The autonomic nervous system (ANS) is responsible for controlling all of the unconscious (autonomous) functions of the body. These autonomous functions maintain internal homeostasis, and also prepare the body to support appropriate voluntary (ie, non-autonomous) responses to external stimuli.

As such, dysfunction in the ANS can contribute to problems maintaining internal homeostasis in general (including problems with digestion, heart rate, and blood pressure, among others), but also problems involving maladaptive responses to external stimuli.

Many levels of control and regulation ultimately feed into control of the ANS, so by no means is this “autonomous” system detached from conscious and voluntary thoughts and behaviors, but understanding the inner workings of the ANS is very helpful as a foundation for understanding the physiological regulatory processes of the body, including emotional and cognitive processes.

To that end, this article will provide a general overview of the structure and function of the ANS, and a brief discussion of some problems with the common “fight or flight” versus “rest and digest” dichotomy of ANS function.

Table of Contents
Divisions of the autonomic nervous system
Anatomy of the sympathetic nervous system
Anatomy of the parasympathetic nervous system
Anatomy of the general visceral afferents
Anatomy of the vagus nerve
Sympathetic and parasympathetic signaling
Physiology of the autonomic nervous system
        Sympathetic/parasympathetic antagonism
        Autonomic innervation of tissues
        Autonomic tone
Problems with the “fight or flight” vs “rest and digest” dichotomy
References

Pick up any large textbook of neuroscience and in its 1000+ pages you will find a relatively short chapter (∼25 pages) devoted to the autonomic nervous system (ANS) and the involuntary control of visceromotor function. This is in contrast to the several hundred pages devoted to the somatomotor nervous system that governs the voluntary control of skeletal muscle contraction to maintain posture and permit locomotion. At the 2015 Society for Neuroscience meeting, none of the scientific sessions over a 5-day meeting had titles that included the word autonomic, sympathetic, or parasympathetic; and less than 50 oral or poster presentations included one of these terms in its title. In light of this limited coverage of the ANS in prominent neuroscience textbooks and scientific meetings, one would think that the ANS is not a very important component of the neurosciences. To the contrary, the ANS influences the function of nearly every organ in the body via its innervation of smooth muscle, cardiac muscle, and glands. In fact, the ANS is responsible for the control of all innervated organs and tissues except skeletal muscles.

Wehrwein et al. Overview of the Anatomy, Physiology, and Pharmacology of the Autonomic Nervous System. (2016)

Divisions of the Autonomic Nervous System

The autonomic nervous system (ANS) includes three divisions that are anatomically and functionally distinct from each other: sympathetic, parasympathetic, and enteric.

The enteric nervous system is the nervous system of the gut, and is a relatively self-contained web of neurons. Although some sympathetic and parasympathetic neurons synapse into the enteric nervous system enabling adaptive control of digestive functions by the CNS, the gut can still carry out its digestive activities through local feedback loops if these connections are broken.

To keep things a bit more manageable, I’m going to leave further discussion of the enteric nervous system for another post, and focus just on the sympathetic and parasympathetic divisions of the ANS here. (Of note, the heart also has an intrinsic nervous system, although apparently it’s not a big enough deal to warrant inclusion as a division of the ANS.)

One additional division bears mentioning: the general visceral afferents.

All neurons are classified as either efferent (motor neurons that travel from the CNS to target tissues and trigger a response) or afferent (sensory neurons that travel from the target tissue back to the CNS carrying sensory data).

The distinction between sympathetic and parasympathetic only exists for efferent neurons. The afferent neurons of the ANS are simply referred to as general visceral afferents, and the sensory information they provide is integrated at many levels – from ganglia to the spinal cord to the brainstem – ultimately promoting a (hopefully) adaptive response to a given situation, whether via sympathetic neurons or parasympathetic neurons or some combination of the two.

It’s debated whether these afferents should be classified as part of the ANS at all, but this is more an issue of semantics than anything. No matter how you classify them, the sensory data provided by general visceral afferents is critical to the proper efferent function of the ANS and its complex regulatory circuits.

Anatomy of the Sympathetic Nervous System

Both the sympathetic and parasympathetic nervous systems generally consist of neuron pairs, where the first neuron originates in the central nervous system (CNS; either the brain or spinal cord) and synapses into a ganglion (a cluster of nerve cell bodies outside of the CNS), and the second neuron originates in the ganglion and synapses at its final effector location (such as a blood vessel, gland, or organ).

