole mount TH immunostaining of E12.5 (top) and E13.5 (bottom) Olig2-Cre; DTA embryos (right) and control littermates (left). Yellow arrowheads point to fragmented sympathetic chain in mutants; red arrowheads indicate abnormal sympathetic axon growth. Representative images of at least n = 5 embryos per genotype at each stage. j Volume measurements of sympathetic chain ganglia, cervical ganglia, and adrenal/paraganglia. Datapoints represent the average volume of ganglia from individual embryos (n = 3 control, n = 4 mutant). Mean ± SEM, one-way ANOVA using Šidák correction for multiple comparisons (**) p = 0.0032; (*) p = 0.0251; ns: p = 0.9815. k Oblique view of whole mount immunostaining for TH, Neurofilament (2H3), and vascular marker CD31 of E12.5 control embryo. The outlined forelimb region is shown in ( l ). l Forelimbs of E11.5 (top) and E12.5 (bottom) controls (left) and Olig2-Cre; DTA (right) littermates. Red arrowheads point to ectopic TH + neurons extending axons aberrantly into the limb. m Length of TH + sympathetic axons innervating the forelimb in control littermates vs Olig2-Cre; DTA embryos (at E11, controls n = 4, mutants n = 3; at E12.5, controls n = 3, mutants n = 4). Mean ± SEM, one-way ANOVA using Šidák correction for multiple comparisons (***) p = 0.0003; (*) p = 0.0118. n Schematic showing both ectopic and normally positioned sympathetic neurons (blue) projecting prematurely and along inappropriate paths in association with sensory fibers in motor-ablated mutants. The sympathetic chain is fragmented. DRG dorsal root ganglia, MN motor neurons, NT neural tube, OZ organ of Zuckerkandl, SCPs Schwann cell precursors, SG sympathetic chain ganglia. Scale bars: a , b : 100 µm, c : 500 µm; d : 200 µm (top and middle), 300 µm (bottom); h , i : 100 µm (top), 200 µm (bottom); k : 500 µm; l : 200 µm (top), 300 µm (bottom).

Whole mount immunofluorescent staining revealed a constellation of ectopic TH + cell clusters around the sympathetic chain throughout the thoracolumbar region (Fig.  5c, d ), that were numerous in motor-ablated embryos but virtually absent in controls (Fig.  5e, f ). These cells were found at a considerable distance from the sympathetic chain, extending as far as the limbs (Fig.  5g ). The same phenotype was observed in a second independent mouse model of motor nerve ablation, Hb9-Cre; Isl2-DTA in which the DTA is expressed in postmitotic motor neurons based on overlapping expression of Hb9 and Isl2 (Suppl Fig.  5 ). Possibly as a consequence of sympathetic neuron misplacement, Olig2-Cre; DTA embryos presented severe disruption of the thoracic (Fig.  5h ) and lumbar (Fig.  5i ) sympathetic chain. In motor nerve-ablated embryos, the normally continuous, smoothly curved sympathetic chain became fragmented, with individual ganglia exhibiting a rounded, amorphous morphology (Fig.  5h, i , yellow arrowheads, and additional examples in Suppl Fig.  6 ), and was significantly smaller than in Cre-negative controls (Fig.  5j ).

Aberrant sympathetic axon growth was also observed in nerve-ablated embryos, both from ectopic sympathetic neurons, as well as those properly positioned in the sympathetic chain (Fig.  5d , h, i). The misplaced sympathoblasts in nerve-ablated embryos extended axonal projections by E11.5, when sympathetic outgrowth had not yet commenced in controls (Fig.  5a , d ). At later stages (E12.5-E13.5) in mutant embryos, sympathetic axons grew longer and visibly altered, spreading throughout the thoracolumbar region (Fig.  5d ), ultimately invading the DRGs (Fig.  5h, i , red arrowheads). Sympathoblasts misplaced near the forelimbs (Fig.  5k–m ) and hindlimbs (Suppl Fig  7 ) extended very long projections that abnormally innervated these regions in the mutant embryos.

The observation that removal of motor nerves enables the neurogenic potential within nerve-associated SCPs far away from traditional sites (sympathetic chain and dorsal aorta) (Fig.  5n ) implies that motor nerves might inhibit this differentiation process during normal development. In addition, motor nerves appear to prevent premature and inappropriate innervation patterns, hinting they might serve as outgrowth and navigational controllers for sympathetic neuron projection.

Early interactions with motor nerves direct morphogenesis of cervical ganglia

Although the fragmentation phenotype was mostly evident in the thoracic and lumbar parts of the trunk, the morphology of the superior cervical ganglion (SCG) was also affected in Olig2-Cre; DTA embryos. In mutants, the SCG was normal until E12.5 (Suppl Fig  8a ) but became gradually more deformed starting from E13.5 (Suppl Fig  8b ). Since these defects developed at later stages than those observed in the sympathetic chain, we used Chat-Cre allele to drive R26-DTA in postmitotic motor neurons starting at E11.5 (as opposed to Olig2-Cre that is expressed in progenitors). Unexpectedly, Chat-Cre; R26-DTA embryos exhibited a less severe SCG phenotype compared to Olig2-Cre; DTA embryos, showing only a moderate elongation of the ganglia in a few mutants (Suppl Fig  5b ). Therefore, the different severity of the phenotypes observed following DTA-mediated cell ablation might depend on the timing of Cre-dependent recombination.

By E14.5 sympathoblasts in the cervical ganglia of Olig2-Cre; DTA embryos displayed a twofold reduction in volume and a corresponding enlargement of the medial cervical ganglion (MCG, Suppl Fig  8c–e ). Importantly, these defects were exclusively dependent on the ablation of motor nerves, as they were not observed in Neurog1 knockout embryos in which cranial sensory innervation is disrupted (Suppl Fig  8c , f ). Altogether, these results suggest that early recruitment of motor nerve-associated SCPs into cervical ganglia, prior to the complete phenotypic maturation of sympathetic neurons, is critical for later development and morphogenesis of the SCG. These changes occurred without apparent differences in the levels of cell proliferation and apoptosis in the SCG of mutant embryos at E12.5-E13.5 compared to controls (Suppl Fig  8g ), suggesting a collective cell migration event might occur along motor nerves during formation of the SCG.

