Primer on the Autonomic Nervous System

By Italo Biaggioni and Phillip A. Low

Primer on the Autonomic Nervous System, Fourth Edition provides a concise and accessible overview of autonomic neuroscience for students, scientists, and clinicians. The book's 142 chapters draw on the expertise of more than 215 basic scientists and clinicians who discuss key information on how the autonomic nervous system controls the body, particularly in response to stress. This new edition also focuses on the translational crossover between basic and clinical research. In addition to comprehensively covering all aspects of autonomic physiology and pathology, topics such as psychopharmacology decoding and modulating nerve function are also explored.

• Provides concise and practical information on the autonomic nervous system
• Discusses all aspects of autonomic physiology and pathology
• Contains new content on psychopharmacology and modulating nerve function

• Language: English
• Publisher: Academic Press
• Release date: Dec 7, 2022
• ISBN: 9780323854931

Book preview

Section I

Introduction

Outline

Chapter 1. Evolution of the cardiovascular autonomic nervous system in vertebrates

Chapter 2. Central autonomic control

Chapter 3. Peripheral autonomic nervous system

Chapter 1: Evolution of the cardiovascular autonomic nervous system in vertebrates

Tobias Wang ¹ , Renato Filogonio ² , and William Joyce ¹       ¹ Zoophysiology, Department of Biological Sciences, Aarhus University, Aarhus, Denmark      ² Department of Physiological Sciences, Federal University of São Carlos (UFSCar), São Carlos, SP, Brazil

Abstract

The foundations of the autonomic nervous system evolved prior to the appearance of vertebrates and, while rudimentary, there is a division between the parasympathetic and sympathetic systems even in the earliest diverging vertebrates. The dual autonomic innervation of the heart and vasculature, however, did not appear until the evolution of cartilaginous fishes. Within tetrapods, the autonomic innervation of the cardiovascular system is well conserved, but most ectothermic air-breathing vertebrates differ from mammals by having an undivided ventricle and exhibit cardiac shunts that are largely regulated by the parasympathetic nervous system.

Keywords

Adrenergic receptors; Cardiac shunt; Cardiorespiratory interaction; Evolution; Muscarinic receptors; Pulmonary circulation; Respiratory sinus arrhythmia

The need for coordinated control of visceral functions to maintain homeostasis has undoubtedly been of paramount importance in the early evolution of animals, so it is not surprising that a functional analogy of the autonomic nervous system (ANS) has an ancient evolutionary history. Because of the shared evolutionary history of all vertebrates, studies on different animal groups provide fundamental insight to the foundations of both anatomy and function of the ANS in mammals, including humans.

Many of the basic functions of the ANS were originally discovered in ectothermic vertebrates. As prominent examples, Gaskell's demonstrations of the vagal inhibitory role on the heart were performed on turtles and frogs, and Loewi's demonstration of acethylcholine being the postganglionic neurotransmitter within the parasympathetic nervous system (vagus stoff) was based on studies identified in amphibians. These species were probably chosen as animal models because of their extraordinary tolerance to hypoxia and low temperatures, rendering them resilient to experimentation and hence suitable for physiological studies before methods for anesthesia and mechanical ventilation were developed. More recently, studies on ANS functions in ectothermic vertebrates were crucial for the discovery of nonadrenergic noncholinergic neurotransmitters within the sympathetic and parasympathetic nervous systems.

The autonomic nervous system in vertebrates

A phylogeny depicting extant (living) groups of chordates (animals that have a notochord during some stage within their life cycle) is shown in Fig. 1.1, where the vertebrate groups, i.e., animals with skeletal elements surrounding the spinal cord and notochord, are highlighted within the gray box. While tunicates and amphioxus are endowed with a nervous system that resembles the enteric nervous system, the equivalent of an ANS is not present.

The ANS in hagfishes and lampreys is rudimentary with some organs being devoid of innervation, while others lack the dual innervation. In both groups, the left and right vagi unite to form a ramus intestinalis impar that innervates the intestine and the gallbladder. In hagfishes, the ramus intestinalis impar does not reach the heart, whereas the heart of lampreys is vagally innervated. In both hagfishes and lampreys, spinal sympathetic nerves leave the dorsal as well as the ventral spinal nerves, but there are no sympathetic chains or segmental ganglia. The sympathetic nerves innervate several visceral organs, but not the heart. Hagfishes and lampreys have obviously evolved independently over the past several hundred millions years and are therefore unlikely to represent exact copies of the ancestors to extant vertebrates. The eyes of both groups, for example, are degenerated, which may relate to the poor innervation by the ocular nerve. Nevertheless, it seems reasonable to conclude that the ANS was poorly developed in early vertebrates.

Sharks and rays (cartilaginous fishes) have segmentally arranged paravertebral ganglia that are linked by a loose plexus of nerve fibers. The vast majority of the fibers arise from the ventral roots of the spinal nerves. These sympathetic nerves innervate most visceral organs with the notable exception of the heart, and do not appear to enter the head. Cranial autonomic fibers, i.e., the parasympathetic nervous system, occur within the oculomotor (III), facial (VII), glossopharyngeal (IX), and vagus (X) nerves. The vagal fibers reach the stomach and the anterior parts of the intestine. The vagus also innervates the heart and exerts both negative chronotropic and inotropic effects.

Figure 1.1  A phylogeny of the major groups of extant (i.e., living) craniates and vertebrates. Note that only birds and mammals are endothermic and that this trait appears to have evolved independently from two different groups of reptilian and ectothermic ancestors. The figure includes a synopsis of the parasympathetic and sympathetic innervations of the heart and vasculature.

In bony fishes (a group largely comprising of teleosts), the sympathetic chain ganglia are well developed and form distinct sympathetic chains. Some of these sympathetic fibers join the vagus, creating a vagosympathetic trunk. This is also the case in amphibians and reptiles. The overall pattern of innervation and the actions of the autonomic nervous system in bony fishes resemble that found in amphibians, reptiles, birds, and mammals (i.e., the tetrapods). Therefore, while the ANS of early vertebrates can be considered simple in comparison to subsequent groups of vertebrates, the basic foundations of the ANS were established in fishes and evolved prior to the invasion of terrestrial habitats. The swim bladder of bony fishes controls buoyancy, but probably evolved originally as a gas exchange organ, and is therefore considered homologous to the lungs of lungfish and tetrapods. Both lungs and swim bladder form embryologically as an outpocketing of the gut; the swimbladder as a ventral extension, while the lungs derive from a dorsal extension. Both organs receive a dual innervation from the ANS in most species.

Anatomy of the cardiovascular system in vertebrates

As shown in Fig. 1.2, the morphology of the heart and cardiovascular systems of vertebrates have undergone large evolutionary changes associated with the transition between water and air-breathing and during the evolution of endothermy within mammals and birds. Thus, while the cardiac morphology, the number of gill arches, and other characters differ considerably between these groups, they all rely on gills for gas exchange. With some variations, the hearts of all fish consist of a sinus venosus, a single atrium and a single ventricle as well as an outflow tract that may be both muscular and contractile as the conus arteriosus in sharks. The heart ejects the oxygen-poor blood that has returned from the body toward the gills, where the blood is oxygenated before it is delivered to the body. The branchial circulation and the perfusion of the systemic vascular beds of fish, therefore, occur in series and the emergence of parallel circulations arose with evolution of the lungs.

In lungfishes (Dipnoi), the first group of vertebrates with real lungs, the common pulmonary vein draining the lungs empties into the sinus venosus in close proximity to the atrium. The single trabeculated atrium is partially divided by a fold that prevents admixture of the oxygen-rich blood from the lungs and oxygen-poor blood from the systemic circulation. The oxygen-poor blood is preferentially directed through the posterior gill arches and can either enter the pulmonary artery or the dorsal aorta after having perfused the gills. The oxygen-rich blood primarily enters the anterior and degenerated gill arches to enter the dorsal aorta directly.

