The ANS has sympathetic, parasympathetic, and enteric divisions
Output from the central nervous system (CNS) travels along two anatomically and functionally distinct pathways: the somatic motor neurons, which innervate striated skeletal muscle; and the autonomic motor neurons, which innervate smooth muscle, cardiac muscle, secretory epithelia, and glands. All viscera are richly supplied by efferent axons from the ANS that constantly adjust organ function.
The autonomic nervous system (from the Greek for “self-governing,” functioning independently of the will) was first defined by Langley in 1898 as including the local nervous system of the gut and the efferent neurons innervating glands and involuntary muscle. Thus, this definition of the ANS includes only efferent neurons and enteric neurons. Since that time, it has become clear that the efferent ANS cannot easily be dissociated from visceral afferents as well as from those parts of the CNS that control the output to the ANS and those that receive interoceptive input. N14-1 This larger visceral control system monitors afferents from the viscera and the rest of the body, compares this input with current and anticipated needs, and controls output to the body's organ systems.
Types of Afferent Input
Contributed by Emile Boulpaep, Walter Boron
The ANS has three divisions: sympathetic, parasympathetic, and enteric. The sympathetic and parasympathetic divisions of the ANS are the two major efferent pathways controlling targets other than skeletal muscle (Fig. 14-1). Each innervates target tissue by a two-synapse pathway. The cell bodies of the first neurons lie within the CNS. These preganglionic neurons are found in columns of cells in the brainstem and spinal cord and send axons out of the CNS to make synapses with postganglionic neurons in peripheral ganglia interposed between the CNS and their target cells. Axons from these postganglionic neurons then project to their targets. The sympathetic and parasympathetic divisions can act independently of each other. However, in general, they work synergistically to control visceral activity and often act in opposite ways, like an accelerator and brake to regulate visceral function. An increase in output of the sympathetic division occurs under conditions such as stress, anxiety, physical activity, fear, or excitement, whereas parasympathetic output increases during sedentary activity, eating, or other “vegetative” behavior.
FIGURE 14-1 Organization of the sympathetic and parasympathetic divisions of the ANS.
The enteric division of the ANS is a collection of afferent neurons, interneurons, and motor neurons that form networks of neurons called plexuses (from the Latin “to braid”) that surround the gastrointestinal (GI) tract. It can function as a separate and independent nervous system, but it is normally controlled by the CNS through sympathetic and parasympathetic fibers.
Sympathetic preganglionic neurons originate from spinal segments T1 to L3 and synapse with postganglionic neurons in paravertebral or prevertebral ganglia
The cell bodies of preganglionic sympathetic motor neurons are located in the thoracic and upper lumbar spinal cord between levels T1 and L3. At these spinal levels, autonomic neurons lie in the intermediolateral cell column, or lateral horn, between the dorsal and ventral horns (Fig. 14-2). Axons from preganglionic sympathetic neurons exit the spinal cord through the ventral roots along with axons from somatic motor neurons. After entering the spinal nerves, sympathetic efferents diverge from somatic motor axons to enter the white rami communicantes. These rami, or branches, are white because most preganglionic sympathetic axons are myelinated.
FIGURE 14-2 Anatomy of the sympathetic division of the ANS. The figure shows a cross section of the thoracic spinal cord and the nearby paravertebral ganglia as well as a prevertebral ganglion. Sympathetic preganglionic neurons are shown in red and postganglionic neurons in dark blue-violet. Afferent (sensory) pathways are in blue. Interneurons are shown in black.
Axons from preganglionic neurons enter the nearest sympathetic paravertebral ganglion through a white ramus. These ganglia lie adjacent to the vertebral column. Although preganglionic sympathetic fibers emerge only from levels T1 to L3, the chain of sympathetic ganglia extends all the way from the upper part of the neck to the coccyx, where the left and right sympathetic chains merge in the midline and form the coccygeal ganglion. In general, one ganglion is positioned at the level of each spinal root, but adjacent ganglia are fused in some cases. The most rostral ganglion, the superior cervical ganglion, arises from fusion of C1 to C4 and supplies the head and neck. The next two ganglia are the middle cervical ganglion, which arises from fusion of C5 and C6, and the inferior cervical ganglion (C7 and C8), which is usually fused with the first thoracic ganglion to form the stellate ganglion. Together, the middle cervical and stellate ganglia, along with the upper thoracic ganglia, innervate the heart, lungs, and bronchi. The remaining paravertebral ganglia supply organs and portions of the body wall in a segmental fashion.
