Illustrations showing Autonomic nerve roots and relative paths attributing to cancer development
The term autonomic nervous system (ANS) refers to collections of motor neurons (ganglia) situated in the head, neck, thorax, abdomen, and pelvis, and to the axonal connections of these neurons (Fig.1). Autonomic pathways, together with somatic motor pathways to skeletal muscle and neuroendocrine pathways, are the means whereby the central nervous system (CNS) sends commands to the rest of the body. There are also CNS components of the ANS, including brainstem and spinal autonomic preganglionic neurons that project to the autonomic motor neurons in the peripheral ganglia. In this respect preganglionic autonomic motor neurons are clearly distinguished from somatic motor neurons that project from the CNS directly to the innervated tissue (skeletal muscle), without any intervening ganglia. Post-ganglionic axonal processes of motor neurons in the autonomic ganglia innervate organs and tissues throughout the body (eyes, salivary glands, heart, stomach, urinary bladder, blood vessels, etc). The motor neurons in the autonomic ganglia are sometimes referred to as “postganglionic neurons”. This traditional terminology is confusing and we use the term “autonomic motoneurons” or “final motoneurons” for the ganglionic cells. Complex autonomic ganglia in the walls of the stomach and small intestine are separately classified as the enteric nervous system.
History of the definition and functional conception of the ANS
Emotional feeling has traditionally been seen as distinct from rational thought. The brain, locked away in its bony case, was conceived as responsible for rational thought and for ideas that direct behavioral interactions with the external environment. Emotions, visceral rather than rational, were linked with the functions of the internal bodily organs. We have “gut feelings”, the heart is the “seat of love” and we “vent our spleen”. Bichat (1771-1802) divided life into two distinct forms, one (relational life) governed by the brain, and the other (organic, vegetative, life) by the abdominal ganglia. Vegetative life was seen as connected with the passions and independent of education, governed by independently functioning abdominal ganglia, a chain of “little brains”. Phillipe Pinel, one of the founders of psychiatry, and Bichat’s teacher, even considered mental disease to be caused by abnormal function of these ganglia, and modern psychiatry still refers to “vegetative functions”. Langley (1852-1925) coined the term autonomic nervous system. Langley noted the absence of sensory (afferent) nerve cell bodies in autonomic ganglia and defined the ANS as a purely motor system. He nevertheless continued the tradition whereby the ANS is seen as functioning in its own right, with independence from the CNS. It should be noted that Langley did not completely adhere to this simplification. In his introduction to the ANS (1903) he wrote that it is possible to “consider as afferent autonomic fibres those which give rise to reflexes in autonomic tissues, and which are incapable of directly giving rise to sensation”. Moreover, the discovery of primary afferent neurons that are part of the ANS, but lie entirely outside the CNS, and make no direct connection with the CNS, make it difficult to conceive of the ANS as an entirely efferent system (Furness 2006; see further below). Modern experiments have shown that neurons in autonomic ganglia do not have inbuilt discharge patterns sufficiently integrated to regulate physiological functions, with the possible exception of neurons within the enteric nervous system of the small and large intestines. The classic description of hexamethonium man summarizes the state of an individual after drug-mediated separation of the ANS from functional control by the brain. Similarly, when brain control of spinal autonomic preganglionic neurons is removed (as in quadriplegia), cardiovascular, bowel and bladder functions are profoundly impaired. Thus the ANS is best seen as one of the outflows whereby the CNS controls bodily organs, so that “peripheral autonomic pathways” is a better term, but “autonomic nervous system” is well-established. ANS pathways are divided into sympathetic and parasympathetic (around the sympathetic) divisions and enteric plexuses. Preganglionic cell bodies for the sympathetic outflow are in the thoracic spinal cord. Preganglionic cell bodies for the parasympathetic outflow are in the brainstem (cranial) and in the sacral spinal cord (sacral). The idea that the divisions oppose each other is a misleading simplification. Neither division is ever activated in its entirety. Rather, each division consists of a series of discrete functional pathways that may be activated from the CNS either independently or in patterns, according to the particular requirement of the particular daily activity that is contributing to bodily homeostasis. The primacy of integrative brain control of all bodily functions was recognized by Walter Cannon, but his idea that the brain activates sympathetic nerves diffusely and non-specifically during bodily emergencies (“fight or flight reaction”) is an over simplification. Different emergency states require different patterns of autonomic activity, and normal daily life (apart from emergencies) also requires patterned autonomic activity. The individual functions as a whole: there is just one nervous system. Sensory information (visceral afferent information) relevant to autonomic control (eg degree of bladder distention or level of blood pressure) travels in visceral afferent nerves and enters the CNS via spinal afferent pathways, or via vagal or glossopharyngeal afferents that project into the lower brainstem (see white-filled black arrows in Fig. 1).