Motor nerves prevent intermixing of sensory and autonomic ganglia

We next examined the organization of peripheral ganglia at intermediate and late developmental stages in motor nerve ablated embryos . Olig2-Cre; DTA mice are not viable at birth, but survive in the womb, allowing investigation of embryos until birth. At E15.5, the ectopic clusters of sympathetic neurons often appeared larger than the regular sympathetic ganglia (Fig.  6a ) and were frequently abutting the DRGs, resulting in a significantly shorter distance between sympathetic and sensory ganglia (Fig.  6b ). Even more drastic alterations were observed at E18.5, wherein the DRGs and sympathetic chain ganglia were interspersed, with sensory neuroblasts intermingling within the sympathetic ganglia (Fig.  6c , insets). These defects were observed in most of the peripheral ganglia in mutant embryos, but never in controls (Fig.  6d ). Conversely, sympathetic neurons and their axons aberrantly invaded the DRGs thereby disrupting their structure (Fig.  6c , f ). Consequently, sensory ganglia were generally smaller (Fig.  6e ) and exhibited an abnormal morphology (Fig.  6f ).

a Transverse embryo sections at E15.5 showing fusion of sympathetic (TH + , magenta) and dorsal root ganglia (TRKA + , cyan) in Olig2-Cre; DTA (right), but not in control littermates (left). TRKA and TH are shown separately in middle and bottom panels, respectively. b Distance between sympathetic and dorsal root ganglia in Olig2-Cre; DTA and controls. Mean ± SEM, Unpaired two-sided t test (****) p < 0.0001; controls n = 9, mutants n = 7. c Immunostaining for TH (magenta), SOX10 (yellow), and 2H3 (cyan) in sagittal sections of Olig2-Cre; DTA embryos and control littermates. The dorsal root ganglion is outlined with a dotted line. Boxed regions are magnified in the insets showing interspersed sensory neurons in sympathetic ganglia (white arrowheads). Yellow arrowheads point to fusion of DRG and sympathetic ganglia in mutants. d Fraction of ganglia pairs showing aberrant organization such as misplaced sympathoblasts around the sensory ganglia, or misplaced sensory neurons in the sympathetic ganglia. Mean ± SEM, Unpaired two-sided t test (**) p = 0.0046; controls n = 3, mutants n = 3. e Average cross-sectional area of DRGs per embryo. Mean ± SEM, Unpaired two-sided t test (*) p = 0.0196; controls n = 4, mutants n = 5. f Transverse view of fragmented DRG (TRKA + , cyan) (arrowheads) in E18.5 Olig2-Cre; DTA (bottom) but not controls (top). TH (magenta) and TUJ1 (yellow) mark sympathetic projections. Representative images of n = 4 controls and n = 5 mutants. g Schematic showing intermixing of sympathetic (blue) and sensory (red) ganglia in the absence of motor nerves (green). NT neural tube, SG sympathetic ganglia, DRG dorsal root ganglia, MN motor neurons. Scale bars: a : 100 µm; c : 200 µm (insets 50 µm); f : 100 µm.

These findings suggest that motor nerves, potentially through the regulation of progenitor cell placement and axon navigation (or via other mechanisms), function as “insulators”, safeguarding the integrity of boundaries between different types of peripheral ganglia (Fig.  6g ).

Signaling interactions between motor neurons and sympathetic progenitor cells

To investigate how motor neurons participate in signaling interactions with neural crest-derived cells like SCPs and sympathetic neurons, we analyzed single-cell transcriptomic datasets of motor neurons 24 as well as the neural crest lineage, including hub-state SCPs, boundary cap cells, satellite glia, and sympathetic neurons at E12.5 (Suppl Fig  9a ) 20 . The CellChat algorithm 25 was used to predict ligand-receptor interactions between motor neurons and neural crest-derived cell types harvested at E12.5. The highest predicted scores for signaling outgoing from motor neurons, while incoming to peripheral neuroglial cell types, were assigned to class-3 Semaphorin (SEMA3), Pleiotrophin (PTN), Neuregulin (NRG), Macrophage migration inhibitory factor (MIF), Energy Homeostasis Associated (ENHO), and Growth Arrest Specific (GAS) pathways (Suppl Fig  9b, c ). Most motor neuron subtypes, including preganglionic motor neurons (PGCa and PGCb), were predicted to signal via these selected pathways to boundary cap cells, hub-state SCPs, satellite glia and sympathetic neurons (Suppl Fig  9b–d ). Gene expression analysis of receptor/ligand pairs for two of the highest-scoring pathways, SEMA3 and NRG, identified multiple specific ligands in motor neurons, and high levels of cognate receptors in neural crest derivatives (Suppl Fig  9e, f ). Focusing on SEMA3 pathway, the top-ranking ligands expressed in PGC motor neurons were Sema3C, followed by Sema3A (Suppl Fig  9e , g ). Therefore, we hypothesized that deregulation in SEMA3 signaling might be partly responsible for the phenotypes observed in motor nerve-ablated embryos.

To address this possibility, we examined sympathetic chain development in SEMA3-deficient embryos. The top predicted signal, SEMA3C, is highly expressed by motor neurons (Suppl Fig  10a ) and has been shown to control neurovascular interactions through Neuropilin-1 (Nrp-1)/Neuropilin-2 (Nrp-2)/Plexin-D1 receptor complexes in endothelial cells 26 , 27 , 28 . However, the analysis of Sema3C knockout embryos at E12.5 and E13.5 did not reveal abnormalities in sympathetic ganglia (Suppl Fig  10b , c ). The other candidate class-3 semaphorins, Sema3A and Sema3F, were expressed in motor neurons (Suppl Fig  11a , b ) 28 and have been shown to provide chemo-repulsive cues for migrating NCCs and sympathetic fibers expressing cognate Neuropilin and Plexin receptors 29 , 30 , 31 , 32 , 33 . Sympathetic ganglia abnormalities resembling the phenotypes induced by motor nerve ablation were observed in both Sema3a/3   f double knockout embryos (Suppl Fig  11 ) and Wnt1-Cre;Nrp1 flox/flox embryos in which Nrp 1 was deleted from the neural crest 31 (Suppl Fig  12 ). In both mutant models, the sympathetic chain appeared moderately fragmented (Suppl Fig  11c, d , Suppl Fig  12a–f , arrows) and small clusters of misplaced sympathetic neurons were observed at ectopic locations at multiple axial levels mostly dispersing in the forelimbs where they extended aberrant projections (Suppl Fig  11c–f and Suppl Fig  12c–f , arrowheads). In addition, mutants displayed severe disruption of the cervical sympathetic ganglia (Suppl Fig  11d , and Suppl Fig  12f ). Fragmentation of the sympathetic chain and ectopic clusters were also visible in Nrp2 -/- ; Nrp1 Sema/Sema mutants in which all class-3 semaphorin signaling is abolished 34 (Suppl Fig  11g ). However, the abnormally robust outgrowth of sympathetic fibers in the hindlimb and thoracic regions observed in motor nerve-ablated embryos was not recapitulated in Nrp1 and Sema3a/3   f signaling mutants. These results suggest that motor nerve derived SEMA3A/3 F may be partly responsible for the placement of SCPs and structural integrity of sympathetic ganglia, but that motor nerves also use other mechanisms to regulate sympathoblast maturation and axonal outgrowth. These aspects of the motor nerve-driven phenotype, independent of semaphorin signaling, warrant future investigation.

Besides transmitting information through synaptic contacts, peripheral axons influence the innervated tissues in a variety of ways, by secreting morphogenic navigating signals 35 , organizing nerve tracts through axon-axon interactions 36 , 37 , guiding and remodeling blood vessels 28 , 38 , 39 and delivering progenitors of multiple cell types (such as melanocytes, chromaffin cells, autonomic neurons) to their final destination during embryonic development 9 , 11 . Because the PNS is multifunctional, the formation of innervation patterns has far-reaching consequences for organismal physiology 40 . The co-dependency of different nerve types reflects a parsimonious solution for neural wiring and represents an appealing developmental mechanism for generating evolutionary novelty 41 . Here, we addressed whether assembly of the sympathetic autonomic system depends on early-projecting and pioneering visceral motor neurons of the spinal cord 42 .