After entering a paravertebral ganglion, a preganglionic sympathetic axon has one or more of three fates. It may (1) synapse within that segmental paravertebral ganglion, (2) travel up or down the sympathetic chain to synapse within a neighboring paravertebral ganglion, or (3) enter the greater or lesser splanchnic nerve to synapse within one of the ganglia of the prevertebral plexus.
The prevertebral plexus lies in front of the aorta and along its major arterial branches and includes the prevertebral ganglia and interconnected fibers (Fig. 14-3). The major prevertebral ganglia are named according to the arteries that they are adjacent to and include the celiac, superior mesenteric, aorticorenal, and inferior mesenteric ganglia. Portions of the prevertebral plexus extend down the major arteries and contain other named and unnamed ganglia and plexuses of nerve fibers, which altogether make up a dense and extensive network of sympathetic neuron cell bodies and nerve fibers.
FIGURE 14-3 Anatomy of the sympathetic prevertebral plexuses. Each ganglion and its associated plexus are named after the artery with which they are associated.
Each preganglionic sympathetic fiber synapses on many postganglionic sympathetic neurons that are located within one or several nearby paravertebral or prevertebral ganglia. It has been estimated that each preganglionic sympathetic neuron branches and synapses on as many as 200 postganglionic neurons, which enables the sympathetic output to have more widespread effects. However, any impulse arriving at its target end organ has only crossed a single synapse between the preganglionic and postganglionic sympathetic neurons.
The cell bodies of postganglionic sympathetic neurons that are located within paravertebral ganglia send out their axons through the nearest gray rami communicantes, which rejoin the spinal nerves (see Fig. 14-2). These rami are gray because most postganglionic axons are unmyelinated. Because preganglionic sympathetic neurons are located only in the thoracic and upper lumbar spinal segments (T1 to L3), white rami are found only at these levels (Fig. 14-4, left panel). However, because each sympathetic ganglion sends out postganglionic axons, gray rami are present at all spinal levels from C2 or C3 to the coccyx. Postganglionic sympathetic axons from paravertebral and prevertebral ganglia travel to their target organs within other nerves or by traveling along blood vessels. Because the paravertebral and prevertebral sympathetic ganglia lie near the spinal cord and thus relatively far from their target organs, the postganglionic axons of the sympathetic division tend to be long. On their way to reach their targets, some postganglionic sympathetic axons travel through parasympathetic terminal ganglia or cranial nerve ganglia without synapsing. N14-2
FIGURE 14-4 Organization of the sympathetic and parasympathetic divisions of the ANS. The left panel shows the sympathetic division. The cell bodies of sympathetic preganglionic neurons (red) are in the intermediolateral column of the thoracic and lumbar spinal cord (T1–L3). Their axons project to paravertebral ganglia (the sympathetic chain) and prevertebral ganglia. Postganglionic neurons (blue) therefore have long projections to their targets. The right panel shows the parasympathetic division. The cell bodies of parasympathetic preganglionic neurons (orange) are either in the brain (midbrain, pons, medulla) or in the sacral spinal cord (S2–S4). Their axons project to ganglia very near (or even inside) the end organs. Postganglionic neurons (green) therefore have short projections to their targets.
Tracing of Nerve Tracts Using Pseudorabies Virus
Contributed by George Richerson
The CNS neuroanatomy of autonomic control has been difficult to define experimentally. However, a technique developed by Arthur Loewy and his colleagues that traces nerve tracts with the pseudorabies virus has helped to define more clearly the central pathways for autonomic control. For example, if axons of preganglionic sympathetic neurons are exposed to pseudorabies virus, the virus is transported back into the cell bodies, where it replicates. After a delay of several days, neurons that make synapses with these preganglionic neurons (i.e., “premotor” neurons) become infected and the virus is transported to their cell bodies. After longer periods of incubation, neurons farther upstream are also infected. Histological staining can then be used at different time points to visualize neurons that contain the virus at each level upstream.
Jansen ASP, van Nguyen X, Karpitskiy V, et al. Central command neurons of the sympathetic nervous system: Basis of the fight-or-flight response. Science. 1995;270:644–646.
