The nervous system is divided into the central nervous system (CNS; consisting of the brain and spinal cord) and the peripheral nervous system (PNS; everything else—nerve roots, ganglia, peripheral nerves, etc.) [4]. The autonomic nervous system consists of two analogous parts: The central autonomic network (CAN; the central component) and the peripheral autonomic nervous system (the peripheral component) [5]. The CAN is exponentially more complex than the peripheral autonomic nervous system and is still not fully understood. We direct the interested reader to a review by Benarroch [6]. Our primary focus will be on the peripheral autonomic nervous system.

The peripheral nervous system consists of the somatic nervous system and the autonomic nervous system [4, 7]. The somatic nervous system controls “voluntary” motor function and the sensory aspects that we are aware of (e.g., sight, touch, taste, hearing). The ANS handles the “automatic” functions of the body, those that we do not have conscious thought or control over, such as regulating blood pressure and temperature, supporting digestion, and expelling waste (micturition, defecation)—i.e., maintaining homeostasis [7, 8].

The ANS has many components, with different and often overlapping functions. John Langley was the first to describe the ANS as having three parts: The parasympathetic nervous system, the sympathetic nervous system, and the enteric nervous system [9]. The parasympathetic and sympathetic systems are complementary to one another, and both interact with the enteric system. The sympathetic nervous system was later subdivided further into the sympathetic noradrenergic system (SNS), the sympathetic adrenergic system (described by Walter Cannon), and the sympathetic cholinergic system (described by Henry Dale) [3].

The sympathetic and parasympathetic systems are arranged as chains of neurons [10]. Preganglionic neurons arise from the brainstem or spinal cord and synapse on ganglionic neurons (clusters of cell bodies), whose axons then terminate in a synapse on the effector target. The effector target is most often smooth muscle associated with blood vessels or glands. While the preganglionic axons are myelinated, the postganglionic axons are unmyelinated and so have slower transmission [5, 8].

The origin of the preganglionic neurons, the location of the ganglia, the relative lengths of the pre- and post-ganglionic axons, and the effector targets and functions differ depending on whether the chain is part of the parasympathetic or sympathetic system.

The parasympathetic nervous system (PNS) is often described as promoting the “rest and digest” functions of the body. It assists in cardioinhibition (slowing the heart rate, decreasing contractility), digestion (motility, secretions), urination, erection, defecation, lacrimation, and pupillary constriction. The main neurotransmitter used in the PNS is acetylcholine [14].

The parasympathetic preganglionic neurons are of “craniosacral” origin; they arise from the brainstem and sacral spinal cord (S2-4) [8]. From the brainstem, the parasympathetic preganglionic axons travel with several cranial nerves (CN) (III, VII, IX, X) to reach their respective ganglia [7, 8]. These ganglia lie very close to their targets, making the preganglionic axon very long and the postganglionic axon very short. The cranial parasympathetic ganglia are all named. The cranial components of the parasympathetic nervous system are listed in Table 1 (Ref. [1, 3, 4, 8, 10]).

The pre-ganglionic axons travelling with CN III arise from the Edinger-Westphal nucleus in the midbrain [8, 10]. These axons exit the skull through the superior orbital fissure and synapse on the ciliary ganglion in the posterior orbit; the post-ganglionic axons travel with the short ciliary nerves and terminate on the iris sphincter muscle (causing pupillary constriction, “miosis”) and the ciliary muscle (contracting the lens, “accommodation”) [7]. Sensory branches (from the nasociliary nerve, supplying the cornea, iris, and ciliary body) and sympathetic postganglionic axons also travel through the ciliary ganglion but do not synapse there [2].

The pre-ganglionic axons travelling with CN VII arise from the superior salivatory nucleus in the pons. These axons travel with a branch of CN VII (nervus intermedius) and synapse on the pterygopalatine ganglion (via the greater petrosal nerve) and the submandibular ganglion (via chorda tympani and lingual nerves) [2, 7].

The post-ganglionic axons from the pterygopalatine ganglion terminate on the lacrimal gland and mucosa and/or glands of the paranasal sinuses, nasal cavity, pharynx, gingiva, and hard palate—triggering secretion in all of these. Sensory branches (from the maxillary branch of the trigeminal nerve) and sympathetic postganglionic axons also travel through this ganglion but do not synapse within it [2, 7].

The post-ganglionic axons from the submandibular ganglion terminate on the submandibular, sublingual, and lingual glands, also triggering secretion [2, 8].