First, we report that the developing sympathetic chain requires motor innervation to provide a cell source to supplement its growth. The motor nerves are covered by multipotent and neurogenic SCPs, which are neural crest derivatives similarly to sympathetic neurons 43 . In the classical paradigm, migratory neural crest cells arrive at the dorsal aorta and coalesce into primary sympathetic ganglia 7 . We show that as motor axons emerge from the neural tube, they encounter part of the freely migrating neural crest, which becomes associated with growing motor nerves, turning into transcriptionally-defined SCPs—residing along the entire length of the peripheral nerve 43 —and BCCs—residing at CNS nerve exit points 22 . Consequently, the timing of motor axon outgrowth at each rostrocaudal segment coincides with a switch from free- to axon-associated dispersion of neural crest derivatives, consistent with our earlier studies 21 . Early-extending motor axons appear to function as an adhesive barrier that intersects the ventral migratory path of neural crest cells converting them into BCCs and SCPs (Fig.  1b–f ). These highly plastic cell types later contribute to the sympathoblasts and satellite glia of the sympathetic chain, following the initial seeding of the ganglia by early migrating NCCs.

Unexpectedly, we found that SCPs are primed towards the autonomic fate while still moving along the extending visceral motor nerves to reach the sympathetic anlagen. To validate this, we lineage-traced nerve exit point-associated BCCs and their SCP derivatives, revealing their contribution to sympathetic chain neuroblasts and satellite glia. These results were supported by pseudotime trajectory analysis of single-cell transcriptomics data of traced progeny of BCCs. Furthermore, we observed a 20% loss of sympathoblasts in the developing sympathetic chain upon genetic ablation of motor neurons. The contribution of motor nerve-associated BCCs and SCPs to the sympathetic chain is reminiscent of the SCP-dependent origin of parasympathetic neurons, melanocytes, and chromaffin cells of the adrenal medulla 8 , 9 , 11 . Also, it supports the evolutionary concept proposing nerve-assisted tissue invasion as the archetypical mode of neural crest dispersal in prehistoric vertebrates 44 .

The genetic ablation experiment pointed to additional roles for motor nerves besides supplying SCPs to the developing sympathetic chain. For instance, the induction of sympathetic ganglia stationed along sensory fibers in the limb far from the dorsal aorta cannot be attributed solely to the misplacement or limited availability of SCPs for two reasons. First, the number of observed ectopic primed cells outnumbers the corresponding reduction inside the ganglia. Second, the ectopic priming resulting from motor neuron ablation occurs in regions where motor nerves are normally covered with migrating SCP, implying that potential inductive signals present at those location, for instance in the forelimbs, are kept dormant in the presence of motor nerves. Thus, sensory nerve-associated SCPs retain the autonomic neuron differentiation potential, and in the absence of repressing signals from motor axons, they differentiate into sympathetic neurons in response to pro-neurogenic factors secreted by the local environment 7 , 45 . In motor-ablated embryos, the misplaced sympathoblasts, as well as those appropriately located in the ganglia, matured and projected at an accelerated pace compared to controls, suggesting that motor nerves not only serve as a scaffold to guide sympathoblasts but also regulate their neuronal maturation. It would follow that a fine balance exists between gliogenic and neurogenic potential in individual SCPs, with local signaling cues regulating the probability of nerve-associated neurogenesis 10 , 46 . Knowing how motor nerves regulate cell migration and neuroglial cell fate might have implications for neuroblastoma pathogenesis. Specifically, future studies of nerve-derived cues affecting sympathetic priming, especially functional differences between the sensory versus motor niches, might improve our understanding of cell origins of tumors initiated in non-canonical locations 47 .

Previous studies highlighted how early-established motor nerve tracts influence the subsequent trajectories of other nerve fiber types 17 , 37 . This was elegantly demonstrated by Wang et al. showing how different types of nerve ablations affect co-dependent patterns of motor, sensory and sympathetic innervation in skin and limbs 17 . According to Wang et al., motor axons are essential for the subcutaneous navigation of sensory axons, and in turn, sympathetic efferent fibers require those correctly positioned sensory afferents to innervate the dermis. Furthermore, genetic removal of sensory afferent fibers during development showed that sympathetic fibers successfully follow motor nerve trajectories before entering the skin, but subsequently fail to innervate the skin entirely. This dependence of sensory axon on motor axons is anatomy-dependent, because in the absence of motoneurons, the majority of trunk sensory axons successfully navigate along normal peripheral pathways in the ventral root, showing major projection abnormalities only at further extremities such as the limbs and skin. Indeed, our motor ablated embryos show a mainly normal distribution of sensory fibers in the vicinity of the sympathetic chain and DRGs, with only minor or rare deviations (such as slightly shifted branching point of the white ramus). Together with the paucity of viscerosensory axons in the white ramus, these observations suggest that the premature sympathetic nerve outgrowth and abnormal navigation along the ventral root can be most appropriately attributed to the absence of motor fibers.

Given this logic, our findings imply a specific role of motor nerves in inhibiting precocious SG axon outgrowth and sympathetic innervation of DRGs. Indeed, in this experimental setting, both properly positioned and ectopic sympathetic neurons mis-projected into DRGs, away from their canonical path. Ultimately, at later developmental stages, sympathetic and sensory ganglia started to intermingle, causing inappropriate mixing of different neuronal types. This aberrant configuration resembles or may even model human cases of sympathetic pain syndrome, where chronic pain arises from abnormal synaptic connections between sympathetic neurons and pain somatosensory neurons located in DRGs 48 , 49 , 50 . It would be interesting to test whether perturbation of specific motor-derived signals, or transient redirection of SCPs, is sufficient to recreate such syndromes in a mouse model. Altogether, our results point to a restraining effect of preganglionic motor fibers on the projection of sympathetic nerves.

Unmasking the molecular mechanisms underlying the regulatory action of motor nerves on sympathoblast priming, maturation, and outgrowth remains an important biological question for future studies. Notably, the phenotype observed in the absence of motor axons is reminiscent of the defects that arise in the sympathetic chain when Semaphorin-3/Neuropilin signaling is impaired in mutant embryos. Sema3/NRP pathway is required for sympathetic nervous system development 29 and for placing of chromaffin cell precursors in the adrenal medulla following visceral motor nerves 31 . Motor neurons express multiple semaphorins 51 and use them to regulate guidance receptors in an autocrine fashion 52 , and as paracrine signals to control the interactions between developing motor axons and the cells in the innervated tissues, including vascular endothelial cells 27 , 28 . Our results support the possibility that Sema3A and Sema3F ligands released by extending preganglionic motor nerves orchestrate the local induction and spatial organization of sympathoblasts, because the clusters of ectopic nerve-associated sympathoblasts observed in Sema3a/3   f and Nrp1 knockout embryos strongly resemble those in motor nerve-ablated embryos. Other aspects of the motor nerve ablation phenotype in the sympathetic chain were not recapitulated in Sema pathway mutants, suggesting that motor nerves may utilize multiple mechanisms to influence the developing sympathetic system. In addition to this logic, because the activation of Sema3a/3f—Nrp1 signaling has been implicated in peripheral nerve targeting to muscles and adrenal primordia 31 , 53 , 54 , a contribution of motor axonal misrouting to SCP disorganization and ectopic mini-ganglia formation cannot be excluded.

