Cells erect a barrier around themselves (the plasma membrane) to create and maintain an internal environment that is optimized to suit their metabolic needs. The body similarly is covered with the skin to establish an internal environment whose temperature, pH, and electrolyte levels are optimized for tissue function. Maintaining a stable internal environment (i.e., homeostasis) is the responsibility of the autonomic nervous system (ANS). The ANS is organized similarly to the somatic nervous system and uses many of the same neural pathways.
Internal sensory receptors gather information about blood pressure (baroreceptors), blood chemistry (chemoreceptors), and body temperature (thermoreceptors) and relay it to autonomic control centers in the brain. The control centers contain neural circuits that compare incoming sensory data with internal preset values. If comparators detect a deviation from the presets, they adjust the function of one or more organs to maintain homeostasis. The principal organs of homeostasis include the skin, liver, lungs, heart, and kidneys (Figure 7.1). The ANS modulates organ function via two distinct effector pathways: the sympathetic nervous system (SNS) and the parasympathetic nervous system (PSNS). The actions of the SNS and PSNS often appear antagonistic, but, in practice, they work in close cooperation with each other.
Figure 7.1 Principal homeostatic organs.
The term “homeostasis” refers to a state of physiologic equilibrium or the processes that sustain such an equilibrium. An individual must maintain homeostatic control over numerous vital parameters to survive and thrive, including arterial Po2, blood pressure, and extracellular fluid osmolality (see Figure 7.1). Losing control over one or more of these parameters manifests as illness and usually prompts a patient to seek medical attention. It is a physician’s task to identify the underlying cause of the imbalance and intervene to help restore homeostasis.
Homeostatic control pathways are seen at both the cellular and organismal level, and they all include at least three basic components that typically form a negative feedback control system (Figure 7.2). There is a sensory component (e.g., a receptor protein) that detects and relays information about the parameter subject to homeostatic control, an integrator (e.g., a neural circuit) that compares incoming sensory data with a system preset value, and an effector component capable of changing the regulated variable (e.g., an ion pump or excretory organ).
For example, a rise in arterial Pco2 is sensed by chemoreceptors that feed information to a respiratory control center in the brainstem. The control center responds by increasing respiration rate to expel the excess CO2. Conversely, a decrease in Pco2 reduces respiration rate. Homeostasis may also involve a behavioral component. Behavior drives intake of salt (NaCl), water, and other nutrients and, for example, impels one to turn on air conditioning or shed clothing if body temperature is too high.
Figure 7.2 Negative feedback control of Pco2.
CNS = central nervous system.
Homeostasis at the organismal level typically involves multiple control pathways that are layered and often hierarchical, with the number of layers reflecting the relative importance of the parameter under control. Blood pressure, for example, is controlled by numerous local and central regulatory pathways. Layering creates redundancy, but it also ensures that if one pathway fails, one or more redundant pathways can assert control to ensure continued homeostasis. Layering also allows a very fine degree of homeostatic control.
C. Functional reserve
Organ systems that are responsible for homeostasis typically have considerable functional reserve. For example, normal quiet breathing uses only ~10% of total lung capacity, and cardiac output at rest is ~20% of maximal attainable values. Reserves allow the lungs to maintain arterial Po2 and the heart to maintain blood pressure at optimal levels even as body activity level and demand for O2 and blood flow increases (e.g., during exercise). Functional reserve also allows for progressive decreases in functional capacity, such as occurs with age and disease (see 40?II?A).
The ANS, also known as the visceral nervous system, is responsible for maintaining numerous vital parameters. Homeostasis must continue when we sleep or our conscious minds are focused on a task at hand, so the ANS operates subconsciously and largely independently of voluntary control. Exceptions include the voluntary interruption of breathing to allow for talking, for example.
The ANS is organized along similar principles to those of the somatic motor system. Sensory information is relayed via afferent nerves to the central nervous system (CNS) for processing. Adjustments to organ function are signaled via nerve efferents. The main differences between the two systems relate to efferent arm organization. The ANS employs a two-step pathway in which efferent signals are relayed through ganglia (Figure 7.3).
Figure 7.3 Somatic and autonomic nervous system efferent pathways.
A. Afferent pathways
ANS sensory afferents relay information from receptors that monitor many aspects of body function, including blood pressure (baroreceptors); blood chemistry, that is, glucose levels, pH, Po2, and Pco2 (chemoreceptors); skin temperature (thermoreceptors); and mechanical distension of the lungs, bladder, and gastrointestinal (GI) system (mechanoreceptors). Sensory afferent fibers often travel in the same nerves as do autonomic and somatic efferents. Autonomic nerves also contain nociceptive fibers, which provide for visceral pain sensation.