The nerves of the sympathetic nervous system (SNS) originate in the spinal cord and synapse onto ganglia just outside the spinal cord, with the postganglionic neurons traveling from these ganglia to the final destination (all organ systems of the body, including the heart, lungs, blood vessels, digestive and excretory organs, immune organs [like the spleen and thymus], and reproductive organs, as well as various glands).

The columns of ganglia on either side of the spinal cord are referred to as the “sympathetic chain” or “sympathetic trunk,” and I’ve often seen people refer to the entire sympathetic division as the “sympathetic chain.”

Four notable sympathetic ganglia that are located outside the sympathetic chain are the celiac, aorticorenal (not depicted in the image below), superior mesenteric, and inferior mesenteric ganglia. Sympathetic postganglionic neurons that innervate the abdominal visceral organs originate in these ganglia.

One notable exception to the paired-neuron structure of the SNS is the neurons to the adrenal glands. Rather than synapsing into a ganglion and then proceeding to the final target, these neurons travel all the way from the spinal cord to the adrenal medulla, synapsing directly onto chromaffin cells, which adopt the role of a postganglionic neuron and secrete norepinephrine and epinephrine directly into circulation.

Anatomy of the Parasympathetic Nervous System

The structure of the parasympathetic nervous system (PNS) is different from that of the SNS in many respects. Like the SNS, the PNS is generally characterized by neuron pairs, but unlike the SNS, most of the parasympathetic neurons originate in the brainstem rather than the spinal cord. The only parasympathetic neurons that originate in the spinal cord are the pelvic nerves, which innervate the excretory organs (including the distal part of the colon, rectum, and bladder) and reproductive organs.

The rest of the parasympathetic neurons are cranial nerves, including the 10th cranial nerve (and the most significant part of the PNS): the vagus nerve. Note that not all cranial nerves are part of the PNS – only the oculomotor (III), facial (VII), glossopharyngeal (IX), and vagus (X) nerves. The others are sensory or control voluntary, not autonomic, functions, and thus are not part of the PNS.

Most of the parasympathetic neurons, including those of the vagus nerve, synapse onto ganglia that are very close to the target organ, which is what gives the parasympathetic nervous system its name (“para” means “adjacent to”).

Anatomy of the General Visceral Afferents

Most of the sensory information from visceral organs and tissues regulated by the ANS is transmitted to the CNS via the vagus nerve, terminating in the nucleus of the solitary tract (NTS) in the brainstem. In fact, only about 20% of vagal fibers are efferent (and part of the PNS), while the other 80% are afferent. Visceral afferent neurons are also found in a few of the other cranial nerves, and these terminate in the NTS as well.

Other general visceral afferents carry sensory data from visceral organs and tissues to the spinal cord, enabling local reflexive regulation of organ function without involvement of the brain (although plenty of these afferent signals make their way from the spinal cord up to the brain as well).

The visceral afferents collect sensory data from their target tissues using various receptor types, including baroreceptors (pressure), mechanoreceptors (deformation), thermoreceptors (temperature), chemoreceptors (small molecules), and nociceptors (pain).

Anatomy of the Vagus Nerve

The efferent part of the vagus nerve (the 20%) has two different branches that are distinct in both anatomy and function.

One branch of the vagus nerve originates in the dorsal motor nucleus of the vagus nerve (DMNV) and is composed of unmyelinated nerve fibers that supply the subdiaphragmatic organs, as well as some fibers to the heart and lungs.

The other branch of the vagus nerve originates in the nucleus ambiguus and is composed of myelinated nerve fibers that mostly serve the heart and lungs, as well as some of the tissues of the face, head, and throat.

While there is broad agreement about these anatomical features, there does not appear to be consensus about their significance. According to researcher Stephen Porges, this anatomical distinction is crucial for properly understanding the function of the vagus nerve, because the two branches have very distinct modes of operation. His evolutionary and physiological framework for viewing the function of the vagus nerve is known as the polyvagal theory.

However, a great number of modern papers entirely gloss over this distinction when discussing the vagus nerve, and I’ve seen very little acceptance of the polyvagal theory in the literature. It appears to be occasionally refuted, but mostly ignored.

I’ll write a separate post about the polyvagal theory, because I think it’s a fascinating perspective. For now, suffice it to say that these anatomically distinct branches of the vagus nerve exist, and that this knowledge may be useful for further exploration of ANS research.

[Update Nov 6 2022: Full analysis of polyvagal theory published here!]