The exact identification of motor-derived signals that influence sympathetic development is complicated by the fact that this effect could be in part mediated by co-extending sensory axons 17 , 36 , 37 . Also, in our experiments we cannot exclude the influence of semaphorins and other signals derived from local mesodermal populations, including the developing somites 55 . It is possible that a combination of extrinsic cues from different cell sources directs the induction and maturation of sympathetic neurons, as well as controls the navigation of sympathetic nerves. Altogether, these features complicate the unambiguous dissection of the underlying molecular signals, making it a compelling subject for future studies aimed at clarifying how motor fibers influence the surrounding cellular microenvironment.

In conclusion, the role of motor nerves in directing sympathetic chain development is pivotal and multifarious at the same time. Our results demonstrate that motor nerves function as a regulatory brake on the maturation and outgrowth of sympathetic neurons, “insulate” distinct PNS elements to safeguard their integrity, and provide an essential niche and migratory substrate for a portion of motor nerve-associated progenitors, thereby contributing to the development of the sympathetic nervous system.

Mouse lines

All animal work was permitted by the Ethical Committee on Animal Experiments (Stockholm North committee) and Animal Research Committee of IRCCS San Raffaele Hospital, and conducted in compliance with The Swedish Animal Agency’s Provisions and Guidelines for Animal Experimentation recommendations under I.A.’s ethical protocol #15907-19; 18314-21 and The Italian Ministry of Health under D.B.’s protocols #1131/2016-PR and 668/2022-PR. Mice were kept in standard conditions: 24 °C; 12h-12h light dark cycle; 40–60% humidity; food and water ad libitum. R26-Tomato mice were ordered from The Jackson Laboratory (stock number 007914). Plp1-Cre ERT2 mice were received from U. Suter laboratory (ETH Zurich, Switzerland) ( http://www.informatics.jax.org/allele/MGI:2663093 ). R26-YFP mice were received from The Jackson Laboratory (stock number 006148, full strain name B6.129×1-Gt(ROSA)26Sortm1(EYFP)Cos/J). Hb9-Cre (also known as Mnx1-Cre ) mice were received from The Jackson Laboratory, stock number 006600 (full strain name B6.129S1-Mnx1tm4(cre)Tmj/J). Isl2-DTA mice were received from The Jackson Laboratory, stock number 007942 (full strain name B6.Cg-Isl2tm1Arbr/J). R26-DTA alleles were received from The Jackson Laboratory, stock numbers 006331 (full strain name Gt(ROSA)26Sortm1(DTA)Jpmb/J) and 010527 (full strain name B6;129-Gt(ROSA)26Sortm1(DTA)Mrc/J) 56 . Chat-Cre mice were received from K. Meletis lab (Karolinska Institutet) also available from the Jackson Laboratory, stock number 006410 (full strain name B6;129S6-Chattm2(cre)Lowl/J). Olig2-Cre mouse line (C57BL6/n background) was donated by T. Jessel laboratory (Columbia University, New York, US) 57 . Hb9-GFP and MN (218-2) -GFP mouse lines (C57BL6/n background) were donated by S. Pfaff laboratory (Salk Institute, San Diego, US) 58 , 59 . Mouse mutants deficient in semaphorin and neuropilin signaling ( Wnt1-Cre Nrp1 flox/flox , Sema3a/3f-DKO, Nrp1 SEMA Nrp2 KO) as well as strains used for boundary cap cell tracing ( Egr2-Cre , Prss56-Cre ) have been described previously 22 , 29 , 30 , 31 , 34 . Sema3C KO mouse line (CD1 background) was donated by J. Raper (University of Pennsylvania, Philadelphia, US) and (S. Chauvet Aix-Marseille Université, Marseille, France) 60 . For all experiments, the day the plug was detected was considered E0.5. For Plp1-Cre; R26-YFP lineage tracing experiments, tamoxifen (Sigma, T5648) was dissolved in corn oil (Sigma, 8267) and delivered via intra peritoneal (i.p.) injection to pregnant females (0.05 mg/g body weight). For embryo collection, euthanasia was performed via isofluorane overdose followed by cervical dislocation. Sex information was not collected for the experimental analysis of embryonic tissue because sexual dimorphisms are not prominent at the stages investigated.

Motor neuron ablation and lineage tracing experiments

For targeted ablation of the pre-ganglionic neurons, Isl2-DTA or R26-DTA mice were bred to Hb9-Cre , mice, Chat-Cre mice, or Olig2-Cre mice to generate experimental Hb9-Cre/+;Isl2-DTA/+ and control Isl2-DTA /+ embryos, Chat-Cre /+; R26-DTA /+ and control R26-DTA /+ embryos, or Olig2-Cre /+; R26R-DTA /+ and control R26R-DTA /+ embryos. All tracing experiments using Plp1-CreERT2; R26R-YFP were performed using heterozygotes for both the Cre and the reporter R26R-YFP or R26-Tomato . Sample size was determined by availability of mutant embryos from each litter. Images shown in the figures represent comparisons between at least three mutant and three control embryos, for each developmental stage from E10.5-E18.5.

Immunohistochemistry

Embryos were harvested and fixed 4–6 h or overnight using 4% paraformaldehyde dissolved in a PBS buffer (pH 7.4) at 4 °C. Samples were washed in PBS at 4 °C for 1 h and cryopreserved by submerging at 4 °C for 6–24 h in 30% sucrose, diluted in PBS. The samples were then embedded using OCT media, frozen on dry ice, and stored at −20 °C. Tissue blocks were sectioned on an NX70 cryostat at a section thickness of 14–40 μm. Slides were stored at −20 °C after drying at RT for 1 h. For antigen retrieval, slides were immersed in 1x Target Retrieval Solution (Dako, S1699) for 1 h, pre-heated to 90 °C. Sections were washed three times in PBS containing 0.1% Tween‐20 (PBST), incubated at 4 °C overnight with primary antibodies diluted in PBST in a humidified chamber. Finally, sections were washed in PBST and incubated with secondary antibodies and Hoechst stain diluted in PBST at RT for 2 h, washed again three times in PBST, and mounted using Mowiol mounting medium (Dako, #S3023). Rabbit polyclonal anti-TH (1:800, Pel-Freez Biologicals, #P40101-150, RRID:AB_2617184), sheep polyclonal anti-TH (1:2000, Novus Biologicals, #NB300-110), chicken polyclonal anti-TH (1:500, Abcam, #ab76442, RRID:AB_1524535), rabbit polyclonal anti-Hb9 (1:8000, gift from Samuel Pfaff’s laboratory 61 ), mouse monoclonal anti-bIII tubulin/TUJ1 (1:500, Promega, #G712A), mouse monoclonal anti-bIII tubulin/TUJ1 (1:1000, Abcam #ab7751, clone TU-20, RRID:AB_306045), rabbit polyclonal anti-bIII tubulin/TUJ1 (1:1000, Synaptic Systems, cat#302302, RRID:AB_10637424), chicken polyclonal anti-GFP (1:500, Aves Labs Inc., #GFP-1020, RRID:AB_10000240), chicken polyclonal anti-GFP (1:1000, Abcam, ab13970, polyclonal, RRID:AB_300798), rabbit polyclonal anti-GFP (1:5000, Thermo/LifeTech, #A6455, lot#2126798, RRID:AB_221570), goat polyclonal anti-PHOX2B (R&D, 1:1000, #AF4940), mouse monoclonal anti-Neurofilament/NF200 (1:200, Developmental Hybridoma Studies Bank, clone 2H3), goat polyclonal anti-SOX10 (1:500, Santa-Cruz, #sc-17342), rabbit monoclonal anti-SOX10 (1:2000, Abcam, # ab155279, clone EPR4007, RRID:AB_2650603), goat anti-human SOX10 (1:800, R&D Systems, #AF2864, RRID:AB_442208), rabbit polyclonal anti-PRPH (1:500, Chemicon, #AB1530, RRID:AB_90725), rabbit monoclonal anti-KI67 (1:500, Thermo Scientific, #RM-9106, clone SP6, RRID:AB_2341197), rat monoclonal anti-PECAM (1:300, BD Pharmingen, #553370, RRID:AB_394816), goat polyclonal anti-PECAM (1:300, R&D systems #AF3628, RRID:AB_2161028), rabbit monoclonal anti-ITGA4/CD49d (1:500, Invitrogen, #MA5-27947, clone RM268, RRID:AB_2744984), rabbit monoclonal anti-Cleaved Caspase 3/Asp175 (1:500, Cell signaling #96645, clone 5A1E), rabbit polyclonal anti-TrkA (1:500, # 06-574 Sigma-Aldrich, RRID:AB_310180). DAPI (Thermo Fisher Scientific, 1:10,000, #D1306) was used concomitantly with secondary antibodies diluted in PBST buffer. For detection of the primary antibodies, secondary antibodies raised in donkey and conjugated with Alexa-405, −488, −555, and −647 fluorophores were used (1:1000, Molecular Probes, Thermo Fisher Scientific).