Parasympathetic preganglionic neurons originate from the brainstem and sacral spinal cord and synapse with postganglionic neurons in ganglia located near target organs
The cell bodies of preganglionic parasympathetic neurons are located in the medulla, pons, and midbrain and in the S2 through S4 levels of the spinal cord (see Fig. 14-4, right panel). Thus, unlike the sympathetic—or thoracolumbar—division, whose preganglionic cell bodies are in the thoracic and lumbar spinal cord, the parasympathetic—or craniosacral—division's preganglionic cell bodies are cranial and sacral. The preganglionic parasympathetic fibers originating in the brain distribute with four cranial nerves: the oculomotor nerve (CN III), the facial nerve (CN VII), the glossopharyngeal nerve (CN IX), and the vagus nerve (CN X). The preganglionic parasympathetic fibers originating in S2 through S4 distribute with the pelvic splanchnic nerves.
Postganglionic parasympathetic neurons are located in terminal ganglia that are more peripherally located and more widely distributed than are the sympathetic ganglia. Terminal ganglia often lie within the walls of their target organs. Thus, in contrast to the sympathetic division, postganglionic fibers of the parasympathetic division are short. In some cases, individual postganglionic parasympathetic neurons are found in isolation or in scattered cell groups rather than in encapsulated ganglia.
Cranial Nerves III, VII, and IX
The preganglionic parasympathetic neurons that are distributed with CN III, CN VII, and CN IX originate in three groups of nuclei.
1. The Edinger-Westphal nucleus is a subnucleus of the oculomotor complex in the midbrain (Fig. 14-5). Parasympathetic neurons in this nucleus travel in the oculomotor nerve (CN III) and synapse onto postganglionic neurons in the ciliary ganglion (see Fig. 14-4, right panel). The postganglionic fibers project to two smooth muscles of the eye: the constrictor muscle of the pupil and the ciliary muscle, which controls the shape of the lens (see Fig. 15-6).
FIGURE 14-5 Supraspinal nuclei containing neurons that are part of the ANS. These nuclei contain the cell bodies of the preganglionic parasympathetic neurons (i.e., efferent). The Edinger-Westphal nucleus contains cell bodies of preganglionic fibers that travel with CN III to the ciliary ganglion. The superior salivatory nucleus contains cell bodies of preganglionic fibers that travel with CN VII to the pterygopalatine and submandibular ganglia. The inferior salivatory nucleus contains cell bodies of preganglionic fibers that travel with CN IX to the otic ganglion. The rostral portion of the nucleus ambiguus contains preganglionic cell bodies that distribute with CN IX; the rest of the nucleus ambiguus and the dorsal motor nucleus of the vagus contain cell bodies of preganglionic fibers that travel with CN X to a host of terminal ganglia in the viscera of the thorax and abdomen. The NTS, which is not part of the ANS, receives visceral afferents and is part of the larger visceral control system. The figure also illustrates other cranial nerves that are not involved in controlling the ANS (gray labels).
2. The superior salivatory nucleus is in the rostral medulla (see Fig. 14-5) and contains parasympathetic neurons that project, through a branch of the facial nerve (CN VII), to the pterygopalatine ganglion (see Fig. 14-4, right panel). The postganglionic fibers supply the lacrimal glands, which produce tears. Another branch of the facial nerve carries preganglionic fibers to the submandibular ganglion. The postganglionic fibers supply two salivary glands, the submandibular and sublingual glands.
3. The inferior salivatory nucleus and the rostral part of the nucleus ambiguus in the rostral medulla (see Fig. 14-5) contain parasympathetic neurons that project through the glossopharyngeal nerve (CN IX) to the otic ganglion (see Fig. 14-4, right panel). The postganglionic fibers supply a third salivary gland, the parotid gland.
Cranial Nerve X
Most parasympathetic output occurs through the vagus nerve (CN X). Cell bodies of vagal preganglionic parasympathetic neurons are found in the medulla within the nucleus ambiguus and the dorsal motor nucleus of the vagus (see Fig. 14-5). This nerve supplies parasympathetic innervation to all the viscera of the thorax and abdomen, including the GI tract between the pharynx and distal end of the colon (see Fig. 14-4, right panel). Among other effects, electrical stimulation of the nucleus ambiguus results in contraction of striated muscle in the pharynx, larynx, and upper esophagus due to activation of somatic motor neurons (not autonomic), as well as slowing of the heart due to activation of vagal preganglionic parasympathetic neurons. Stimulation of the dorsal motor nucleus of the vagus induces many effects in the viscera, including initiation of secretion of gastric acid, insulin, and glucagon. Preganglionic parasympathetic fibers of the vagus nerve join the esophageal, pulmonary, and cardiac plexuses and travel to terminal ganglia that are located within their target organs.