The preganglionic axons travelling with CN IX arise from the inferior salivatory nucleus in the pons [8]. These axons synapse on the otic ganglion (near the foramen ovale), and the post-ganglionic nerves terminate on the parotid gland, triggering salivation. Sensory fibers (via the auriculotemporal nerve, providing sensation to the parotid gland), sympathetic fibers, and motor fibers (supplying tensor tympani, tensor veli palatini, and medial pterygoid) also pass through this ganglion without synapsing [2].

The dorsal motor nucleus and the nucleus ambiguous give rise to the parasympathetic nerves of CN X (Vagus nerve). The ganglia where they synapse are on or near their thoracic or abdominal targets. The dorsal motor nucleus innervates primarily the gastrointestinal (GI) system, aiding in motility and digestion from the esophagus through the first half of the large intestine [8]. The nucleus ambiguus innervates primarily the heart, providing beat-to-beat heart rate control [2].

Broadly speaking the sympathetic nervous system oversees the “fight or flight or freeze” responses and is the complementary system to the parasympathetic nervous system’s “rest and digest”. The sympathetic nervous system has been described as having three components [3], depending on which neurotransmitter is used at the effector: The SNS, the sympathetic cholinergic system, and the sympathetic adrenergic system. The three components of the sympathetic system utilize different neurotransmitters, have different targets, and so have different effects.

The sympathetic systems arise from the interomediolateral columns of the thoracic and lumbar regions of the spinal cord (T1-L2) [8]. The preganglionic axons leave the spinal canal through the anterior root, through the anterior rami and white rami connectors, and then enter the sympathetic ganglia. There are paravertebral, prevertebral, and previsceral sympathetic ganglia [7, 14].

The paravertebral ganglia are mostly unnamed and exist as an ordered chain that runs parallel on either side of the spinal column [10]. Preganglionic sympathetic axons can synapse directly at their level of entry into this chain; can ascend or descend to a different level and synapse there; or can pass through without synapsing [8]. The paravertebral sympathetic ganglia include three cervical (superior, middle, and inferior), 10–12 thoracic, four lumbar, and four to five sacral ganglia [10, 14].

The superior cervical ganglia are adjacent to C2-3; postganglionic axons arising from here travel with the carotid arteries to supply the head and neck, as well as heart [10]. The middle cervical ganglia lie adjacent to C6; postganglionic axons from here travel to the heart and neck. The inferior cervical ganglia can exist as a standalone structure or can be fused with the first thoracic ganglion (and then called the stellate ganglion). It is adjacent to C7. Postganglionic axons from here provide innervation to the lower neck, heart, arm, and posterior cranial arteries [2].

The prevertebral ganglia lie midline, anterior to the aorta. These include the celiac, aortico-renal, and mesenteric ganglia. The celiac ganglia provide innervation to the stomach, liver, gallbladder, spleen, kidney, ovaries, and parts of the colon (ascending and transverse). The mesenteric ganglia also provide innervation to the GI system, including the small intestine and parts of the colon (ascending and transverse) [2].

Just as in the parasympathetic system, the preganglionic axons of the sympathetic system are myelinated while the postganglionic axons are unmyelinated [8]. As the myelinated preganglionic axons of the sympathetic system are short, synapsing almost immediately on their respective ganglia, the unmyelinated postganglionic axons will stretch longer distances throughout the body to terminate on their ultimate targets. This contrasts to the parasympathetic system, where preganglionic myelinated axons are much longer, and postganglionic unmyelinated axons are shorter. This myelinated versus unmyelinated concept is important as it could have clinical implications. As a larger proportion of the sympathetic pathway is unmyelinated, it can be more vulnerable to metabolic insults (like hyperglycemia) than the parasympathetic system.

The SNS uses acetylcholine at its ganglionic synapse (as do all components of the ANS) but at its final target uses norepinephrine [4]. Targets of the SNS include the smooth muscle in blood vessel walls (leading to vasoconstriction and increased blood pressure), the heart (increasing heart rate and force of contractility), and the iris constrictor (pupil dilation) [3].

The sympathetic cholinergic system uses acetylcholine as its sole neurotransmitter, in both the ganglionic synapse and at the final target (sweat glands). This system is involved in thermoregulation and, when activated, will cause sweating to cool the body [3].