In situ hybridization

For HCR in Fig.  S10 , probe for Sema3C was ordered directly from Molecular Instruments, and the procedure was performed according to the protocol described online ( https://files.molecularinstruments.com/MI-Protocol-RNAFISH-FrozenTissue-Rev3.pdf ) using tissue cryosections from the trunks of day 11.5 mouse embryo. Briefly, slides were pre-treated via a fixation in paraformaldehyde at 4 °C, dehydration with an ethanol gradient, and a 10 µg/µL proteinase K digestion for 10 min before transcript detection. Then, slides were hybridized to 0.4 pmol probes diluted in 100 µL probe hybridization buffer (Molecular Instruments) at 37 °C overnight. After unbound probe was washed away with probe wash buffer (Molecular Instruments) the bound probes were amplified using snap-cooled H1 and H2 hairpins overnight in a dark humidified chamber. After washing excess amplification solution away using SSCT, slides were mounted and imaged on a Zeiss LSM980-Airyscan confocal microscope. For traditional in situ hybridization, embryos were fixed overnight in cold 4% paraformaldehyde/PBS, washed in PBS, dehydrated in methanol, and stored at −20 °C. Then, in situ hybridization was performed using digoxigenin-labeled riboprobes transcribed from plasmids containing Sema3a and Sema3f cDNAs.

Whole mount immunostaining of mouse embryos

Fixed embryos were dehydrated with a methanol gradient, bleached overnight at 4 °C using Dent’s Bleach (20% dimethyl sulfoxide in methanol, mixed 2:1 with 30% hydrogen peroxide), incubated overnight in Dent’s fix (20% dimethyl sulfoxide in methanol) at 4 °C and stored at −20 °C. Antibody dilution was done in a blocking buffer containing 5% normal donkey serum and 20% dimethyl sulfoxide. Embryos were incubated with primary antibody solution for 6–7 days, and incubated with secondary antibody solution for 2–3 days. After incubation of embryos with secondary antibodies and washing steps, the embryos were optically cleared using two different methods according to their size. Embryos at or younger than E11.5 were cleared in BABB solution (1 part benzyl alcohol / 2 parts benzyl benzoate) for 1 h with rotation before imaging on a confocal LSM800 microscope 8 . Embryos at or older than E12.5 were imaged using the CUBIC method (3–7 days in CUBIC1 at 37 degrees, 2–3 days in CUBIC2 solution at room temperature) before imaging on a Zeiss Z1 light sheet microscope 62 . 3D reconstructions of the sympathetic ganglia were performed using IMARIS software (version 9.5, Bitplane) based on segmentations of the TH/PHOX2B staining. In some cases, autofluorescence was used to aid the identification of the vasculature, the outline of the embryo, and the neural tube.

Images were acquired using LSM800 Zeiss confocal microscope, Olympus FLUOVIEW FV3000RS Confocal, or Zeiss Z1 light sheet microscope. Confocal microscope was equipped with 10x/0.45, 20x/0.8, 40x/1.2 and 63x objectives. Laser lines used for excitation included 405 nm, 488 nm, 561 nm, and 640 nm. All images using the light sheet were taken with 5X/0.16 air objective, using 405 nm, 488 nm, 561 nm, and 638 nm for excitation. Light sheet images were acquired in the .czi format in Zen (Black edition, version 3) and processed by stitching with Arivis Vision 4D (Zeiss, version 4.0), down-sampling (1:2 in the XY plane) in FIJI (ImageJ, version 2.14.0), conversion to .ims files using Imaris File Converter (Bitplane, version 9.5), and downstream analysis with Imaris (Bitplane, version 9.5). Confocal images were acquired in .czi format and analyzed in FIJI.

Image analysis of Plp1-Cre ERT2 embryos

Quantification of lineage tracing experiments was performed using FIJI (ImageJ, version 2.14.0). Multicolor, multi-tile, Z-stack images in CZI format with channels for DAPI, TH, and YFP were converted into 8-bit, and all Z-slices were combined using a maximum intensity projection. Binarization of images was based on manual thresholding per image, after it was determined that a fixed threshold per embryo gave similarly trending results across the anteroposterior axis. Image calculation in FIJI was used to find single, double, and triple positive regions. The ratio between the amount of triple positive YFP + TH + DAPI + objects and the amount of double positive TH + DAPI + objects was used to determine the percent of traced neurons in the sympathetic ganglia. Over 1000 cells were counted per axial region per embryo, and the graphical results are from the averages of four analyzed embryos from two different litters.

Image analysis of sympathetic ganglia size

Volumetric quantification of pelvic ganglia was performed using Imaris (version 9.5, Bitplane) with the surface generation tool and a fixed intensity threshold for all samples. Volumetric quantification of sympathetic chain volumes was performed using Imaris (version 9.5, Bitplane) using the surface generating tool. 5 to 7.5 micrometer smoothing was used for all light sheet images, 1.25 micrometer smoothing was used for confocal images. Manual segmentation was used to separate cervical ganglia, sympathetic chain, adrenals, and ectopic micro-ganglia before surface generation. Signal intensity thresholds, which were automatically recommended by the Imaris software for each whole unsegmented image, were used for automatic surface generation. Volumes of right and left sympathetic chain ganglia were averaged.