The cell bodies of preganglionic parasympathetic neurons in the sacral spinal cord (S2 to S4) are located in a position similar to that of the preganglionic sympathetic neurons—although they do not form a distinct intermediolateral column. Their axons leave through ventral roots and travel with the pelvic splanchnic nerves to their terminal ganglia in the descending colon and rectum (see p. 862), as well as to the bladder (see pp. 736–737) and the reproductive organs of the male (see p. 1104) and female (see p. 1127).
The visceral control system also has an important afferent limb
All internal organs are densely innervated by visceral afferents. Some of these receptors monitor nociceptive (painful) input. Others are sensitive to a variety of mechanical and chemical (physiological) stimuli, including stretch of the heart, blood vessels, and hollow viscera, as well as , , pH, blood glucose, and temperature of the skin and internal organs. Many visceral nociceptive fibers travel in sympathetic nerves (blue projections in Fig. 14-2). Most axons from physiological receptors travel with parasympathetic fibers. As is the case with somatic afferents (see p. 271), the cell bodies of visceral afferent fibers are located within the dorsal root ganglia or cranial nerve ganglia (e.g., nodose and petrosal ganglia). Ninety percent of these visceral afferents are unmyelinated.
The largest concentration of visceral afferent axons can be found in the vagus nerve, which carries non-nociceptive afferent input to the CNS from all viscera of the thorax and abdomen. Most fibers in the vagus nerve are afferents, even though all parasympathetic preganglionic output (i.e., efferents) to the abdominal and thoracic viscera also travels in the vagus nerve. Vagal afferents, whose cell bodies are located in the nodose ganglion, carry information about the distention of hollow organs (e.g., blood vessels, cardiac chambers, stomach, bronchioles), blood gases (e.g., , , pH from the aortic bodies), and body chemistry (e.g., glucose concentration) to the medulla.
Internal organs also have nociceptive receptors that are sensitive to excessive stretch, noxious chemical irritants, and very large decreases in pH. In the CNS, this visceral pain input is mapped (see pp. 400–401) viscerotopically at the level of the spinal cord because most visceral nociceptive fibers travel with the sympathetic fibers and enter the spinal cord at a specific segmental level along with a spinal nerve (see Fig. 14-2). This viscerotopic mapping is also present in the brainstem but not at the level of the cerebral cortex. Thus, awareness of visceral pain is not usually localized to a specific organ but is instead “referred” to the dermatome (see p. 273) that is innervated by the same spinal nerve. This referred pain results from lack of precision in the central organization of visceral pain pathways. Thus, you know that the pain is associated with a particular spinal nerve, but you do not know where the pain is coming from (i.e., from the skin or a visceral organ). For example, nociceptive input from the left ventricle of the heart is referred to the left T1 to T5 dermatomes and leads to discomfort in the left arm and left side of the chest, whereas nociceptive input from the diaphragm is referred to the C3 to C5 dermatomes and is interpreted as pain in the shoulder. This visceral pain is often felt as a vague burning or pressure sensation.
The enteric division is a self-contained nervous system of the GI tract and receives sympathetic and parasympathetic input
The enteric nervous system (ENS) is a collection of nerve plexuses that surround the GI tract, including the pancreas and biliary system. Although it is entirely peripheral, the ENS receives input from the sympathetic and parasympathetic divisions of the ANS. The ENS is estimated to contain >100 million neurons, including afferent neurons, interneurons, and efferent postganglionic parasympathetic neurons. Enteric neurons contain many different neurotransmitters and neuromodulators. Thus, not only does the total number of neurons in the enteric division exceed that of the spinal cord, but the neurochemical complexity of the ENS also approaches that of the CNS. The anatomy of the ENS as well as its role in controlling GI function is discussed in Chapter 41.