All preganglionic autonomic neurons, both sympathetic and parasymapthetic use acetylcholine (ACh) as their fast excitatory transmitter. In the ganglia, ACh acts on a subclass of nicotinic receptors, distinct from nicotinic receptors at the skeletal muscle neuromuscular junction. Many preganglionic autonomic neurons also contain neuropeptides (co-transmitters) that mediate slow excitatory post-synaptic potentials, facilitating cholinergic transmission. Most sympathetic final motor neurons utilise noradrenaline (norepinephrine) as their primary transmitter, together with co-transmitters such as ATP and peptides such as neuropeptide Y (NPY) and galanin. Some sympathetic final motor neurons (especially those innervating sweat glands) use ACh as their main non-peptide transmitter. Parasympathetic final motor neurons pathways usually use ACh, nitric oxide, or both as non-peptide transmitters, as well as a wide range of co-transmitter peptides including vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP), somatostatin and opioid peptides. No parasympathetic neurons use noradrenaline as a transmitter. ACh is also a major transmitter utilised by enteric neurons. Other enteric neurotransmitters are substance P, VIP, enkephalin, 5-HT and ATP. Axons of final motor neurons ramify throughout their target tissues, typically smooth muscle, secretory tissue or cardiac muscle. Axon terminals are specialized for neurotransmission, but they usually lack the structures characteristic of conventional synaptic contacts. A number of target tissues are innervated by both sympathetic and parasympathetic nerves (eg the heart, the iris muscle, some salivary glands, the gastrointestinal tract and pelvic organs).
Cranial parasympathetic pathways
The cranial parasympathetic pathways project to a wide variety of targets in the head, neck, thorax and abdomen (Fig. 1). The pathways are associated with four of the cranial nerves: the oculomotor (III), facial (VII), glossopharyngeal (IX) and the vagus (X). Most final motor neurons in these cranial autonomic pathways are in four pairs of major ganglia: the ciliary ganglia (III), sphenopalatine or pterygopalatine ganglia (VII), submandibular ganglia (VII), and otic ganglia (IX). The final motor neurons of the vagal autonomic pathways lie mostly in microganglia located near or within the target organs. The major target of cranial parasympathetic pathways are secretory glands associated with the eye (tears), mouth (saliva) and nose (mucus). They stimulate the secretion of watery fluid, often with a concomitant vasodilation. Parasympathetic pathways also have a critical role in focusing the eye and regulating pupil diameter. Blood vessels in the brain also receive a parasympathetic vasodilator innervation, but the actual physiological function of these nerves is not well understood. The vagus nerve innervates microganglia in the neck, thorax and abdomen, including the airways, heart, thyroid, pancreas, gall bladder and the upper gastrointestinal tract. Consequently, the vagus nerve has a vast array of actions. It alters resistance to airflow and increases mucus secretion from the upper respiratory tract; it slows the heart; it stimulates secretion of digestive enzymes and bicarbonate from the pancreas; it either increases or decreases both secretory activity and smooth muscle contractility in the stomach. Some parasympathetic pathways tend to be tonically active (eg vagal pathways that keep heart rate low when we are not exercising) whereas others are activated only when required, eg salivary secretion during eating; relaxation of gastric smooth muscle; or near focus of the eyes when reading.