Boundary cap lineage tracing single-cell sequencing study

Krox20-Cre; R26-Tomato and Prss56-Cre; R26-Tomato mouse strains were used for lineage tracing boundary cap cells. For single-cell analysis at E11.5- E12.5, embryos were dissected to separate the meninges with all DRGs and ventral and dorsal roots. Specifically, E11.5 and 12.5 Egr2Cre/+; R26-Tomato and Prss56cre/+; R26-Tomato embryos were identified on the basis of Tomato expression under fluorescent stereomicroscope (Leica, Nussloch, Germany). Meninges and DRGs with dorsal and ventral roots were dissected and then digested with collagenase/dispase type I (Merck/Roche) for 15 min at 37 °C. Digestion was stopped by addition of 0.1 ml of fetal calf serum. Samples were slowly mechanically dissociated, and the cell suspension was filtered. Dissociated cells were then resuspended in PBS, 1% BSA, and subjected to FACS. Tomato-positive cells were isolated, while dead cells and doublets were excluded by gating on a forward-scatter and side-scatter area versus width. Log RFP fluorescence was acquired through a 530/30 nm bandpass. Internal Tomato-negative cells served as negative controls for FACS gating. Tomato-positive cells were sorted directly into PBS, 0.04% BSA for scRNA-seq experiments. Around 5,000 cells were loaded into one channel of the Chromium system using the V2 single-cell reagent kit (10X Genomics). Following capture and lysis, cDNAs were synthesized, then amplified by PCR for 12 cycles as per the manufacturer’s protocol (10X Genomics). The amplified cDNAs were used to generate Illumina sequencing libraries that were each sequenced on one flow cell NextSeq500 Illumina.

Single cell transcriptomics pre-processing and analysis

10x Genomics Cell Ranger v7.0.0 63 was used to process raw sequencing data. This pipeline converted Illumina base call files into Fastq format, aligned sequencing reads to a mm39 transcriptome using the STAR aligner 64 , and quantified the expression of transcripts in each cell using Chromium barcodes. The Cell Ranger outputs were given to the velocyto.py pipeline (version 0.17.17) 65 to generate spliced/unspliced expression matrices further used for RNA velocity estimation. Scanpy package pipeline (version 1.9.3) 66 was used for the downstream analysis. To retain only high-quality cells, we filtered out the cells with high mitochondrial content (more than 10%); the cells with less than 2000 UMIs (1000 UMIs for Egr2_E12 dataset); and cells defined as putative doublets (with a doublet score equal to or greater than 0.2, calculated by Scrublet version 0.2.3) 67 . The filtered datasets first were analyzed separately to extract the cells belonging to BCC lineage and then integrated with Harmony (3000 highly variable genes, 30 principal components (PC), max number of iterations = 20) 68 . The new PCs adjusted by Harmony were used to compute a nearest neighbor graph with further clustering and embedding by the Leiden algorithm 69 and UMAP (Uniform Manifold Approximation and Projection), respectively. Cell types were identified based on the Leiden clusters and marker gene expression. For RNA velocity estimation, we used the Scvelo package (version 0.3.1) 70 with a dynamical model to learn the transcriptional dynamics of splicing kinetics.

Cell-cell interaction analysis

Single cell transcriptomics datasets used for the study were downloaded from ( https://github.com/LouisFaure/glialfates_paper ) and ArrayExpress accession: E-MTAB-10571. Standard pre-processing workflows such as QC, cell selection, data normalization, identification of highly variable features, scaling, dimensional reduction, clustering, and integration of the datasets was performed in R (version 4.3.2) using Seurat (version 5.0.3) according to the instructions provided ( https://satijalab.org ). Cell interaction analysis was performed using the R package CellChat (v 1.6.1). A subset of CellChatDB (“Secreted signaling”) was used to seek cell-cell interactions between cell clusters in the merged motor-crest Seurat object ( https://github.com/sqjin/CellChat ). For specific code pipelines used for the analysis of single-cell data, please visit the GitHub link: https://github.com/ipoverennaya/motor_nerve_paper 71 .

Statistics and reproducibility

Statistical analysis was performed with GraphPad Prism (version 9.5.1) software. Description of statistical tests used can be found in each figure legend. No statistical method was used to predetermine sample size. No data were excluded from the analyses. The experiments were not randomized. The investigators were not blinded to allocation during experiments and outcome assessment. Analysis of covariation was performed in the case of determining the correlation between peripheral nerve length and features of neural crest migration using linear regression.

Reporting summary

Further information on research design is available in the  Nature Portfolio Reporting Summary linked to this article.

Data availability

Source data are provided with this paper as a Source Data File. Information provided in the text, figures and supplementary information contained in the present manuscript is sufficient to assess whether the claims of this study are supported by the evidence. Neural crest single-cell transcriptomics datasets used for the cell interaction study are available from GEO via accession GSE201257 and are viewable from https://adameykolab.hifo.meduniwien.ac.at/cellxgene_public/ . Motor neuron datasets can be found using the ArrayExpress accession: E-MTAB-10571 . Dataset for the lineage tracing study has been submitted to GEO under accession code GSE261748 . Raw microscopy files generated for this research project are available to interested parties upon request.  Source data are provided with this paper.

Code availability

The code used for single cell analysis, both tracing boundary cap cells and for predicting cell interactions between motor neurons and SCPs, can be found at the GitHub link: https://github.com/ipoverennaya/motor_nerve_paper 71 .

Wehrwein, E. A., Orer, H. S. & Barman, S. M. Overview of the anatomy, physiology, and pharmacology of the autonomic nervous system. Compr. Physiol . 6 , 1239–1278 (2016).

Ernsberger, U. & Rohrer, H. Sympathetic tales: subdivisons of the autonomic nervous system and the impact of developmental studies. Neural Dev. 13 , 20 (2018).

Article   PubMed   PubMed Central   Google Scholar  

McCorry, L. K. Physiology of the autonomic nervous system. Am. J. Pharm. Educ. 71 , 78–78 (2007).

Newbern, J. M. Molecular control of the neural crest and peripheral nervous system development. Curr. Top. Dev. Biol. 111 , 201–231 (2015).

Article   CAS   PubMed   PubMed Central   Google Scholar  

Serbedzija, G. N., Bronner-Fraser, M. & Fraser, S. E. A vital dye analysis of the timing and pathways of avian trunk neural crest cell migration. Development 106 , 809–816 (1989).

Article   CAS   PubMed   Google Scholar  

Kasemeier-Kulesa, J. C., Kulesa, P. M. & Lefcort, F. Imaging neural crest cell dynamics during formation of dorsal root ganglia and sympathetic ganglia. Development 132 , 235 (2005).

Saito, D. et al. The dorsal aorta initiates a molecular cascade that instructs sympatho-adrenal specification. Science 336 , 1578–1581 (2012).

Article   ADS   CAS   PubMed   Google Scholar  

Adameyko, I. et al. Schwann cell precursors from nerve innervation are a cellular origin of melanocytes in skin. Cell 139 , 366–379 (2009).

Dyachuk, V. et al. Neurodevelopment. Parasympathetic neurons originate from nerve-associated peripheral glial progenitors. Science 345 , 82–87 (2014).

Espinosa-Medina, I. et al. Parasympathetic ganglia derive from Schwann cell precursors. Science 345 , 87 (2014).