In amphibians and most reptiles (i.e., snakes, lizards and turtles), there are two separate atria receiving the venous blood from the systemic and pulmonary circulations. While the ventricular anatomy differs enormously among these groups, they are characterized by having a single ventricle, but distinct outflows to either the systemic or pulmonary circulations. In reptiles, the systemic circulation is served by two major vessels emanating from the heart; the left and right aortic arches. In crocodiles, which are more closely related to birds than the other reptiles, a complete septum divides the ventricle, but because the left aorta arises from the right ventricle, blood can bypass the pulmonary circulation. Birds have a cardiac anatomy that closely resembles mammals, but an independent evolution of the divided ventricle is indicated by birds retaining the right aortic arch during ontogenetic development, whereas mammals retain the left aortic arch.

Figure 1.2  The evolution of the cardiovascular system among the major groups of extant vertebrates. In this representation, the cardiovascular design of hagfish, lampreys as well as the cartilaginous and bony fishes are presented as a general piscine design. Note that only mammals and crocodiles have a complete division of the ventricle and that lungfishes, amphibians, and reptiles have the capacity to mix oxygen-rich and oxygen-poor blood within the ventricle. Modified from Jensen B, Nielsen JM, Axelsson M, Pedersen M, Löfman C, Wang T. How the python heart separates pulmonary and systemic blood pressures and blood flows. J Exp Biol. 2010;213:1611–1617.

Autonomic regulation of the heart

The aneural myogenic hagfish heart is devoid of any innervation and is remarkably insensitive to acetylcholine or cholinergic antagonists. The hagfish heart, nevertheless, is under a tonic paracrine β-adrenergic tone that seems to derive from catecholamine stores within the heart. It remains uncertain whether the cardiac release of catecholamines and hence the adrenergic tone is regulated. Heart rate increases markedly upon increased filling, a response that is independent of adrenergic stimulation and this may be important to increase cardiac output when venous return is elevated. The mechanism underlying this response remains to be understood. Hagfish inhabit hypoxic sediments and exhibit a marked tolerance to oxygen deprivation, associated with a pronounced reduction in heart rate that may be the direct effect of lack of oxygen on the pacemaker cells. Consistent with the lack of innervation, hagfish exhibit only small changes in heart rate during exercise.

Lampreys represent the first group of chordates with a vagal innervation of the heart, where the vagus travels along the jugular vein to the sinus venosus where the primary pacemaker region is located. This innervation, however, differs fundamentally from the rest of the vertebrates by being excitatory and that cardiac acceleration can be blocked by nicotinic cholinoceptor antagonists. Although there is no sympathetic innervation, the lamprey heart, nevertheless, exhibits positive inotropic and chronotropic responses to β-adrenergic stimulation and heart rate. As in hagfish, catecholamines are released in a paracrine fashion from cardiac stores in lampreys and increased filling of the heart also causes tachycardia.

The typical inhibitory action of the vagus nerve did not appear until the evolution of cartilaginous fishes, while the opposing role of an excitatory sympathetic innervation evolved later, but before the divergence of bony fishes. This cardiac innervation has remained the same within all subsequent groups of vertebrates. Interestingly, although the lungfish heart lacks sympathetic innervation, it does respond with increased rate and contractility to β-adrenergic stimulation originating from catecholamines stored within the heart.

Innervation of the systemic vasculature

In tunicates and Amphioxus, the endothelium within the blood vessel is either very poorly developed or absent, and there is no endothelial innervation among protostomes. Also there is no evidence for adrenergic receptors affecting vascular tone. Sympathetic nerves appear to be present in both hagfish and lampreys, and the systemic vasculature responds to adrenergic agonists as well as acetylcholine. In all other groups of vertebrates, there are both α- and β-adrenergic receptors causing constriction and dilatation, respectively. This innervation is present on both the arterial and venous sides of the circulatory system, but very little is known about putative difference between the different vascular beds to specific organs. The sympathetic innervation therefore is involved in both blood pressure regulation and regulation of venous tone and cardiac filling. The endothelium of ectothermic vertebrates releases nitric oxide as in mammals, but endothelial nitric oxide synthase (eNOS) only seems to have evolved in tetrapods, so neural NOS is responsible for NO production in the endothelium of fish.

Autonomic regulation of the pulmonary circulation

Lungs and the pulmonary circulation evolved prior to the separation of the ventricle by a complete ventricular septum that is a characteristic of mammals and birds (Fig. 1.2). The ventricle in lungfish, amphibians, snakes, lizards, and turtles, accordingly, is not fully divided and, with very few exceptions, systolic blood pressures in the systemic and pulmonary circulations are identical. α and β adrenergic receptors seem to be mostly responsible for vascular tonus in ectotherms. Vagal innervation is widespread at the reptilian pulmonary arterial tree and, with the exception of the pulmonary truncus in squamates, causes strong vasoconstriction. Differences in the muscarinic receptor expression (M1 and M3) within the different regions of the pulmonary artery may indicate functional specialization, where the extrinsic region to the pulmonary artery is likely to regulate overall pulmonary blood flow, while regulation of the intrinsic arteries are likely to be involved in the matching of local ventilation and perfusion. In mammals and birds, this vagal regulation of pulmonary blood vascular resistance is not present.

Cardiorespiratory integration and respiratory sinus arrythmia

Heart rate typically exhibits beat-to-beat variations termed heart rate variability (HRV), which is the consequence of multiple regulatory mechanisms (both autonomic and nonadrenergic, noncholinergic) acting concomitantly at the cardiac pacemaker. One of the most important stimulations affecting HRV is the respiratory rhythm, when heart rate increases immediately at the onset of inspiration. This phenomenon is known as the respiratory sinus arrythmia (RSA), and is observable in all vertebrate classes.

Figure 1.3  The cardiovascular changes in a freshwater turtle (Trachemys scripta) during the transition from apnea to ventilation of the lungs. Heart rate and pulmonary blood flow are low during breathholding (apnea), but increase markedly during ventilation associated with a change in the cardiac shunt pattern. Modified from Wang T, Hicks JW. Cardiorespiratory synchrony in turtles. J Exp Biol. 1996;199:1791–1800.

Efferent vagal activity in the heart occurs by cardiac vagal preganglionic neurons (CVPN) originating from two main regions in the brainstem: (i) the dorsal motor nucleus of the vagus (DVN), from where slow-conducting C-fibers originate; (ii) the nucleus ambiguus (NA), from where fast-conducting myelinated B-fibers originate. In ectotherms, these CVPN occupy a ventrolateral region analogous to the mammalian NA. During inspiration, the CVPN at the NA are silenced and the vagal tone withdrawn, causing an immediate tachycardia. The fast-conducting nature of the fibers in this region allows for the fast coupling between respiration and changes in heart rate.

In reptiles, the pulmonary blood flow also increases during ventilation due to a reduction in the pulmonary vascular resistance after vagal withdrawal. Interestingly, the vagal preganglionic neurons from the pulmonary artery originate from the same two regions of the brainstem occupied by the CVPN. This suggests that the RSA is orchestrated with the transient changes in pulmonary blood flow by vagal neurons occupying the same region in the brainstem.

In organisms lacking intraventricular septation, this mechanism promotes varying degrees of admixture between oxygen-rich blood from the lungs with oxygen-poor blood returning from the systemic circulation. As in the example presented in Fig. 1.3, where blood flows were recorded in a freshwater turtle, the degree of mixing of oxygen-rich and oxygen-poor blood within the ventricle as well as the distribution of blood flows between the systemic and pulmonary circulations changes consistently with pulmonary ventilation Thus, during apnea, which in turtles and other diving species can last for more than 1hour, heart rate and pulmonary blood flow are low and much of the oxygen poor blood returns directly into the systemic circulation (i.e., a large right-to-left cardiac shunt). As soon as pulmonary ventilation resumes, pulmonary blood flow and heart rate then increase abruptly, while systemic blood flow is less affected. In several species of reptiles and amphibians, pulmonary blood flow exceeds systemic blood flow during ventilation, implying that a significant fraction of the blood returning from the lungs is returned directly to the pulmonary circulation (i.e., a left-to-right cardiac shunt). While the changes in cardiac shunt pattern act to provide a temporal matching of pulmonary ventilation and perfusion, the functional significance of these cardiovascular changes remains to be understood.