B. Efferent pathways
In the somatic motor system, motor neuron cell bodies originate within the CNS (see Figure 7.3). In the ANS, the cell bodies of motor efferents are contained within ganglia, which lie outside the CNS, often in close proximity to their target organs (Figure 7.4; also see Figure 7.3).
Figure 7.4 Autonomic nervous system organization.
CN = cranial nerve. Modified from Bear, M.F., Connors, B.W., and Paradiso, M.A. Neuroscience—Exploring the Brain. Third Edition. Lippincott Williams ; Wilkins, 2007
1. Autonomic ganglia
Ganglia comprise clusters of nerve cell bodies and their dendritic trees. Commands originating in the CNS are carried to ganglia by myelinated preganglionic neurons. Unmyelinated postganglionic neurons relay the commands to the target tissues.
Sympathetic ganglia are located close to the spinal cord. Therefore, sympathetic preganglionic neurons are relatively short. Postganglionic neurons are relatively long, reflecting the distance between the ganglia and the target cells. There are two types of sympathetic ganglia. Paravertebral ganglia are arranged in two parallel sympathetic chains located to either side of the vertebral column. The ganglia within the chains are linked by neurons that run longitudinally, which allows signals to be relayed vertically within the chains as well as peripherally. Prevertebral ganglia are located in the abdominal cavity.
Parasympathetic ganglia are located in the periphery near or within the target organ. Thus, parasympathetic preganglionic neurons are much longer than the postganglionic neurons.
2. Sympathetic efferents
The cell bodies of sympathetic preganglionic neurons are located in nuclei contained within upper regions of the spinal cord (T1–L3). Neurons located rostrally regulate the upper regions of the body, including the eye, whereas caudal neurons control the function of lower organs, such as the bladder and genitals. Preganglionic neurons leave the spinal cord via a ventral root, enter a nearby paravertebral ganglion, and then terminate in one of several possible locations:
- within the paravertebral ganglion;
- within a more distant sympathetic chain ganglion; or
- within a prevertebral ganglion, a more distal ganglion, or the adrenal medulla.
3. Parasympathetic efferents
Preganglionic neurons of the PSNS originate in brainstem nuclei or in the sacral region of the spinal cord (S2–S4). Their axons leave the CNS via cranial or pelvic splanchnic nerves, respectively, and terminate within remote ganglia located close to or within the walls of their target organs.
The differences between the somatic motor system and the ANS become more apparent when transmitters and synaptic structure are reviewed (Figure 7.5).
Figure 7.5 Autonomic nervous system neurotransmitters.
ACh = acetylcholine; M1 AChR, M2 AChR, and M3 AChR = muscarinic ACh receptors; N1 and N2 AChR = nicotinic ACh receptors.
A. Preganglionic transmitters
All ANS preganglionic neurons (SNS and PSNS) release acetylcholine (ACh) at their synapses. The postsynaptic membrane bears nicotinic ACh receptors (nAChRs), which mediate Na+ influx and membrane depolarization when activated, as in skeletal muscle. However, whereas skeletal muscle expresses an N1-type AChR, ANS preganglionic cell bodies and chromaffin cells in the adrenal medulla express an N2-type AChR.
N1- and N2-type AChRs have different sensitivities to nAChR antagonists, which makes it possible to inhibit the entire ANS output while leaving the skeletal musculature unaffected, or vice versa.1 Pancuronium is an N1-type receptor antagonist used in general anesthesia to relax skeletal muscle and aid intubation prior to surgery. It has relatively minor effects on ANS function. Conversely, trimethaphan is an N2-type antagonist that blocks both arms of the ANS while having little effect on the skeletal musculature.
B. Postganglionic transmitters
Somatic motor neurons act through an ionotropic nAChR and are always excitatory. In contrast, ANS effector neurons communicate with their target cells via G protein–coupled receptors and, thus, may have an array of consequences.
All PSNS postganglionic neurons release ACh from their terminals. Target cells express M1- (salivary glands, stomach), M2- (cardiac nodal cells), or M3-type (smooth muscle, many glands) muscarinic AChRs (see Table 5.3).
Most SNS postganglionic neurons release norepinephrine from their terminals. Target cells may express ?1- (smooth muscle); ?1- (cardiac muscle); ?2- (smooth muscle); or, less commonly, ?2- (synaptic terminals) adrenergic receptors (see Table 5.3). The exceptions are the SNS efferents that regulate eccrine sweat glands, which release ACh at their terminals and act through an M3-type AChR (see 16?VI?C?2).
C. Postganglionic synapses
Somatic motor nerves terminate at highly organized neuromuscular junctions. The site of synaptic contact between an ANS neuron and its target cell is very different. Many postganglionic nerve axons exhibit a string of beadlike varicosities (swellings) in the region of their target cells (Figure 7.6). Each represents a site of transmitter synthesis, storage, and release, functioning as a nerve terminal.