The plexuses of the ENS are a system of ganglia sandwiched between the layers of the gut and connected by a dense meshwork of nerve fibers. The myenteric or Auerbach's plexus (Fig. 14-6) lies between the outer longitudinal and the inner circular layers of smooth muscle, whereas the submucosal or Meissner's plexus lies between the inner circular layer of smooth muscle and the most internal layer of smooth muscle, the muscularis mucosae (see Fig. 41-3). In the intestinal wall, the myenteric plexus is involved primarily in the control of motility, whereas the submucosal plexus is involved in the control of ion and fluid transport. Both the myenteric and the submucosal plexuses receive preganglionic parasympathetic innervation from the vagus nerve (or sacral nerves in the case of the distal portion of colon and rectum). Thus, in one sense, the enteric division is homologous to a large and complex parasympathetic terminal ganglion. The other major input to the ENS is from postganglionic sympathetic neurons. Thus, the ENS can be thought of as “postganglionic” or as a “terminal organ” with respect to the parasympathetic division and “post-postganglionic” with respect to the sympathetic division. Input from both the sympathetic and parasympathetic divisions modulates the activity of the ENS, but the ENS can by and large function normally without extrinsic input. The isolated ENS can respond appropriately to local stimuli and control most aspects of gut function, including initiating peristaltic activity in response to gastric distention, controlling secretory and absorptive functions, and triggering biliary contractions (Box 14-1).
FIGURE 14-6 The myenteric (Auerbach's) plexus. The image is a scanning electron micrograph of the myenteric plexus of the mouse large intestine. The external longitudinal muscle of the intestine was removed so that the view is of the plexus (the highly interconnected meshwork of neuron cell bodies, axons, and dendrites on the surface) spreading over the deeper circular layer of muscle. (From Burnstock G: Autonomic neuromuscular junctions: Current developments and future directions. J Anat 146:1–30, 1986.)
Master Gene of the Visceral Control System
During development, a complex genetic program expressed in each progenitor cell determines cell fate—ensuring that the cell migrates to the correct location and differentiates into the correct mature cell type. The genes that encode some transcription factors (see pp. 81–88) turn on at a specific time during development and trigger normal migration or differentiation of specific cell types. phox2b is a transcription factor required for the development of nearly all neurons within the visceral control system and almost no other class of neuron.
phox2b is expressed early in development in all neurons of the mammalian visceral control system—including preganglionic and postganglionic parasympathetic neurons, postganglionic (but not preganglionic) sympathetic enteric neurons, all visceral afferents, and neurons of the NTS, on which they synapse. No other cells express phox2b, except for neurons of the locus coeruleus in the pons (which plays an important role in cardiovascular control) and certain cranial nerve nuclei (most of which are important for respiratory output and for feeding). Knockout of the mouse PHOX2B gene leads to loss of development of all these neurons and is fatal. N14-9 In humans, heterozygous mutations in the PHOX2B gene cause congenital central hypoventilation syndrome (CCHS), a congenital form of Ondine curse (see Box 32-5). Infants with this condition have problems with breathing while they sleep, probably because of a deficiency in detection of O2 or CO2 in their blood or defective integration of this information by the NTS and other nuclei of the medulla. A subset of patients with PHOX2B mutations also have Hirschsprung disease (see Box 41-2), in which the ENS does not develop normally in a portion of the colon. This combination of CCHS and Hirschsprung disease is called Haddad syndrome. Some CCHS patients also develop tumors of derivatives of the sympathetic nervous system called neuroblastomas.
Contributed by George Richerson
At one time, scientists searched for “master genes” responsible for directing the development of each group of neurons that share a common function (e.g., all motor neurons or all neurons that contain gamma-aminobutyric acid). This search has been largely fruitless, except for PHOX2B, which is the closest example of a master gene in that it is expressed almost uniquely and nearly ubiquitously in neurons of the visceral control system. The implication is that these neurons are so closely related to each other in their function that they are bound together by a common developmental program. This common bond is so primitive that a homolog of PHOX2B is even found in neurons of Ciona, a urochordate that is a marine animal made up primarily of an intestine that filters seawater.
As a rule, the neural circuits that carry out individual tasks or behaviors (e.g., locomotion, sleep, vision) are formed by several classes of neurons that follow unrelated developmental pathways before they assemble into a circuit. So far, the visceral control system is unique in that most of its constituent neuronal types differentiate under the control of the same highly specific transcription factor, phox2b. PHOX2B can thus be considered the “master gene” of the visceral control system.