The degree of oxygenated and deoxygenated blood mixing and the distribution of blood flows between the systemic and pulmonary circulations are dictated by the vascular resistance in the lungs and body. Thus, when pulmonary vascular resistance is low compared to the systemic circulation, blood will primarily be distributed toward the lungs and vice versa. The resistance of the pulmonary circulation is regulated by the ANS, where vagal innervation of smooth muscle in the pulmonary artery can cause constriction and reduce pulmonary blood flow.

The evolution of adrenergic and muscarinic receptors

The neurotransmitters of the autonomic nervous system exert their actions by binding to a variety of adrenergic or cholinergic receptor subtypes. The many receptor subtypes have mainly arisen from whole genome duplication events that provided a major source for genetic diversity in vertebrate evolution. Two whole genome duplications occurred in the earliest vertebrates, after the separation of tunicates and the vertebrate lineage. It remains debated when these duplications occurred with respect to the divergence of hagfishes and lampreys (the cyclostomes), where gene sequences of the receptors have been particularly troublesome to resolve. We therefore focus on the origin and evolution of the major receptor subtypes in gnathostome vertebrate (i.e., sharks, fishes, and tetrapods), where the evolution of β-adrenergic receptors (β-ARs), α-adrenergic receptors (α-ARs), and muscarinic cholinergic receptors (mAChRs) has been recently elucidated using phylogenetic methods.

Figure 1.4  A simplified chordate cladogram showing how whole genome duplications have shaped the autonomic receptor (AR) subtype repertoire in modern vertebrates. Gene duplication and loss (crossed boxes) shown for β-adrenergic receptors (ADRB), α1-and α2-adrenergic receptors (ADRA1 and ADRA2), and cholinergic muscarinic receptors (CHRM). Based on Céspedes, HA, Zavala, K, Vandewege MW, Opazo JC. Evolution of the α2-adrenoreceptors in vertebrates: ADRA2D is absent in mammals and crocodiles. Gen Comp Endocrinol. 2017; 250:85–94; Pedersen JE, Bergqvist CA, Larhammar, D. Evolution of the muscarinic acetylcholine receptors in vertebrates. 2018; eNeuro 5, ENEURO.0340-18.2018; Zavala K, Vandewege MW, Hoffmann FG, Opazo JC. Evolution of the β-adrenoreceptors in vertebrates. Gen Comp Endocrinol. 2017;240:129–137.

The predecessor of vertebrates likely possessed the equivalent to one β-AR, two α-ARs (i.e., α1-AR and α2-AR), and two mAChRs (Fig. 1.4). After the two whole genome duplications, the number of genes for each receptor quadrupled, but many copies were rapidly lost, such as the fourth β-AR, meaning that the last common ancestor of gnathostome vertebrate had the same three β-ARs that exist today (β1-AR, β2-AR, and β3-AR). Similarly, only five of the eight mAChRs were fixed. These receptor subtypes have persisted in most extant lineages and have acquired specific, but often complementary, functions (sub/neofunctionalization). For instance, all three β-ARs may be expressed in the myocardium, but their influence on contractility vary greatly between species. Some of the genes show lineage specific losses, and sometimes convergency can be observed such as the independent disappearance of α2D-AR in both crocodiles and mammals.

There is strong evidence for a third whole genome duplication event in teleost fish, resulting in paralogs within each receptor subclass. For example, the zebrafish genome contains both β2a and β2b as well as β3a and β3b subtypes, although the second β1 gene was lost. Researchers studying autonomic control in fish models, such as zebrafish, should be aware of the pitfalls, as well as potential advantages associated with the additional receptor diversity in teleosts.

Cardiovascular responses to altered pressure, exercise, and hypoxia

A barostatic regulation of heart rate mediated through the ANS is present in fishes. Being aquatic, the circulatory system of fishes is not influenced by gravity; and blood pressure control therefore seems to have evolved prior to any orthostatic pressure changes. The ancestral evolutionary benefit of an inhibitory vagal effect on heart rate and an opposing positive chronotropic and inotropic responses from sympathetic stimulation (or release of catecholamines) is likely to have been the ability to accommodate changes in metabolism with appropriate changes in heart rate and stroke volume, while maintaining a stable perfusion pressure. In all of the ectothermic vertebrates, metabolism changes in accordance with altered body temperatures; typically metabolism increases two-to-threefold when temperature increases 10°C. In these cases, heart rate increases proportionally, primarily because of a direct effect of temperature on the cardiac pacemaker and the scope for autonomic regulation normally remains intact. Therefore, the animals can increase heart rate during exercise while the capacity to increase aerobic metabolism remains intact over a broad range of temperatures. Similarly, the ectothermic animals retain the capacity for heart rate to respond to altered blood pressure over a broad temperature range.

Hypoxia is common in aquatic habitats. Given that the foundations of autonomic regulation evolved in vertebrates relying on aquatic respiration over the gills, it is interesting that cartilaginous and bony fishes typically respond to hypoxia with a reduction in heart rate. Cardiac output typically remains unchanged, because the bradycardia is accompanied by increased stroke volume. The hypoxic bradycardia does not appear to enhance gas exchange efficiency across the gills, and may have evolved to protect the heart from lack of oxygen. Regardless of the functional benefit of the hypoxic bradycardia, it is interesting that mammals also exhibit bradycardia during hypoxic stimulation of peripheral chemoreceptors but only when afferent feedback from pulmonary stretch receptors is ablated. Hence, this somewhat counter-intuitive cardiovascular response to hypoxia is likely to reflect a piscine condition that evolved prior to pulmonary gas exchange.

Further reading

[1]. Burnstock G. Evolution of the autonomic innervation of visceral and cardiovascular systems in vertebrates.  Pharmacol Rev . 1969;21:247–324.

[2]. Farrell A.P. Cardiovascular systems in primitive fishes. In: McKenzie D.J, Farrell A.P, Brauner C.J, eds.  Fish physiology: primitive fishes . Elsevier; 2007:53–120.

[3]. Filogonio R, Sartori M.R, Mogensen S, Tavares D, Campos R, Abe A.S, et al. Cholinergic regulation along the pulmonary arterial tree of the South American rattlesnake: vascular reactivity, muscarinic receptors, and vagal innervation.  Am J Physiol . 2020;319(2):R156–R170.

[4]. Taylor E.W, Leite C.A.C, Sartori M.R, Wang T, Abe A.S, Crossley II. D.A. The phylogeny and ontogeny of autonomic control of the heart and cardiorespiratory interactions in vertebrates.  J Exp Biol . 2014;217(5):690–703.

[5]. Joyce W, Wang T. Regulation of heart rate in vertebrates during hypoxia: a comparative overview. Acta Physiol. 234, e13779.

6. Jensen B, Nielsen J.M, Axelsson M, Pedersen M, Löfman C, Wang T. How the python heart separates pulmonary and systemic blood pressures and blood flows.  J Exp Biol . 2010;213:1611–1617.

7. Wang T, Hicks J.W. Cardiorespiratory synchrony in turtles.  J Exp Biol . 1996;199:1791–1800.

8. Céspedes H.A, Zavala K, Vandewege M.W, Opazo J.C. Evolution of the α2-adrenoreceptors in vertebrates: ADRA2D is absent in mammals and crocodiles.  Gen Comp Endocrinol . 2017;250:85–94.

9. Pedersen J.E, Bergqvist C.A, Larhammar D. Evolution of the muscarinic acetylcholine receptors in vertebrates.  eNeuro . 2018;5 ENEURO.0340-18.2018.