Sympathetic and Parasympathetic Signaling

For autonomic signaling, two molecules play the leading roles: norepinephrine and acetylcholine.

Preganglionic neurons in both the SNS and PNS generally signal with acetylcholine at the ganglia. Postganglionic neurons in the PNS also signal using acetylcholine, while postganglionic neurons in the SNS generally use norepinephrine (with some exceptions).

Both neurotransmitters are very rapidly removed from the synaptic cleft, either through reuptake (norepinephrine) or degradation (acetylcholine). However, recall that the adrenal medulla functions as a specialized postganglionic neuron in the SNS, secreting its norepinephrine (along with epinephrine) directly into circulation. These circulating neurotransmitters/hormones must be taken up and degraded by the liver, which takes a couple minutes rather than a couple milliseconds.

Several different receptor types are sensitive to norepinephrine and acetylcholine, with the main three receptor categories being adrenergic (for norepinephrine) and muscarinic and nicotinic (for acetylcholine). Preganglionic acetylcholine signaling in both the SNS and PNS typically acts through nicotinic receptors, while postganglionic signaling typically acts through adrenergic receptors in the SNS and muscarinic receptors in the PNS.

Both sympathetic and parasympathetic neurons often release signaling peptides and other compounds in addition to the main neurotransmitter, which provides one of many mechanisms introducing complexity into autonomic signaling. The coexistence of acetylcholine or norepinephrine with another molecule in functional groups of neurons is called neurochemical coding, although it’s sometimes referred to as non-adrenergic non-cholinergic (NANC) transmission.

Another modulating factor in autonomic nervous transmission is the existence of autoreceptors and heteroreceptors on ANS neurons. This allows for autoinhibitory feedback (whereby release of either acetylcholine or norepinephrine by a neuron prevents further release of that same neurotransmitter), as well as reciprocal inhibition of cholinergic vs adrenergic signaling in tissues that are innervated by both sympathetic and parasympathetic neurons. However, it also allows for positive feedback, whereby neurotransmitter release can facilitate, rather than inhibit, the release of other neurotransmitters in the region.

I won’t get too into the complexity of signaling here, so suffice it to say that not only does each type of receptor have several subtypes (eg, alpha and beta adrenergic receptors), but the effect a given type of receptor will have on a specific tissue is totally dependent on the internal signaling cascade within the tissue itself. So despite only using two neurotransmitters (plus epinephrine), the sympathetic and parasympathetic nervous systems exert extremely granular control over their target tissues.

Physiology of the Autonomic Nervous System

“The ultimate responsibility of the ANS is to ensure that the physiological integrity of cells, tissues, and organs throughout the entire body is maintained (homeostasis) despite perturbations exerted by both the external and internal environments.

Wehrwein et al. Overview of the Anatomy, Physiology, and Pharmacology of the Autonomic Nervous System. (2016)

As mentioned in the introduction, the ANS is responsible for the unconscious functions of the body to maintain a state of homeostasis. Functionally, this means it controls all innervated tissues and organs except for skeletal muscle. It regulates airway resistance, blood flow, blood pressure, body temperature, digestion, energy balance, waste excretion, fluid volume, glandular secretions, heart rate, immune function, inflammatory processes, salt and water balance, sexual function, and urination. Notably, some autonomic functions, such as breathing and excretion, can also be brought under conscious voluntary control.

The hypothalamus and brainstem are the main regulatory centers that receive afferent feedback and trigger efferent autonomic impulses, which are carried out by the peripheral nerves of the SNS and PNS. Some sensory/motor integration and regulation also happens at the level of ganglia (bundles of nerve cells) and plexuses (groupings of ganglia), either in the spinal sympathetic chain or closer to the target organs.

Sympathetic/Parasympathetic Antagonism

Although there’s a common conception of the sympathetic and parasympathetic divisions as antagonistic, that’s only true insofar as each of the two divisions predominates during different externally-oriented physiological states (as discussed further in subsequent sections). In organs that receive dual innervation, the two divisions do tend to control opposite functions, but on the level of tissues, usually only sympathetic or parasympathetic innervation is present.

One likely reason for the persistent focus on antagonism between the two systems is the fact that historically, the heart has been the focus of much of the research on autonomic function and regulation, largely because it offers so many metrics (heart rate, blood pressure, etc) that can be measured noninvasively. And the heart is probably the best example of true antagonism between the SNS and PNS, with several tissues (including the sinoatrial note and atrial muscle) receiving both sympathetic and parasympathetic innervation that have opposing functions.