Furlan, A. et al. Multipotent peripheral glial cells generate neuroendocrine cells of the adrenal medulla. Science 357 , eaal3753 (2017).

Kastriti, M. E. et al. Schwann cell precursors generate the majority of chromaffin cells in Zuckerkandl organ and some sympathetic neurons in paraganglia. Front. Mol. Neurosci . 12 , 6 (2019).

Uesaka, T., Nagashimada, M. & Enomoto, H. Neuronal differentiation in Schwann cell lineage underlies postnatal neurogenesis in the enteric nervous system. J. Neurosci. 35 , 9879–9888 (2015).

Wang, L. & Marquardt, T. What axons tell each other: axon–axon signaling in nerve and circuit assembly. Curr. Opin. Neurobiol. 23 , 974–982 (2013).

Stainier, D. Y. & Gilbert, W. Pioneer neurons in the mouse trigeminal sensory system. Proc. Natl Acad. Sci. USA 87 , 923–927 (1990).

Article   ADS   CAS   PubMed   PubMed Central   Google Scholar  

Xueyuan, N. et al. Mapping of extrinsic innervation of the gastrointestinal tract in the mouse embryo. J. Neurosci. 40 , 6691 (2020).

Article   Google Scholar  

Wang, L. et al. A conserved axon type hierarchy governing peripheral nerve assembly. Development 141 , 1875 (2014).

Espinosa-Medina, I. et al. The sacral autonomic outflow is sympathetic. Science 354 , 893 (2016).

Kameneva, P. et al. Single-cell transcriptomics of human embryos identifies multiple sympathoblast lineages with potential implications for neuroblastoma origin. Nat. Genet . 53 , 694–706 (2021).

Kastriti, M. E. et al. Schwann cell precursors represent a neural crest-like state with biased multipotency. EMBO J. 41 , e108780 (2022).

Adameyko, I. et al. Sox2 and Mitf cross-regulatory interactions consolidate progenitor and melanocyte lineages in the cranial neural crest. Development 139 , 397–410 (2012).

Gresset, A. et al. Boundary caps give rise to neurogenic stem cells and terminal glia in the skin. Stem Cell Rep. 5 , 278–290 (2015).

Article   CAS   Google Scholar  

Gerschenfeld, G. et al. Neural tube-associated boundary caps are a major source of mural cells in the skin. eLife 12 , e69413 (2023).

Amin, N. D. et al. A hidden threshold in motor neuron gene networks revealed by modulation of miR-218 dose. Neuron 109 , 3252–3267.e6 (2021).

Jin, S. et al. Inference and analysis of cell-cell communication using CellChat. Nat. Commun. 12 , 1088 (2021).

Vieira, J. M., Schwarz, Q. & Ruhrberg, C. Selective requirements for NRP1 ligands during neurovascular patterning. Development 134 , 1833–1843 (2007).

Vieira, J. R. et al. Endothelial PlexinD1 signaling instructs spinal cord vascularization and motor neuron development. Neuron 110 , 4074–4089.e6 (2022).

Martins, L. F. et al. Motor neurons use push-pull signals to direct vascular remodeling critical for their connectivity. Neuron 110 , 4090–4107 (2022).

Maden, C. H. et al. NRP1 and NRP2 cooperate to regulate gangliogenesis, axon guidance and target innervation in the sympathetic nervous system. Dev. Biol. 369 , 277–285 (2012).

Kawasaki, T. et al. Requirement of neuropilin 1-mediated Sema3A signals in patterning of the sympathetic nervous system. Development 129 , 671–680 (2002).

Lumb, R. et al. Neuropilins guide preganglionic sympathetic axons and chromaffin cell precursors to establish the adrenal medulla. Development 145 , dev162552 (2018).

Waimey, K. E. et al. Plexin-A3 and plexin-A4 restrict the migration of sympathetic neurons but not their neural crest precursors. Dev. Biol. 315 , 448–458 (2008).

Lumb, R. et al. Neuropilins define distinct populations of neural crest cells. Neural Dev. 9 , 24 (2014).

Gu, C. et al. Neuropilin-1 conveys semaphorin and VEGF signaling during neural and cardiovascular development. Dev. Cell 5 , 45–57 (2003).

Castillo-Azofeifa, D. et al. Sonic hedgehog from both nerves and epithelium is a key trophic factor for taste bud maintenance. Development 144 , 3054 (2017).

CAS   PubMed   PubMed Central   Google Scholar  

Gallarda, B. W. et al. Segregation of axial motor and sensory pathways via heterotypic trans-axonal signaling. Science 320 , 233–236 (2008).

Wang, L. et al. Anatomical coupling of sensory and motor nerve trajectory via axon tracking. Neuron 71 , 263–277 (2011).

Carmeliet, P. & Tessier-Lavigne, M. Common mechanisms of nerve and blood vessel wiring. Nature 436 , 193–200 (2005).

Mukouyama, Y.-S. et al. Sensory nerves determine the pattern of arterial differentiation and blood vessel branching in the skin. Cell 109 , 693–705 (2002).

Adameyko, I. & Fried, K. The nervous system orchestrates and integrates craniofacial development: a review. Front. Physiol . 7 , 49 (2016).

Chédotal, A. Roles of axon guidance molecules in neuronal wiring in the developing spinal cord. Nat. Rev. Neurosci. 20 , 380–396 (2019).

Article   PubMed   Google Scholar  

Bonanomi, D. & Pfaff, S. L. Motor axon pathfinding. Cold Spring Harb. Perspect. Biol. 2 , a001735 (2010).

Furlan, A. & Adameyko, I. Schwann cell precursor: a neural crest cell in disguise? Dev. Biol. 444 , S25–S35 (2018).

Ivashkin, E. & Adameyko, I. Progenitors of the protochordate ocellus as an evolutionary origin of the neural crest. Evodevo 4 , 12 (2013).

Morikawa, Y. et al. BMP signaling regulates sympathetic nervous system development through Smad4-dependent and -independent pathways. Development 136 , 3575–3584 (2009).

Erickson, A. G., Kameneva, P. & Adameyko, I. The transcriptional portraits of the neural crest at the individual cell level. Semin Cell Dev. Biol. 138 , 68–80 (2023).

Ponzoni, M. et al. Recent advances in the developmental origin of neuroblastoma: an overview. J. Exp. Clin. Cancer Res. 41 , 92 (2022).

Geron, M., Tassou, A. & Scherrer, G. Sympathetic yet painful: autonomic innervation drives cluster firing of somatosensory neurons. Neuron 110 , 175–177 (2022).

Zheng, Q., Dong, X. & Green, D. P. Peripheral mechanisms of chronic pain. Med Rev. 2 , 251–270 (2022).

Chung, K., Yoon, Y. W. & Chung, J. M. Sprouting sympathetic fibers form synaptic varicosities in the dorsal root ganglion of the rat with neuropathic injury. Brain Res 751 , 275–280 (1997).

Cohen, S. et al. A semaphorin code defines subpopulations of spinal motor neurons during mouse development. Eur. J. Neurosci. 21 , 1767–1776 (2005).

Sanyas, I. et al. Motoneuronal Sema3C is essential for setting stereotyped motor tract positioning in limb-derived chemotropic semaphorins. Development 139 , 3633–3643 (2012).