10. Zavala K, Vandewege M.W, Hoffmann F.G, Opazo J.C. Evolution of the β-adrenoreceptors in vertebrates.  Gen Comp Endocrinol . 2017;240:129–137.

Chapter 2: Central autonomic control

Kamal Shouman, and Eduardo E. Benarroch     Department of Neurology, Mayo Clinic, Rochester, MN, United States

Abstract

The autonomic outputs mediated by the preganglionic sympathetic and parasympathetic neurons are controlled by several interconnected areas distributed throughout the central nervous system. They include lower brainstem areas mediating autonomic reflexes, including the nucleus of the solitary tract, ventrolateral medulla, medullary raphe nuclei, and parabrachial nucleus; these areas integrate autonomic with respiratory control. Areas in the upper brainstem such as the periaqueductal gray, locus coeruleus, and pedunculopontine nucleus integrate autonomic and respiratory control with behavioral arousal. Descending commands from the hypothalamus (primarily the paraventricular and dorsomedial nuclei and lateral hypothalamic area), centromedial nucleus of the amygdala, and cerebral cortex (primarily the insula and anterior cingulate cortex) control the premotor and autonomic nuclei in the brainstem and spinal cord.

Keywords

Amygdala; Anterior cingulate; Dorsomedial; Insula; Nucleus of the solitary tract; Parabrachial; Paraventricular; Periaqueductal gray; Ventrolateral medulla

Central autonomic control: overview

The central autonomic control is distributed throughout the neuraxis and is hierarchically organized. Areas in the medulla and lower pons mediate cardiovascular, respiratory, gastrointestinal, and micturition reflexes and relay visceral information to the upper brainstem and forebrain. The upper pons and midbrain contain areas that integrate autonomic control with pain modulation, that respond to stress, behavioral arousal, and motor responses. The hypothalamus functions as a pattern generator for integrated autonomic, endocrine, and behavioral responses to ensure bodily homeostasis and adaptation to environmental challenges. The amygdala, insular cortex, and anterior cingulate cortex are core providers of inputs to the hypothalamus and premotor autonomic areas of the brainstem. The primary excitatory transmitter in these pathways is L-glutamate; the primary inhibitory transmitter is gamma aminobutyric acid (GABA). Cholinergic, monoaminergic, and peptidergic influences from the brainstem, basal forebrain, and hypothalamus exert a state-dependent modulation of central autonomic control. Local interaction mediated by signals such as nitric oxide and ATP, including those involving astrocytes, is increasingly recognized as important for central control of autonomic reflexes and other responses.

Lower brainstem and autonomic reflexes

The nucleus of the solitary tract (NTS) is the first relay station for visceral afferent information and has a viscerotropic organization. The rostral NTS receives input from taste receptors, the intermediate portion from gastrointestinal receptors, and the caudal portion receives afferents from baroreceptors, cardiac receptors, chemoreceptors, and pulmonary receptors and relay these information to other areas of the brainstem and forebrain. The NTS is the central relay for all reflexes controlling arterial blood pressure (ABP), heart rate (HR), respiration, and upper gastrointestinal function. The rostral ventrolateral medulla (RVLM) contains glutamatergic and adrenergic (C1 area) sympathoexcitatory neurons that mediate the baroreflex and function as sensors and mediators of responses to internal stressors such as hypoxia and hypoglycemia. These neurons project to the intermediolateral cell column (IML) and excite sympathetic preganglionic neurons controlling the cardiac output and total peripheral resistance. Whereas C1 neurons do not appear to be critical for maintenance of ABP during wakefulness, they are involved in ABP maintenance during anesthesia and mediate both sympathoexcitatory responses to hypoxia and the increase in arterial pressure following baroreceptor denervation. The baroreceptor reflex is the principal buffering mechanism for short-term regulation of ABP. It is triggered on a beat-to-beat basis by mechanosensitive carotid baroreceptor afferents responsive to mechanical stretch. These afferents provide an excitatory input to neurons in the caudal NTS, which in turn initiates two parallel pathways, sympathoinhibitory and cardioinhibitory. The sympathoinhibitory pathway is mediated by GABAergic neurons in the caudal VLM, which inhibit the premotor sympathoexcitatory neurons of the RVLM. This provides for the baroreflex control of total peripheral resistance, which is the primary mechanism that prevents orthostatic hypotension. The baroreflex cardioinhibitory pathway involves a direct input from the NTS to vagal preganglionic neurons located in the ventrolateral portion of the nucleus ambiguus (NAmb), which provide inputs to the cardiac ganglia and inhibit the automatism of the sinus node on a beta-to-beat basis, resulting in bradycardia. The rhythmic discharge of these cardiovagal NAmb neurons is strongly modulated by respiration due to influences from the neighboring respiratory oscillator and from pulmonary stretch afferents via the NTS. The rostral ventromedial medulla (RVMM) and medullary raphe, including serotonergic neurons of nucleus raphe pallidus (RPa), contribute another major source of sympathoexcitatory outputs to the IML. Unlike neurons of the C1 area, these medullary neurons are not controlled by the baroreflex but rather initiate responses to cold and external stressors triggered by descending inputs from the hypothalamus. The brainstem control of cardiovascular function is intimately coupled to control of respiration. Several neuronal groups participate in respiratory rhythmogenesis and central chemosensitivity. The pre-Bötzinger complex, located in the ventrolateral medulla, is the critical pattern generator of inspiration and contains glutamatergic neurons that project to pontine and medullary premotor respiratory regions driving motoneurons controlling the inspiratory pump and airway resistance. The primary central respiratory chemosensitive zone is referred to as retrotrapezoid nucleus or ventral parafacial nucleus, which contains glutamatergic neurons that are activated by increased PCO2 via intrinsic proton receptors as well as paracrine mechanisms mediated by signals from astrocytes. These neurons also drive active expiration and receive synaptic input from peripheral chemoreceptors activated by hypoxia via a relay in the NTS. Respiratory chemosensitivity also involves serotonergic neurons of the medullary raphe, which provide widespread innervation to all respiratory groups exerting a global excitatory effect on the respiratory network. The input to spinal motoneurons innervating the respiratory muscles originates in a continuous cell column that extends from the rostral to the caudal portions of the ventrolateral medulla and known as the ventral respiratory group. This includes, from rostral to caudal, the Bötzinger complex containing expiratory neurons, the rostral ventral respiratory group containing inspiratory neurons, and the caudal ventral respiratory group, including the nucleus retroambiguus. The parabrachial nucleus (PB) located in the dorsolateral pons has several critical roles in homeostasis. It receives visceral, nociceptive, and thermoreceptive inputs from lamina I of the dorsal horn and from the NTS and sends projections to the thalamus, hypothalamus, basal forebrain, and amygdala that are critical for arousal, control of satiety, and pain control. Components of the PB nuclear complex, including the external lateral PB, lateral crescent, and Kölliker-Fuse nucleus, have a major role in respiratory phase-switching and generate distinct respiratory patterns and changes in the upper airway via descending projections to the NTS and to different groups of premotor neurons of the ventral respiratory column.

The medulla is also the primary site of integration of vago-vagal reflexes controlling the motility of the esophagus and stomach. The preganglionic neurons for these reflexes, as well as airway reflexes, are located in the dorsal motor nucleus of the vagus (DMV). The DMV provides parallel excitatory and inhibitory pathways controlling gastrointestinal motility.