Autonomic Innervation of Tissues

However, in most other organs, the SNS and PNS innervate different tissues, allowing for complementary and synergistic control of organ function in different states. And in many cases, an entire gland or organ only receives input from one division of the ANS.

For instance, the lacrimal glands and nasopharyngeal glands only have parasympathetic innervation, while the adrenal medulla, most blood vessels, the gallbladder, kidney, and the immune organs receive only sympathetic innervation. It’s often claimed that brown adipose tissue, liver, and spleen are also exclusively sympathetic, but there’s some evidence that the dorsal vagus also innervates these tissues.

The following table shows some examples of target tissues and their response to SNS or PNS activation. A better and more detailed table that also includes parasympathetic receptors is available in this paper (Table 4). Table 1.1 in this book (available online) is also very good.

Autonomic Tone

While this table shows the results of stimulation of sympathetic or parasympathetic nerves, it’s also important to note that both systems are tonically active, meaning they have a baseline level of activity to a specific set of tissues and organs.

Autonomic tone is probably best characterized in the heart, where the PNS (specifically the ventral vagus) is tonically active. In the absence of external nervous impulses, the heart would beat at around 100 bpm, so the baseline vagal tone functions as a “vagal brake” keeping resting heart rate below that in healthy humans.

Functionally, this allows for rapid increases in heart rate (up to 100 bpm) by decreasing vagal influence (taking the foot off the brake) without the need for sympathetic activation (putting the foot on the accelerator).

The iris of the eye is another autonomic muscle that is under tonic parasympathetic control. On the other hand, most blood vessels are under tonic sympathetic control, as are the kidney and the bladder. Sympathetic neurons in the bladder keep the urethral sphincter contracted and the bladder wall relaxed, allowing it to fill with urine; only when you pee does sympathetic activity withdraw, allowing parasympathetic neurons to trigger relaxation of the urethral sphincter and contraction of the bladder.

These are just a few examples to illustrate the cooperative control of autonomic body systems by the SNS and PNS in the ambient state.

Problems with the “Fight or Flight” vs “Rest and Digest” Dichotomy

So far, we’ve been pretty “zoomed in,” looking at the ANS on the level of tissues and organs. On the level of the organism, the scientific conception of the physiological roles of the sympathetic and parasympathetic divisions of the ANS is largely the same as the popular conception: that the SNS is responsible for states of “fight or flight,” while the PNS is responsible for states of “rest and digest.”

In a sense, this is true. The sympathetic division does predominate in states that require mobilization of the organism, including defensive “fight or flight” states as well as non-defensive mobilization (such as exercise). These physiological states require liberation of fuel and transport of oxygen to optimally power the skeletal muscles of the body. This results in the sympathetically-mediated physiological changes we’re all familiar with, such as increased heart rate and respiration, routing of blood flow toward skeletal muscle at the expense of the visceral organs, and release of stored glucose and fatty acids into circulation.

On the other hand, the parasympathetic division predominates in resting states, commonly referred to as “rest and digest,” promoting physiological processes such as digestion and storage of food energy and tissue repair.

However, there seems to be a common misconception that the SNS and PNS are reciprocal and inhibitory on a systemic level, leaving an organism in either a systemically sympathetic-dominant state of “fight or flight” where parasympathetic functions are suppressed, or a systemically parasympathetic-dominant state of “rest and digest” where sympathetic functions are suppressed.

This is not the case. Rather than a seesaw, the SNS and PNS function more like an orchestra, where different internal and external landscapes require differential recruitment of the two systems on a granular level.

Sex is a great example of this. Parasympathetic activity to the genitals is required for sexual arousal (lubrication and erection), while concomitant sympathetic influence on the heart and blood vessels increases heart rate and blood pressure, and sympathetic influence on the eyes and skin causes pupil dilation and flushing or sweating. And although parasympathetic activity to the genitals is necessary for arousal, sympathetic activity is necessary to achieve orgasm and ejaculation.