The sympathetic adrenergic system is a special case. The preganglionic neurons that are part of this system do not synapse on any of the sympathetic ganglia; they pass through the ganglia without synapsing, ultimately making their way to the adrenal gland, where they synapse on chromaffin cells of the adrenal medulla, using acetylcholine as the neurotransmitter [1, 3]. When activated, this will trigger the release of primarily epinephrine. Epinephrine enters the blood stream and circulates widely throughout the body, acting on any adrenergic receptor it comes across. This is the only system of the ANS that uses this type of hormonal transmission. Epinephrine can act on the adrenergic receptors in the blood vessel walls (leading to vasoconstriction and increased blood pressure), the heart (increasing heart rate and contractility), the pupil (leading to pupil dilation), the liver (triggering glycogenolysis), and sweating of the palms, soles, etc. [3].

As a final side note: There are postganglionic sympathetic nerves that have targets in the kidney; these postganglionic neurons release dopamine and control the rate of blood filtration in the kidney [2].

With the exception of the final step of the sympathetic adrenergic system, the parasympathetic and sympathetic systems use neurotransmitters acting at nearby targets for local effects [3]. Neurotransmitters are stored within vesicles inside the cell. When it is time for their release, the vesicle will move towards the cell membrane and then fuse with the membrane via the help of a soluble NSF attachment protein receptor (SNARE) complex [3]. The SNARE complex is made of many different proteins (including SNAP, syntaxin, and synaptobrevin); it attaches to the vesicle and pulls it closer to the membrane. Once the vesicle has fused with the membrane, an opening (pore) forms, and the neurotransmitter contents are expelled into the synaptic terminal [3].

The primary neurotransmitters used in the ANS are acetylcholine, norepinephrine, and epinephrine. Table 2 (Ref. [1, 2, 3, 4, 10]) depicts an overview of the different neurotransmitters of the autonomic nervous system.

Acetylcholine serves as the primary neurotransmitter within all autonomic ganglia, within the adrenal gland (SAS), and at the final target synapses of the PNS and sympathetic cholinergic system. Acetylcholine is made within the cytoplasm of cholinergic neurons, using choline and acetyl coenzyme A, via choline acetyltransferase. The acetylcholine is then transported into vesicles via VAChT (vesicular acetylcholine transporter) [31]. This transporter’s function depends on an ATP-fueled proton gradient; as protons leak from the (acidic) vesicle, acetylcholine will enter. After release into the synaptic junction, acetylcholine is rapidly metabolized by AChE (acetylcholinesterase), regenerating both acetate and choline. The metabolism of acetylcholine is so efficient that there is essentially no leakage of it outside of the synapse, meaning it cannot be measured in the blood as other neurotransmitters can [3].

The neurotransmitters norepinephrine and epinephrine, and their predecessor dopamine, arise from the amino acid tyrosine [3].

Tyrosine $\to$ DOPA (3,4-dihydroxyphenylalanine)$\to$ Dopamine $\to$ Norepinephrine $\to$ Epinephrine

In the cytoplasm of dopaminergic and noradrenergic neurons, tyrosine is converted to DOPA via tyrosine hydroxylase in a reaction that requires oxygen, iron, and tetrahydrobiopterin (BH4). DOPA is then converted to dopamine via L-aromatic amino acid decarboxylase (LAAAD or dopa decarboxylase), which requires vitamin B6 [3].

In the noradrenergic neurons in the brain, CNS, and adrenal medulla, after conversion from DOPA to dopamine, the dopamine is then transported into a vesicle via type II vesicular monoamine transporter (VMAT 2). As with the acetylcholine transporter, VMAT 2 depends on an ATP-fueled proton gradient; as protons leave the acidic vesicle, dopamine enters. Inside the vesicle, dopamine is converted to norepinephrine via dopamine beta-hydroxylase, which requires copper, vitamin C, and oxygen [3].

After norepinephrine is released at the synaptic terminal, it is recycled and re-enters the cytoplasm via the norepinephrine transporter (NET). Inside the cytoplasm, it is either reloaded into the vesicle via vesicular monoamine transporter 2 (VMAT2) or is metabolized by monoamine oxidase (MAO, on the outer mitochondrial membrane) [3].

In the adrenergic cells of the adrenal medulla, norepinephrine will either leak from vesicles or will be taken up from outside the cell via norepinephrine transporter (NET) on the cell membrane. phenylethanolamine N methyoltransferase (PNMT), a cytoplasmic enzyme, then converts norepinephrine to epinephrine. Inside the adrenal gland, epinephrine and norepinephrine are metabolized to metanephrine and normetanephrine, respectively [3].