Upper brainstem and integration of autonomic with arousal and stress responses

Several upper brainstem areas interact with lower brainstem autonomic areas and orchestrate autonomic responses associated with arousal, stress, and other behavioral states. They include the locus coeruleus (LC), pedunculopontine tegmental nucleus (PPN/PPT), and periaqueductal gray (PAG). The LC contains noradrenergic neurons that send diffuse projections throughout the central nervous system and have a major role in arousal, attention, and stress response. These neurons also project to autonomic areas such as the DMV, sacral preganglionic neurons, and central gray and dorsal horn of the spinal cord. These LC catecholaminergic inputs, together with those from adjacent area A7 and nucleus subcoeruleus, provide polysynaptic collateral projections to both the IML and the ventral horn and may thus have an important role in integration of sympathetic and somatomotor output. The PPT/PPN contains intermingled populations of cholinergic, glutamatergic, and GABAergic neurons that promote thalamocortical activation and REM sleep, participate in control of locomotion, and increase dopamine release from midbrain neurons in response to reward. Putative command neurons in the PPT/PPN are connected to both motor and autonomic areas and may integrate the somatomotor and sympathetic functions during different behaviors, including arousal and locomotion. The PAG provides an anatomical and functional interface between the forebrain areas involved in cognitive and emotional processing and lower brainstem circuits mediating autonomic reflexes, pain modulation, and motor responses. Different columns of the PAG initiate distinct patterns of response to stress according to the types of stressor and the ability to cope to stress. For example, the lateral column of the PAG contains neurons that are activated by superficial painful stimuli and initiate sympathoexcitatory and motor fight-or-flight responses. In contrast, neurons of the ventrolateral column of the PAG are activated by muscle and visceral painful stimuli and initiate sympathoinhibitory responses, immobilization, and opioid-dependent analgesia. The ventrolateral PAG also contains neurons that integrate excitatory inputs from the bladder and inhibitory inputs from the prefrontal cortex to determine the timing for initiation of micturition. The micturition reflex involves neurons located in the pelvic organ control center (also known as Barrington nucleus). This nucleus is located in the upper dorsolateral pons, receives afferents from pelvic organs both directly and via the PAG, and is critical for the coordination of the micturition reflex and participates in the control of the function of the lower gastrointestinal tract and sexual organs.

Hypothalamus: central pattern generator for homeostasis and adaptation

The hypothalamus is critical for basic vital functions, including energy metabolism, fluid and electrolyte balance, thermoregulation, wake-sleep cycle, responses to internal or environmental stressors, and reproduction. The hypothalamus receives and integrates interoceptive, humoral, and emotional signals and functions as a pattern generator for coordinated autonomic and endocrine responses to restore the internal milieu and adapt to challenges to survival. Allostasis refers to the active process by which the body responds to daily events and maintains homeostasis. The hypothalamic projections control autonomic responses, endocrine function, state of arousal, and motivation. The output to autonomic nuclei originates primarily in the paraventricular nucleus (PVH), dorsomedial nucleus (DMH), and perifornical region including orexin (ORX, hypocretin) neurons. These projections control the output of preganglionic sympathetic and parasympathetic neurons either directly or, more commonly, via a relay on brainstem preautonomic neurons located in the RVLM, rostral ventromedial medulla (RVMM), and nucleus raphe pallidus (RPa); the PAG is also an important relay of hypothalamic outputs controlling autonomic responses via these lower brainstem nuclei. Hypothalamic projections also target viscerosensory relay nuclei such as the NTS and PB. The two hypothalamic effector systems activated by stress are the sympathetic-adrenomedullary and the hypothalamic-pituitary-adrenal axis. Whereas the acute release of epinephrine and cortisol promotes adaptation to acute stressors, chronic elevation of these same mediators can cause deleterious pathophysiological consequences.

Several hypothalamic areas trigger autonomic responses to stress, including the PVH, DMH, and lateral hypothalamus. Autonomic PVH neurons respond to internal stressors, such as hypotension, hypoglycemia, or cytokines and send projections to the IML, RVLM, and NTS controlling sympathetic outflow to the heart, kidneys, and other organs. These PVH neurons have a major role in vasomotor responses to long-term challenges, such as sustained water deprivation or chronic intermittent hypoxia. The PVH also orchestrates the immunomodulatory responses to inflammatory signals both via neural end endocrine outputs. The PVH, in part via its projections to the C1 area of the RVLM promotes sympathetic output to lymphoid organs, including the spleen, which elicits potent antiinflammatory responses The parvocellular neurons of the PVH release corticotrophin releasing hormone and are thus critical components of the hypothalamic-pituitary-adrenal axis leading to release of cortisol, which exerts potent inhibitory effects on lymphoid cells and is critical for metabolic regulation.

The DMH has a major role in sympathoexcitatory responses to psychological stressors via inputs to the RVMM and medullary raphe (particularly the RPa) projecting to the IML eliciting tachycardia. The DMH is also a fundamental component of thermoregulatory responses to cold. Thermoregulation involves feedback and feedforward mechanisms integrated at the preoptic area of the hypothalamus; thermoregulatory responses are primarily mediated by the sympathetic output to the skin. An increase in core temperature evokes a negative feedback that results in skin vasodilation and sweating. These responses are initiated by warm-sensitive neurons in the medial preoptic area (MPO), which respond to increase in core temperature, tonically inhibit cold sensitive neurons, and initiate feedback responses for heat dissipation. These include sweating triggered by cholinergic sympathetic neurons via muscarinic M3 receptors, and skin vasodilation, which may involve several and incompletely defined mechanisms. The primary thermoregulatory feedforward sensory signal comes from cold and warm thermoreceptors in the skin. Neurons in the median preoptic area (MnPO) receive inputs from warm and cold receptors via inputs from the dorsal horn relayed by different portions of the lateral PB and interact with other hypothalamic thermoregulatory groups. Cold-sensitive neurons of the MnPO inhibit the warm-sensitive neurons in the MPO and activate cold-responsive neurons of the DMH and rostral RPa. Both the MnPO and the DMH also send direct excitatory projections to the RPa. The rostral RPa sends glutamatergic and serotonergic inputs to preganglionic sympathetic neurons in the spinal cord triggering cutaneous vasoconstriction mediated by α1 adrenergic receptors and thermogenesis in the brown adipose tissue via β receptors. In addition to its major function in thermoregulation, the preoptic area has a major role in sleep induction and regulation of water and sodium homeostasis. Both the ventrolateral preoptic area and the MnPO promote initiation of sleep, under the influence of circadian rhythms, homeostatic sleep pressure, and body temperature.

The critical areas involved in osmoregulation and fluid homeostasis are located in the lamina terminalis in the anterior wall of the third ventricle and include the subfornical organ (SFO), vascular organ of the lamina terminalis (OVLT), and MnPO. Both the SFO and the OVLT are circumventricular organs that lack a blood–brain barrier and contain osmosensitive neurons and astrocytes that detect extracellular sodium concentrations. Both regions express AT1 receptors that respond to circulating angiotensin II released in response to hypotension or hypovolemia. The MnPO functions as an integration center. Both an increase in blood osmolarity and hypovolemia trigger an integrated response that includes thirst, anorexia, and secretion of AVP (antidiuretic hormone, ADH) by magnocellular neurons of the PVH and supraoptic nucleus and increased sympathetic activity to maintain blood pressure.

The ORX neurons of the lateral hypothalamus and perifornical region have a major role in maintenance of arousal via their excitatory projections to wake-active cholinergic and monoaminergic neurons of the brainstem, basal forebrain, and hypothalamus and are also an important component of the reward system via projections to the dopaminergic neurons of the ventral tegmental area. ORX neurons also activate cardiovascular and respiratory responses associated with behavioral arousal, reward and motivated behavior, and stress. These neurons send excitatory projections to the PVH and to brainstem autonomic and respiratory nuclei; they trigger sympathetic cardiovascular activation and attenuation of the baroreflex, and promote respiratory responses to hypercapnia.