Figure 7.6 Autonomic nerve varicosities.
V. Effector Organs
The somatic motor system innervates skeletal musculature. The ANS innervates all other organs. Most visceral organs are innervated by both arms of the ANS. Although the two divisions typically have opposite effects on organ function, they usually work in a complementary rather than antagonistic fashion. Thus, when sympathetic activity increases, output from the parasympathetic division is withdrawn and vice versa. The principal targets and effects of ANS control are summarized in Figures 7.1 and 7.4.
ANS output can be influenced by many higher brain regions, but the main areas involved in autonomic control include the brainstem, the hypothalamus, and the limbic system. The relationship between these areas is shown in Figure 7.7. The brainstem is the primary ANS control center and can maintain most autonomic functions for several years even after clinical brain death has occurred (see 40?II?C). The brainstem comprises nerve tracts and nuclei. The nerve tracts convey information between the CNS and the periphery. Nuclei are clusters of nerve cell bodies, many of which are involved in autonomic control.
Figure 7.7 Autonomic control centers.
ANS = autonomic nervous system.
A. Preganglionic nuclei
Preganglionic nuclei are the CNS equivalents of ganglia, comprising clusters of nerve cell bodies at the head of one or more cranial nerves (CNs). Nuclei usually also contain interneurons that create simple negative feedback circuits between afferent and efferent nerve activity. Such circuits mediate many autonomic reflexes, such as reflex slowing of heart rate when blood pressure is too high and receptive relaxation of the stomach when it fills with food (see Clinical Application 7.1).
The brainstem contains several important PSNS preganglionic nuclei, including the Edinger-Westphal nucleus, superior and inferior salivatory nuclei, the dorsal motor nucleus of vagus, and the nucleus ambiguus (Figure 7.8). The nucleus ambiguus contains both glossopharyngeal (CN IX) and vagal (CN X) efferents that innervate the pharynx, larynx, and part of the esophagus. The nucleus helps coordinate swallowing reflexes, and it also contains vagal cardioinhibitory preganglionic fibers.
Figure 7.8 Principal autonomic brainstem nuclei.
CN = cranial nerve; GI = gastrointestinal.
B. Nucleus tractus solitarius
The nucleus tractus solitarius (NTS) is a nerve tract running the length of the medulla through the center of the solitary nucleus (see Figure 7.8) that coordinates many autonomic functions and reflexes. It receives sensory data from most visceral regions via the vagus and glossopharyngeal nerves (CNs IX and X) and then relays this information to the hypothalamus. It also contains intrinsic circuits that facilitate local (brainstem) reflexes controlling respiration rate and blood pressure, for example.
Clinical Application 7.1: Autonomic Dysfunction
Disruption of autonomic pathways can result in specific functional deficits or more generalized loss of homeostatic function, depending on the nature of the underlying pathology. Horner syndrome is caused by disruption of the sympathetic pathway that raises the eyelid, controls pupil diameter, and regulates facial sweat gland activity. The result is a unilateral ptosis (drooping eyelid), miosis (inability to increase pupil diameter), and local anhidrosis (inability to sweat).
More generalized autonomic dysfunctions are common among patients on maintenance dialysis and those with diabetes whose glucose levels are poorly controlled (diabetic autonomic neuropathy, or DAN). DAN can manifest as an inability to control blood pressure following a meal (postprandial hypotension) or upon standing (postural hypotension), gastrointestinal motility disorders (difficulty swallowing and constipation), or bladder dysfunction, among other symptoms.
Tests designed to assess autonomic function include monitoring cardiac responses during changes in posture, hand immersion in ice water (the cold pressor test, designed to induce intense pain), and a Valsalva maneuver
A Valsalva maneuver involves forced expiration against a resistance, designed to cause intrathoracic pressures to rise to 40 mm Hg for 10–20 s. The pressure increase prevents venous blood from entering the thorax, so cardiac filling is impeded, and arterial pressure falls. In a healthy individual, a fall in arterial pressure is sensed by arterial baroreceptors, initiating a reflex increase in heart rate that is mediated by sympathetic efferents traveling in the vagus nerve. Patients with DAN may have impaired baroreceptor or vagal nerve function and, thus, fail to respond to a Valsalva maneuver with the expected tachycardia.
C. Reticular formation
The reticular formation comprises a collection of brainstem nuclei with diverse functions, including control of blood pressure and respiration (as well as sleep, pain, motor control, etc.). It receives sensory data from the glossopharyngeal and vagal nerves and helps integrate it with effector commands from higher autonomic control centers located in the limbic system and hypothalamus.
D. Control centers
Brainstem areas that have related functions are considered control centers, even if separated spatially. Brainstem control centers include the respiratory center, cardiovascular control center, and micturition center (Table 7.1).
Table 7.1:Brainstem Control Centers