The recycling and metabolism of norepinephrine and epinephrine are not as effective as acetylcholine metabolism. Because of this, norepinephrine and epinephrine are measurable in the blood.

The primary receptors of the ANS are adrenergic and cholinergic receptors [2].

Cholinergic receptors can be nicotinic or muscarinic.

The preganglionic neurons of parasympathetic and sympathetic systems are all cholinergic, releasing acetylcholine onto nicotinic receptors of the autonomic ganglia (or the adrenal gland for the SAS). The parasympathetic ganglionic neurons are also cholinergic, releasing acetylcholine onto the muscarinic receptors of their targets. There are 5 types of muscarinic receptors: M1, M2, M3, M4, and M5 that are distributed throughout the central and peripheral nervous system. Most cells will have multiple receptor subtypes [2]. Muscarinic receptors can give excitatory or inhibitory responses. All five receptor subtypes are present in the brain, which could explain the cognitive effects of anticholinergic agents [40, 41, 42, 43]. The various muscarinic receptor locations and actions are listed in Table 3 (Ref. [2, 14, 44, 45, 46]).

The sympathetic ganglionic nerves can be cholinergic or adrenergic.

In the sympathetic cholinergic system, the ganglionic neurons release acetylcholine which acts on muscarinic receptors. M3 receptors are present in sweat glands and, when activated, increase sweating [2]. The sympathetic cholinergic system is activated in thermoregulatory conditions to keep the body from overheating.

The sympathetic adrenergic and noradrenergic system utilize adrenergic receptors [2, 3]. Adrenergic receptors can be alpha ($\alpha$1, $\alpha$2) and beta ($\beta$1, $\beta$2, $\beta$3). Stimulation of $\alpha$1 receptors leads to increased activity at the target; stimulation of $\alpha$2receptors leads to decreased activity at the target.

$\alpha$1receptors are located on the iris (leading to pupil dilation), vessels in skeletal muscle, skin, cranium, and viscera (constriction), bladder neck (urine retention), and erectile tissue and vas deferens (ejaculation) [2, 3].

$\alpha$2 receptors are located throughout the GI system (inhibiting secretions) and on the presynaptic terminals of sympathetic noradrenergic nerves (inhibitory autoreceptors) and parasympathetic cholinergic nerves (reducing AcH release) [2, 3].

$\beta$1 receptors are located in the heart (increasing heart rate and contractility). $\beta$2 receptors are in the bronchi (bronchodilation), skeletal muscle vessels (vasodilation), GI system (inhibiting motility), the bladder detrusor (relaxing muscle, urine retention), and rectal smooth muscle (relaxing muscle, inhibiting defecation). $\beta$3receptors are also in the bladder wall (relaxing muscle, inhibiting micturition) [2, 3].

In the SNS, ganglionic neurons release norepinephrine which acts on adrenergic receptors. Norepinephrine will act on both alpha receptors ($\alpha$1, $\alpha$2) and the $\beta$2 receptor. The SNS is activated primarily with orthostatic stress (standing) [2, 3].

The end result of activation of the sympathetic adrenergic system is release of epinephrine into the circulation. Epinephrine is distributed widely throughout the body and can activate any of the adrenergic receptors [3]. The sympathetic adrenergic system is activated in situations that stress the body physically (hypoglycemia, hypotension, exercise, hypothermia) or emotionally. Epinephrine release causes constriction of blood vessels in the skin, conserving heat and causing the characteristic “paleness” someone can have with overactivation of this system. Epinephrine will also lead to breakdown of glycogen, increasing serum glucose [47].

Though they have competing functions, the PNS and SNS do not function antagonistically. Rather, they work synergistically to maintain homeostasis. One of the best examples of this is the regulation of blood pressure.

Blood pressure is one of the most tightly controlled variables in the body, as it determines the amount of blood flow to each organ. Blood pressure can be neither too high nor too low or else the brain and other organs could be damaged. The ANS monitors blood pressure (particularly cerebral blood flow) via baroreceptors. Baroreceptors are stretch-sensitive pressure sensors; there are arterial and venous baroreceptors, and both are activated via distortion.