Amygdala: tagging of stimulus valence and innate survival responses

The amygdala provides automatic tagging of the valence (positive or negative) and intensity of environmental stimuli. The outputs of the amygdala to the hypothalamus, PAG, and brainstem autonomic nuclei trigger automatic survival responses to either unconditioned stimuli, such as pain, or conditioned stimuli, such as fear. These outputs originate in the centromedial nucleus (CeM) and its functional extension, the bed nucleus of the stria terminalis. A major source of aversive information to the amygdala is the PB, which conveys pain and visceral sensation either directly to the CeM, triggering innate survival responses, or via thalamus to the lateral nucleus, triggering conditioned responses via the intrinsic amygdala circuit involving the lateral and the basal nuclei. The CeM sends dense GABAergic and peptidergic projections to the hypothalamus, PAG, PB, NTS, RVLM, and vagal nuclei. Via these outputs, the CeM initiates several innate survival responses, including sympathetic or parasympathetic activation, secretion of stress hormones, and motor responses such as vocalization, startle, and freezing.

Insular cortex: interoception, bodily awareness, and autonomic control

The insula integrates multiple sensations to generate the awareness of the state of the body. The dorsal posterior insula is the primary interoceptive cortex; it receives and integrates inputs from visceral, pain, and thermal receptors via thalamic nuclei that relay inputs from lamina I of the dorsal horn, PB, and NTS. The posterior insula projects via the midinsula to the anterior insula, which integrates interoceptive signals with emotional and cognitive processing and is involved in conscious experience of bodily sensation. Interoception includes information from visceral organs as well as signals from hormones, nutrients, and inflammatory mediators. An indicator of interoception is cardiovascular arousal, which refers to the ability of individuals to perceive their own heartbeats at rest. Whereas the insula is the primary viscerosensory cortical area, it is also a visceromotor area controlling both the sympathetic and parasympathetic outputs, primarily via a relay in the lateral hypothalamus. There may be a lateralization of insular control of cardiovascular function, with a right sided dominance for sympathetic activation in response to mental stress or during the Valsalva maneuver. This putative lateralization has been linked to susceptibility to cardiac arrhythmias and other cardiovascular changes after stroke. The insular cortex also appears to be involved in the perceptual top-down cardiovascular control during exercise.

Anterior cingulate cortex, predictive motor commands to autonomic nuclei

The anterior cingulate cortex (ACC) is intimately interconnected with the amygdala, orbitofrontal cortex, anterior insula, and anterior midcingulate cortex. The ACC consists of a subgenual region and a pregenual region that participate in assessment of subjective relevance of body feelings for value-based decision making. In addition, the ACC initiates predictive visceromotor commands that are compared to interoceptive inputs reaching the insular cortex. Central autonomic commands from the ACC and anterior insula may be sent as predictive signals about the expected sensory consequences that would result from activation of the target organs. The mismatch between feedforward commands and feedback signals conveyed to the posterior insula generates an error prediction signal that influences cognitive and emotional processing. The pregenual ACC as well as the ventral anterior insula (frontoinsular cortex) are hub components of the salience network. These areas contain large layer five projection neurons, called von Economo neurons, and respond to homeostatically relevant stimuli. These neurons are more abundant in the right than in the left hemisphere, which may underlie some lateralization of autonomic control. The subgenual portion of the ACC projects to autonomic areas involved in parasympathetic control of the heart and its stimulation results in a decrease in blood pressure. Activation of the subgenual ACC correlates with indices of cardiovagal activity such as heart rate variability. The dorsal anterior insula and anterior midcingulate cortex (MCC) are the hub of a cingulo-opercular task-control network that is thought to have a major role in task set initiation and maintenance in part by providing for sustained vigilance. Functional neuroimaging studies have shown activation of this network during several tasks associated with increased sympathetic activation.

According to recent models, prior interoceptive experiences are generated as predictions that are sent to effector organs as probable interoceptive consequences; the difference between an expected internal state and the actual afferent interoceptive information generates a prediction error signal. The function of this top-down efferent neural drive to the peripheral nervous system would be to change the internal bodily state and thus minimize prediction errors by changing the viscerosensory (feedback) input at its source. Unpredicted interoceptive inputs generate prediction errors, which trigger both emotional feelings and homeostatic responses. According to this model, projection neurons in the pregenual ACC and anterior insula generate predictions about physiological states that are sent, via cortico-cortical projections, to the midinsular and posterior insular cortex. In the posterior insula, visceromotor simulations are compared to afferent interoceptive inputs, and this comparison generates prediction errors that are sent back to agranular cortices. Von Economo neurons in the anterior insula and ACC project to the anterior insular cortex and also target brainstem nuclei involved in visceral sensation and autonomic control, including the PAG and PB; these projections may thus convey interoceptive error attenuation.

Further reading

[1]. Dampney R.A. Central neural control of the cardiovascular system: current perspectives.  Adv Physiol Educ . 2016;40:283–296.

[2]. Gourine A.V, Machhada A, Trapp S, Spyer K.M. Cardiac vagal preganglionic neurones: an update.  Auton Neurosci Basic Clin . 2016;199:24–28.

[3]. Stornetta R.L, Guyenet P.G. C1 neurons: a nodal point for stress?  Exp Physiol . 2018;103:332–336.

[4]. Guyenet P.G, Stornetta R.L. Rostral ventrolateral medulla, retropontine region, and autonomic regulation.  Aut Neurosci: Basic and Clinical . 2022;237:102922.

[5]. Saper C.B, Lowell B.B. The hypothalamus.  Curr Biol . 2014;24:R1111–R1116.

[6]. Madden C.J, Morrison S.F. Central nervous system circuits that control body temperature.  Neurosci Lett . 2019;696:225–232.

[7]. Shoemaker J.K, Norton K.N, Baker J, Luchyshyn T. Forebrain organization for autonomic cardiovascular control.  Auton Neurosci . 2015;188:5–9.

[8]. Critchley H.D, Harrison N.A. Visceral influences on brain and behavior.  Neuron . 2013;77:624–638.

[9]. Cechetto D.F. Cortical control of the autonomic nervous system.  Exp Physiol . 2014;99:326–331.

[10]. Barrett L.F, Simmons W.K. Interoceptive predictions in the brain.  Nat Rev Neurosci . 2015;16:419–429.

Chapter 3: Peripheral autonomic nervous system

Waqar Waheed, and Margaret A. Vizzard     The Larner College of Medicine at the University of Vermont, Department of Neurological Sciences, Burlington, VT, United States

Abstract

This chapter focuses on the sympathetic nervous system and parasympathetic nervous system aspects of the peripheral autonomic nervous system. An autonomic nerve pathway involves two nerve cells. One cell (preganglionic) is located in the brain stem or spinal cord where it is connected by nerve fibers to the other cell (postganglionic), located in a cluster of nerve cells (called an autonomic ganglion). Nerve fibers from these ganglia connect with internal organs. Most of the sympathetic ganglia are located adjacent and bilaterally to the spinal cord. The parasympathetic ganglia are located near or in the organs they innervate. Many organs are controlled primarily by either the sympathetic or the parasympathetic division of the ANS; however, sometimes the two divisions have opposing effects on the same organ with the overall goal of coordinating bodily functions to ensure homeostasis. This chapter will briefly address the functional neuroanatomy, physiology, and pharmacology of the peripheral autonomic nervous system. Clinical manifestations of autonomic dysfunctions and the effects of stress on autonomic function are also discussed in a limited manner.

Keywords

Adrenal; Neurotransmitters; Parasympathetic; Paravertebral ganglia; Plurichemical transmission; Prevertebral ganglia; Psychosocial stress; Sympathetic; Synucleinopathies; Terminal ganglia

Introduction

The autonomic nervous system (ANS) is structurally and functionally positioned as interface between the internal and external milieu, coordinating bodily functions to ensure homeostasis (cardiovascular and respiratory control, thermal regulation, gastrointestinal motility, urinary and bowel excretory functions, reproduction, and metabolic and endocrine physiology), and adaptive responses to stress (flight or fight response). Thus, the ANS has the daunting task of ensuring the survival as well as the procreation of the species. These diverse roles require complex responses and depend upon the integration of behavioral and physiological responses that are coordinated centrally and peripherally.