Another example is postprandial (i.e. post-meal) autonomic regulation. True to its “rest and digest” designation, the PNS stimulates digestive functions in the gut and other digestive organs (like the pancreas), but that doesn’t mean the entire body is in maximum “parasympathetic mode.” On the contrary – sympathetic outflow to the heart and vasculature is increased postprandially to maintain blood pressure homeostasis. (Source 1, 2, 3) There’s even some evidence that sympathetic nervous system activation is partially responsible for the thermogenic effect of food. (Source 1, 2)

A final example is the diving reflex, which is the ANS-mediated reflex found in all mammals in response to the face being submerged. To conserve oxygen, parasympathetic nerves trigger significant bradycardia, while sympathetic nerves constrict most peripheral blood vessels to constrain blood to the heart and brain. (Source)

Even within the heart itself, sympathetic and parasympathetic activation can co-occur to accommodate specific physiological demands. For instance, during the above mentioned heart rate decrease as a result of vagal effects on the sinoatrial node, there’s also a concurrent sympathetic activation to the ventricles to increase stroke volume. (Source) (For a really interesting discussion of the diving reflex, you can check out this Scientific American article from 1963 !)

So clearly, despite the predominance of the “sympathetic = fight or flight and parasympathetic = rest and digest” dichotomy, the two divisions of the ANS operate synergistically, and with regional control rather than necessarily systemic activation.

The point is that just because whole-body states of maximal SNS or PNS activation are possible, does not mean that these two divisions operate antagonistically on a systemic level. You are not always in either “fight or flight” or “rest and digest.” Always remember that the body is complex and does not lend itself to binaries and dichotomies.

I really like the way Shaun Morrison puts it in his 2001 review Differential control of sympathetic outflow, so I’ll close with that:

Recognition of the important role of the autonomic nervous system (ANS) in coping with life-threatening challenges led to the earliest concepts of the sympathetic nervous system as a monolithic effector, activated to globally enhance organ function and substrate availability for fight or flight and to protect cerebral perfusion in the event of significant injury. In contrast, the parasympathetic component of the ANS is engaged in the aftermath of such challenges to coordinate recovery, a reduction in energy utilization, and replenishment of energy stores.

However, compared with our ancestors, modern lifestyles have all but eliminated the danger of predatory aggression, and we rarely engage the central autonomic networks developed by evolutionary pressure to cope with the most stressful challenges to homeostasis. In their stead, we are faced with the increasing awareness and prevalence of diseases such as hypertension, obesity, cardiac arrhythmia, heart failure, and diabetes, in which altered development or control of the ANS can play a significant role.

Within this framework and, importantly, with the availability of more powerful and precise electrophysiological and anatomic techniques, research on the regulation of autonomic outflow has eclipsed earlier views with an organizational model that emphasizes the differential central control of sympathetic outflows to functionally specific targets and the hierarchical interactions among defined populations of neurons that produce the patterns of autonomic efferent activity supporting behavior and reflex responses.

The focus has evolved toward an understanding of the central neural networks generating and controlling the levels of ANS activity to specific tissues, including those with noncardiovascular functions, with the recognition that the fight-or-flight response is just one of many options in an extensive repertoire of effector activation states in which the central autonomic network may exist.

Shaun Morrison. Differential control of sympathetic outflow. (2001)

References

Ernsberger, et al. The sympathies of the body: functional organization and neuronal differentiation in the peripheral sympathetic nervous system. (2021)

Goldstein, David. Principles of autonomic medicine. (Version 3) [700+ page open-source PDF written with the layperson/patient in mind]

Karemaker, John. An introduction into autonomic nervous function (2017) [this gives a wonderful sense of the complexity of the physiology of the ANS and an evolutionary perspective, and also makes a point to mark sections that reflect the author’s as-yet speculative thoughts and hypotheses vs well-accepted facts]

Low, Phillip. Overview of the Autonomic Nervous System. (2021) [this is a good basic overview if you want something simple]

Mathias and Bannister. Autonomic Failure: A Textbook of Clinical Disorders of the Autonomic Nervous System. (2013)

McCorry, Laurie Kelly. Physiology of the Autonomic Nervous System (2007)

Morrison, Shaun. Differential control of sympathetic outflow. (2001)

Mueller et al. Structural and functional connections between the autonomic nervous system, hypothalamic-pituitary-adrenal axis, and the immune system: a context and time dependent stress response network. (2022)

Sanvictores and Tadi. Neuroanatomy, Autonomic Nervous System Visceral Afferent Fibers and Pain (2021)

Waxenbaum et al. Anatomy, Autonomic Nervous System. (2021)

Wehrwein et al. Overview of the Anatomy, Physiology, and Pharmacology of the Autonomic Nervous System. (2016) [awesome awesome review, highly suggest giving it a read if you want a more complex overview than the merck manuals thing above]