Huber, A. B. et al. Distinct roles for secreted semaphorin signaling in spinal motor axon guidance. Neuron 48 , 949–964 (2005).

Saller, M. M. et al. The role of Sema3-Npn-1 signaling during diaphragm innervation and muscle development. J. Cell Sci. 129 , 3295–3308 (2016).

Goldstein, R. S. & Kalcheim, C. Normal segmentation and size of the primary sympathetic ganglia depend upon the alternation of rostrocaudal properties of the somites. Development 112 , 327–334 (1991).

Wu, S., Wu, Y. & Capecchi, M. R. Motoneurons and oligodendrocytes are sequentially generated from neural stem cells but do not appear to share common lineage-restricted progenitors in vivo. Development 133 , 581–590 (2006).

Dessaud, E. et al. Interpretation of the sonic hedgehog morphogen gradient by a temporal adaptation mechanism. Nature 450 , 717–720 (2007).

Amin, N. D. et al. Loss of motoneuron-specific microRNA-218 causes systemic neuromuscular failure. Science 350 , 1525–1529 (2015).

Lee, S. K. et al. Analysis of embryonic motoneuron gene regulation: derepression of general activators function in concert with enhancer factors. Development 131 , 3295–3306 (2004).

Feiner, L. et al. Targeted disruption of semaphorin 3C leads to persistent truncus arteriosus and aortic arch interruption. Development 128 , 3061–3070 (2001).

Thaler, J. et al. Active suppression of interneuron programs within developing motor neurons revealed by analysis of homeodomain factor HB9. Neuron 23 , 675–687 (1999).

Susaki, E. A. et al. Advanced CUBIC protocols for whole-brain and whole-body clearing and imaging. Nat. Protoc. 10 , 1709–1727 (2015).

Zheng, G. X. Y. et al. Massively parallel digital transcriptional profiling of single cells. Nat. Commun. 8 , 14049 (2017).

Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29 , 15–21 (2013).

La Manno, G. et al. RNA velocity of single cells. Nature 560 , 494–498 (2018).

Article   ADS   PubMed   PubMed Central   Google Scholar  

Wolf, F. A., Angerer, P. & Theis, F. J. SCANPY: large-scale single-cell gene expression data analysis. Genome Biol. 19 , 15 (2018).

Wolock, S. L., Lopez, R. & Klein, A. M. Scrublet: computational identification of cell doublets in single-cell transcriptomic data. Cell Syst. 8 , 281–291.e9 (2019).

Korsunsky, I. et al. Fast, sensitive and accurate integration of single-cell data with Harmony. Nat. Methods 16 , 1289–1296 (2019).

Traag, V. A., Waltman, L. & van Eck, N. J. From Louvain to Leiden: guaranteeing well-connected communities. Sci. Rep. 9 , 5233 (2019).

Bergen, V. et al. Generalizing RNA velocity to transient cell states through dynamical modeling. Nat. Biotechnol . 38 , 1408–1414 (2020).

Poverennaya, I., ipoverennaya/motor_nerve_paper. 2024: Zenodo.

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Acknowledgements

A.G.E. was supported by StratNeuro SRP Postdoctoral Research Fellowship and a Ruth L. Kirschstein National Research Service Award (F32/NRSA) from the National Institute of Dental and Craniofacial Research of the National Institute of Health (NIDCR/NIH) under award number 1F32DE029662. I.A. was supported by ERC Consolidator grant STEMMING-FROM-NERVE and ERC Synergy Grant KILL-OR-DIFFERENTIATE, Swedish Research Council, Knut and Alice Wallenberg Foundation, Bertil Hallsten Research Foundation, Cancerfonden, Paradifference Foundation, Austrian Science Fund (FWF) Stand-Alone grants, Austrian Science Fund (FWF) SFB F78 consortium grant, and the Austrian Science Fund (FWF) Emerging Fields "Brain Resilience" consortium grant. D.B. was supported by European Research Council Starting Grant 335590 and a Career Development Award from the Giovanni Armenise-Harvard Foundation. I.P. was supported by the European Union’s Horizon 2020 Research and Innovation Program under Marie Sklodowska-Curie (grant agreement No. 860635, ITN NEUcrest). C.R. was supported by Wellcome Investigator Award 205099/Z/16/Z. We graciously thank Hjalmar Brismar and Hans Blom from the national Advanced Light Microscopy unit in SciLifeLab for permission to use the light sheet microscope. We thank the advanced microscopy laboratory (ALEMBIC) of San Raffaele Hospital for expertise and instrumentation. Finally, we give thanks to Emma Erickson for the lovely illustrations, and to Hanna Helene Daryapeyma for technical assistance.

Open access funding provided by Karolinska Institute.

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These authors contributed equally: Alek G. Erickson, Alessia Motta.

Authors and Affiliations

Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden

Alek G. Erickson, Maria Eleni Kastriti, Daniel Wies & Igor Adameyko

Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milano, Italy

Alessia Motta & Dario Bonanomi

Center for Brain Research, Department of Neuroimmunology, Medical University Vienna, Vienna, Austria

Maria Eleni Kastriti, Irina Poverennaya & Igor Adameyko

Department of Applied Physics, KTH Royal Institute of Technology, Stockholm, Sweden

Steven Edwards

Mondor Institute for Biomedical Research (IMRB), INSERM, Créteil, France

Fanny Coulpier & Piotr Topilko

University of Claude Bernard Lyon 1, MeLiS, CNRS, INSERM, NeuroMyoGene Institute, Lyon, France

Emy Théoulle, Jeremy Ganofsky & Valerie Castellani

Department of Neuroscience, Biomedicum, Karolinska Institute, Stockholm, Sweden

Aliia Murtazina, Francois Lallemend, Saida Hadjab & Kaj Fried

University College London, Department of Ophthalmology London, London, UK

Giovanni Canu & Christiana Ruhrberg

Center for Cancer Biology, University of South Australia, Adelaide, SA, Australia

Quenten Schwarz

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Contributions

A.G.E., I.A., D.B., A.M. [Motta] conceived the study. A.G.E., A.M. [Motta], M.E.K., F.C., E.T., A.M. [Murtazina], G.C., and Q.S. performed experiments. A.G.E., A.M. [Motta], E.T., I.P., D.W., J.G., F.L., S.H., C.R., V.C., D.B., I.A. analyzed data. M.E.K., S.E., F.C., E.T., G.C., F.L., P.T., S.H., K.F., C.R., Q.S., V.C. provided experimental support and materials. D.B., K.F., P.T., and I.A. funded the project and supervised the study. A.G.E., A.M. [Motta], D.B., and I.A. wrote the initial draft of the manuscript; all other authors contributed to writing and approved the final version.

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Correspondence to Dario Bonanomi or Igor Adameyko .

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Erickson, A.G., Motta, A., Kastriti, M.E. et al. Motor innervation directs the correct development of the mouse sympathetic nervous system. Nat Commun 15 , 7065 (2024). https://doi.org/10.1038/s41467-024-51290-0

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Received : 09 June 2021

Accepted : 02 August 2024

Published : 16 August 2024

DOI : https://doi.org/10.1038/s41467-024-51290-0

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