In 1898, Langley, a Cambridge University physiologist, coined the term autonomic nervous system and identified three separate components (sympathetic, parasympathetic, and enteric). The following section of the Primer will focus on the first two aspects of the peripheral ANS: sympathetic nervous system (SNS) including the adrenal medulla; and parasympathetic nervous system (PNS). The following précis will address the neuroanatomy of the SNS, adrenal medulla, and PNS, and then present a more detailed, albeit brief, review of the functional neuroanatomy, physiology, and pharmacology of the peripheral autonomic nervous system. Importantly, the role of the ANS at multiple interfaces in normal and abnormal physiology is emerging as a key mediator of pathophysiology in a range of complex disorders (anxiety and panic, chronic fatigue syndrome, regional pain syndromes, autonomic failure) and a critical substrate underpinning the field of neurocardiology. The following information will serve as a framework from which to view the complexity of the ANS as revealed in the more detailed descriptions that follow in subsequent chapters in this Primer.

Sympathetic nervous system (SNS)

Origin

The cell bodies of the presynaptic neurons (preganglionic) of the sympathetic division of the ANS are located in the intermediolateral nucleus of the lateral gray column, extending from the first thoracic to the second lumbar level of the spinal cord (thoracolumbar outflow) (Fig. 3.1). These cell bodies within the thoracolumbar segments of the spinal cord provide preganglionic efferent innervation to sympathetic neurons that reside in ganglia dispersed in three arrangements: paravertebral, prevertebral, and previsceral or terminal ganglia. Paravertebral ganglia (sympathetic trunk) are paired structures that are located bilaterally along the vertebral column. They extend from the superior cervical ganglia (SCG), located rostrally at the bifurcation of the internal carotid arteries, to ganglia located in the sacral region. All told, there are three cervical ganglia (the SCG, middle cervical ganglion, and inferior cervical ganglion; the latter termed the cervicothoracic or stellate ganglion because it is a fused structure combining the inferior cervical and first thoracic paravertebral ganglia), 11 thoracic ganglia, four lumbar ganglia, and four to five sacral ganglia. More caudally, two paravertebral ganglia join to become the ganglion impar. Prevertebral ganglia are midline structures located anterior to the aorta and vertebral column, and are represented by the celiac ganglia, aortico-renal ganglia, and the superior and inferior mesenteric ganglia. Previsceral, or terminal ganglia, are small collections of sympathetic ganglia located close to target structures; they are also referred to as short noradrenergic neurons since their axons cover limited distances.

Figure 3.1  Schematic diagram of the sympathetic and parasympathetic divisions of the peripheral autonomic nervous system. The paravertebral chain of the sympathetic division is illustrated on both sides of the spinal outflow in order to demonstrate the full range of target structures innervated. Although the innervation pattern is diagrammatically illustrated to be direct connects between preganglionic outflow and postganglionic neurons, there is overlap of innervation such that more than one spinal segment provides innervation to neurons within the ganglia.

Although the principal neurons generally have been viewed as located in intermediolateral cell column-(IML), four additional major groups of autonomic neurons exist in intermediolateralis pars principalis (ILP), intermediolateralis pars funicularis (ILF), nucleus intercalatus spinalis (ICS), and the central autonomic nucleus (CAN) or dorsal commissural nucleus (DCN) (anatomical nomenclature is nucleus intercalatus pars paraependymalis (ICPE)). For paravertebral ganglia, >85%–90% of the presynaptic fibers originate from cell bodies in ILP or ILF. Prevertebral ganglia and terminal ganglia receive a larger proportion of preganglionic terminals from the CAN/DCN. The nucleus intercalatus also contributes preganglionic fibers, but the exact contribution is not fully understood and is probably limited.

Outflow

The axons of presynaptic neurons, being motor fibers, leave the spinal cord through ventral roots and enter the anterior rami of spinal nerves T1–L2 or L3. Almost immediately after entering, all the presynaptic sympathetic fibers leave the anterior rami of these spinal nerves and pass to the sympathetic trunks through myelinated white rami communicantes. Within the sympathetic trunks, presynaptic fibers follow one of the following courses:

1. The preganglionic neuron ascends superiorly to synapse with a higher sympathetic paravertebral ganglion. From here, the postganglionic sympathetic neuron traveling back out the gray ramus communicans are for: innervation of the head, cervical cardiopulmonary splanchnic nerves, and spinal nerves to the neck, upper trunk, and upper limb. The postsynaptic sympathetic fibers stimulate contraction of the blood vessels (vasomotion) and arrector pili muscle (pilomotion) and cause sweating (sudomotion). These anatomical facts provide the basis for complex regional pain syndrome (CRPS), where following a trauma or nerve injury, the coupling between the sympathetic and peripheral nociceptive nervous systems leads to a debilitating pain syndrome characterized clinically by severe pain along with signs and symptoms of autonomic dysfunction (sudomotor, vasomotor, and/or trophic finding); sympathetic nerve block provides symptomatic improvement.

2. Descend in the sympathetic trunk to synapse with a postsynaptic neuron of a lower paravertebral ganglion. Postsynaptic fibers exiting via gray ramus communicans are distributed by spinal nerves to the lower trunk and lower limb.

3. The preganglionic neuron can synapse with a postganglionic sympathetic neuron in the sympathetic paravertebral ganglion at that level. From here, the postganglionic sympathetic neuron can travel back out the gray ramus communicans of that level to the mixed middle trunk spinal nerves and on to the thoracic cardiopulmonary splanchnic nerves.

4. The preganglionic neuron passes through the paravertebral ganglion without synapsing, continuing as a preganglionic nerve fiber until it reaches a distant prevertebral ganglion (celiac, superior mesenteric, and inferior mesenteric ganglia) located anterior to the vertebral column. From here, the postganglionic sympathetic neuron can travel out the gray ramus communicans of that level to its visceral effector organ.

5. Some presynaptic sympathetic fibers pass through the celiac prevertebral ganglia without synapsing, continuing to terminate directly on cells of the medulla of the adrenal gland. The suprarenal medullary cells function acting as a special type of postsynaptic neuron; instead of releasing their neurotransmitter (epinephrine) onto the cells of a specific effector organ, they release it into the bloodstream leading to a widespread sympathetic response.

Because paravertebral and prevertebral ganglia are relatively close to the spinal cord, the presynaptic fibers are relatively short, whereas the postsynaptic fibers are relatively long, having to extend to all parts of the body (Fig. 3.2).

Figure 3.2  Schematic illustration of the segmental spinal arrangement of the sympathetic and parasympathetic nervous system. Although segmental interactions exist, they are polysynaptic operating via interneurons; the primary input to spinal preganglionic neurons is supraspinal originating from brainstem structures (not shown).

The outflow from the spinal cord to the peripheral ganglia is segmentally organized with some overlap. Retrograde tracing studies indicate that there is a rostral-caudal gradient: SCG receives innervation from spinal segments T1–T3; stellate ganglia from spinal segments T1–T6; adrenal gland from spinal segments T5–T11; celiac and superior mesenteric ganglia from spinal segments T5–T12; and inferior mesenteric and hypogastric ganglia from spinal segments L1–L2. The distribution of postsynaptic fibers also follows a regional pattern with the head, face, and neck receiving innervation from the cervical ganglia (spinal segments T1–4), the upper limb and thorax from the stellate and upper thoracic ganglia (spinal segments T1–8); the lower trunk and abdomen from lower thoracic ganglia (spinal segments T4–12), and the pelvic region and lower limbs from lumbar and sacral ganglia (spinal segments T10–L2).

Neurotransmitters

The preganglionic neurotransmitter for the sympathetic nervous system is acetylcholine, and the postganglionic neurotransmitter is norepinephrine for all end-organ connections, with few exceptions: (1) sympathetic ganglion neurons innervating the sweat glands are cholinergic except on some areas of glabrous skin (palms and soles) where norepinephrine is released as the neurotransmitter; (2) acetylcholine is the receptor for postganglionic transmission to chromaffin cells in the adrenal medulla; and (3) postganglionic sympathetic fibers to the kidney release dopamine.