Arterial baroreceptors are sensitive to high pressure; they are located within the carotid sinus (in the carotid wall at the bifurcation of the common carotid artery) and in the aortic arch [1, 48]. When blood pressure is elevated outside of the desired range, there is increased stretch of the arterial walls, leading to distortion (and increased firing) of these baroreceptors. This information travels with CN IX (from the carotid sinus) and CN X (from the aortic arch) to the Solitary Nucleus in the medulla [1, 48]. This leads to inhibition of the sympathetic nervous system (via inhibition of rostral ventrolateral medulla, which normally tonically activates the sympathetic system) and activation of the parasympathetic nervous system (via CN X)—causing a decrease in heart rate, decrease in vasoconstriction, decrease in heart rate contractility, and so a decrease in blood pressure. As blood pressure drops, there is less distortion (and less firing) of the baroreceptors. There is less activation of the Solitary Nucleus, leading to disinhibition of the RVLM, increasing sympathetic innervation and activity.

If blood pressure drops too low, the venous baroreceptors are activated. These are low pressure-sensitive baroreceptors in the large veins and atria. When these are activated, there will be an increase in the secretion of antidiuretic hormone (ADH), renin, and aldosterone. These will increase fluid retention, increasing blood volume, increasing blood pressure.

If any part of the ANS malfunctions—whether by overactivity or underactivity—symptoms will arise. The ANS can be affected by medications or disease processes. Sometimes, though, in cases of “autonomic dysfunction”, the autonomic nervous system itself is intact; it is merely responding to deleterious stimuli. The ANS does not discern between different etiologies of a stimulus; it will respond to a given stimulus in the same way, no matter the cause. For instance, if someone has tachycardia upon standing, there can be a tendency to blame the ANS for “malfunctioning”. However, there are many physiologic reasons the ANS could be overactive:

- With dehydration, when someone stands, their blood pressure will drop, activating the sympathetic system and increasing norepinephrine which will cause a rise in the heart rate. This is not a pathologic response. This is a compensatory response to support the blood pressure.

- With heart failure, cardiac contractility can be reduced so that when someone stands, blood pressure falls, activating the sympathetic system, increasing norepinephrine and heart rate. Again, this is a compensatory response to support blood pressure.

- If someone is in pain when they stand, the pain and emotional stress will activate the sympathetic system, increasing heart rate.

- If someone is sufficiently anxious, then emotional stress can also activate the sympathetic system, increasing heart rate.

In none of these scenarios is the ANS “malfunctioning”. The ANS is responding, as it should, to different stimuli—hypotension, stress, and pain. The sources of the stimuli, in these instances, are the pathologic processes and are what should be addressed. Treating only the symptoms (i.e., giving beta blockers to control tachycardia) would not fix the underlying problem; it would only suppress the messenger, the ANS.

When the parasympathetic nervous system is overactive, there can be miosis (worsening night vision), increased lacrimation, hypersalivation, GI distress (diarrhea, vomiting), bronchoconstriction, bradycardia, urination, erection, and increase in gastric acid and insulin secretion [1, 3].

When the parasympathetic nervous system is underactive (parasympathetic failure), there can be dry eye and mouth, mydriasis (photophobia), bronchodilation, constipation, urinary retention, erectile failure, and a constant heart rate without variability [1, 3].

When the sympathetic system is overactive, there can be hyperhidrosis, pallor, mydriasis (photophobia), hypertension, tachycardia, constipation, bronchodilation, and tremor [1, 3].

If the sympathetic system is underactive (sympathetic failure), there can be hypohidrosis, ptosis, miosis (worsening night vision), and orthostatic hypotension [1, 3].

The enteric system is the lesser known of the three main divisions of the ANS. The enteric system can function independently but is also affected by the parasympathetic and sympathetic systems.

Neurons of the enteric system surround the entire GI tract (from esophagus to anus) and control GI motility and secretion. The myenteric plexus (Auerbach’s plexus) runs within the layers of the muscularis. The submucosal plexus (Meissner’s plexus) runs within the submucosa beneath the muscularis. Many neurotransmitters are used in the enteric system, including acetylcholine, dopamine, and serotonin.

The CAN is exponentially more complex than the peripheral autonomic nervous system and is not fully understood. In brief, the CAN regulates the outflow of information to the ANS—increasing or decreasing activation of its component parts in response to various stimuli. There are cortical centers (prefrontal cortex, anterior and midcingulate cortex, and insular cortex), subcortical centers (central nucleus of the amygdala, paraventricular nucleus of the hypothalamus); and brainstem centers (periaqueductal gray in the midbrain, parabrachial nucleus at the junction of the midbrain/pons, locus coeruleus in the dorsal pons, raphe nuclei in the rostral ventrolateral medulla, dorsal motor nucleus of the vagus, nucleus ambiguous, and nucleus of the solitary tract in the medulla) [1, 5].