Central autonomic network

The spinal autonomic nuclei receive substantial supraspinal input from multiple transmitter systems located at multiple levels of the neuraxis; the forebrain and brainstem provide the largest input. The pattern of innervation viewed in horizontal sections reveals a ladderlike arrangement of the distribution of nerve terminals. Without detailing the source or course of specific systems, it is important to point out that the following different neurotransmitter systems impinge on preganglionic neurons within this ladderlike structure: monoamines—epinephrine, norepinephrine (NE), serotonin; neuropeptides—substance P, thyrotropin-release hormone (TRH), met-enkephalin, vasopressin, oxytocin, and neuropeptide Y (NPY); amino acids—glutamate, GABA, and glycine. Undoubtedly, others exist and more will be found.

The central autonomic control areas which modulate the activity of preganglionic sympathetic and parasympathetic neurons include: anterior and mid-cingulate cortex (autonomic responses to salient stimuli and correlate with sympathetic activity); insular cortex (conscious bodily sensation, interoception); amygdala (provides emotional value to incoming sensory information and triggers multiple downstream autonomic and neuroendocrine responses to stress); hypothalamus (connected with the remainder of the central autonomic network primarily by way of the dorsal longitudinal fasciculus but also the medial forebrain bundle, and the mammillotegmental tract; responsible for pattern generator for homeostasis and stress responses via projection from the paraventricular and dorsomedial nuclei and orexin/hypocretin neurons); midbrain periaqueductal gray (integration of stress, autonomic, and pain modulatory responses); pontine parabrachial nucleus (arousal, respiratory control, and modulation of cardiovascular and gastrointestinal reflexes); nucleus of the solitary tract (first relay station for cardiovascular, respiratory, and gastrointestinal reflexes); rostral ventrolateral medulla, including the C1 group (mediate the baroreflex and responses to hypoxia and other internal stressors); and rostral ventromedial medulla and nucleus raphe pallidus (mediate sympathoexcitatory responses to external stressors and exposure to cold).

It is apparent that dysfunction of these supraspinal systems or alterations of these neurotransmitters by disease or pharmacological agents will alter the spinal control of peripheral ganglia and result in clinical dysfunction. Some of the examples of central autonomic dysfunction include autonomic dysreflexia from spinal transection above the spinal T5 level resulting in unpatterned activation of preganglionic sympathetic activation, manifesting as severe hypertensive crises provoked by a full bladder, impacted colon, or even stroking of the skin; chronic hypertension in type A or stressed individuals from increased central autonomic outflow in response to increased limbic system input; autonomic hyperactivity from dysfunction of diencephalon/upper midbrain circuits in anti N-Methyl-D-Aspartate (NMDA) receptor and voltage-gated potassium channel (VGKC) antibody-associated encephalitides; severe orthostatic hypotension in multiple system atrophy related to degeneration of preganglionic autonomic brain stem, particularly neurons in the rostral ventrolateral medulla; and sudden, unexpected death in epilepsy-related to seizures related blood pressure alteration.

Organization of SNS

It is apparent that the structural organizational of the SNS permits the integration and dissemination of responses depending on demand. Multiple supraspinal descending pathways provide a dense innervation of all four major autonomic cell groups in the spinal cord, but clearly specific topographic responses exist as well. In turn, each preganglionic neuron innervates 4 to 20 postganglionic sites, and each spinal outflow level may reach multiple peripheral ganglia which in turn supply multiple targets, permitting additional dispersion of sympathetic responses when indicated. At each thoracic level, there are an estimated 5000 preganglionic neurons (these counts have generally been limited to the cells located in the ILP). Since preganglionic output to prevertebral ganglia originates from more medially placed cell bodies, it is conceivable that a greater number of neurons at certain segmental levels contribute to the output. Thus, a given spinal segment has a powerful base to influence greater than 100,000 postganglionic neurons. Although original thinking suggested that responses were all-or-none and widespread, anatomical studies have continued to reveal subtleties of structural arrangements that indicate that the system is not only poised for generalized activation of the peripheral sympathetic nervous system but is also able to exert control of relatively specific sites and functions.

The postganglionic fibers in the SNS travel quite lengthy paths to arrive at target organs. For instance, fibers from the SCG traverse the extracranial and intracranial vasculature to reach such targets as the lacrimal glands, parotid glands, pineal gland, and pupils. Fibers from the stellate ganglia course through the brachial plexus to reach vascular and cutaneous targets in the upper limb and hand. Within the abdomen, axons originating from the paravertebral ganglia supply the viscera as well as the mesenteric vasculature. Lumbar and sacral paravertebral ganglia course distally along peripheral nerves and blood vessels to reach the distal vasculature and cutaneous structures in the feet. In humans, the innervation to the leg requires a sympathetic axon to be 50cm long and with an estimated overall diameter of 1.2μm the axonal volume is approximately 565,000μm³. This axonal cytoskeleton and its metabolic requirements are supported by a perikaryon of ∼30μm with a somal volume of 14,000μm³. With this structural architecture to maintain, these neurons are vulnerable to various metabolic and structural insults. Although most preganglionic fibers have a relatively short course to their ganglion targets, the upper thoracic preganglionic fibers travel relatively longer distances to reach the stellate and SCG, and preganglionic fibers to the adrenal medulla and prevertebral ganglia course through the paravertebral chain reaching these visceral targets as the splanchnic nerves. Along the course, fiber systems may be interrupted, resulting in local autonomic dysfunction. For example, the Horner syndrome results from lesion of either preganglionic fibers to the SCG or the postganglionic axons which leave the SCG to innervate Müller muscle of the upper eyelid, pupillodilator muscles, facial vasculature, and sudomotor structures of the face (see Fig. 3.1).

The autonomic neuroeffector junction is generally a poorly defined synaptic structure lacking the pre- and postjunctional specializations that are observed in the central nervous system or skeletal muscle motor end plates. The unmyelinated, highly branched postganglionic fibers become beaded with varicosities as they approach their targets. The varicosities are not static; they move along as structures with a diameter of 0.5–2μm, and a length of approximately 1μm. The number of varicosities varies from 10,000/mm³ to over 2 million/mm³ depending on the target being innervated. The varicosities are packed with mitochondria and vesicles containing various transmitters, and are at varying distances from their target organs. For instance, for smooth muscle targets, this distance varies from 20nm in the vas deferens to 1–2μm in large arteries. In a sense, the release of transmitter is accomplished en passage as the impulse travels along an autonomic axon. The lack of a restrictive synaptic arrangement permits the released neurotransmitter (NT) to diffuse various distances along a target organ and activate multiple receptors, again expanding the overall effect of sympathetic activation. Between 100 and 1000 vesicles exist in each varicosity in noradrenergic fibers. Traditional teaching suggests that vesicle characteristics indicate the transmitter system: small granular vesicles are noradrenergic; small agranular vesicles are cholinergic; large granular vesicles are peptidergic. However, exceptions to these correlations exist.

The principal neuronal phenotype in peripheral sympathetic ganglia is the noradrenergic neuron which is generally multipolar in character with synapses mainly located more on dendrites than somata. Depending on which ganglia are examined, studies indicate that from 80% to 95% of ganglion cells will stain positively for tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis, or have positive catecholamine fluorescence. The remaining cells have a mixture of transmitters or are postganglionic cholinergic cells (the sudomotor and periosteal components of sympathetic function). Within sympathetic ganglia, there is a small group of small intensely fluorescent (SIF) neurons. The transmitters identified in SIF cells include dopamine, epinephrine, or serotonin. As will be described later, the original concept that preganglionic neurons in the SNS are cholinergic and postganglionic neurons are noradrenergic has evolved to support a greater understanding that a whole array of molecules (e.g., cholinergic, catecholaminergic, monoaminergic,