Neurons of the sympathetic division of the autonomic nervous system are aggregated into two main collections of ganglia: the paravertebral ganglia, which form the sympathetic chain each side of the vertebral column, and the prevertebral ganglia lying around the origins of the coeliac and mesenteric arteries (Fig. 1). Sympathetic neurons project to most tissues of the body, commonly reaching them by traveling with major nerves containing predominantly sensory and somatic motor nerve fibers. Sympathetic pathways have a diverse range of activities. Many are active nearly all the time, eg, vasoconstrictor pathways to the muscles that maintain central blood pressure, vasoconstrictor pathways to the skin that help prevent excessive heat loss, or prevertebral pathways to the gastrointestinal tract that help prevent excessive water loss from the gut. Other sympathetic pathways are activated only on demand, eg those to that increase heart rate during exercise; sudomotor neurons stimulating sweating during high body temperature; or those stimulating ejaculation during sexual activity. In some circumstances, sympathetic and parasympathetic pathways to a target tissue are co-activated eg sympathetic pathways to the salivary glands are co-activated with parasympathetic pathways when we eat something potentially noxious, such as hot chillies. The sympathetic co-activation results in the production of a thicker, more viscous saliva. Sympathetic pathways normally are never activated all at once. Despite the widespread belief that they are only activated during stressful situations, on-going activity of specific sympathetic pathways are essential for our day-to-day health and well-being. Even when we are faced with extreme stress, only a subset of sympathetic pathways will be involved.
Pelvic autonomic pathways
Regulation of the activity of many pelvic organs requires coordinated control via both sympathetic and sacral parasympathetic pathways, often in association with the relevant somatic motor pathways. Indeed, many of the ganglia in pelvic pathways contain mixtures of neurons, some of which receive preganglionic inputs from lumbar spinal levels (by definition, sympathetic) and others of which receive preganglionic input from sacral spinal levels (by definition, parasympathetic). Some individual neurons receive convergent inputs from both lumbar and sacral preganglionic neurons, and there may be considered to lie in both sympathetic and parasympathetic pathways. Control of bladder function requires sympathetic and somatic activity to relax the bladder wall and keep sphincters closed during continence. In contrast, micturition (urination) involves parasympathetic activation to contract the bladder wall and relax the sphincters, along with somatic motor pathways to increase intra-abdominal pressure. During sexual activity, erection requires coordinated activity of parasympathetic and somatic pathways, whilst ejaculation is the result of coordinated sympathetic and somatic motor activity.
Brain and spinal cord pathways regulating autonomic outflow
Preganglionic neurons for parasympathetic and sympathetic autonomic outflow are located in the brainstem and in regions of the spinal cord (Fig. 1). Brain centres controlling these preganglionic neurons have been defined by physiological studies and by a neuroanatomical technique in which a live virus, with affinity for autonomic nerves, is injected into a bodily organ, eg the wall of the stomach, the bladder or one of the salivary glands in experimental animals. The virus is transported to the autonomic nerve cell body in the ganglion. Here it replicates, spreads trans-synaptically and is then transported back into the CNS, to the preganglionic neurons, and then to neurons with direct axonal inputs to preganglionic neurons. For the sympathetic outflow, brain regions containing premotor neurons include medulla oblongata, pons and hypothalamus. Many of these premotor neurons synthesize a monoamine (noradrenaline, adrenaline, dopamine or serotonin). “Higher order” brain regions relevant to control of autonomic function are then labeled in the subsequent waves of spreading viral infection.
Afferent inputs to autonomic pathways
Nearly all neural communication from one viscera to another (eg from the gut or the lung to the heart) are mediated via afferent neurons with cell bodies in the dorsal root ganglia (near the spinal cord) or in the nodose and petrosal ganglia of the lower cranial nerves (located in the neck), as shown in Fig. 1. These visceral afferent neurons have a central process that projects into the dorsal horn of the spinal cord or into afferent nuclei in the brainstem (eg the nucleus tractus solitarius in the dorsal medulla oblongata). Langley initially expected to find afferent cell bodies in autonomic ganglia, with projections to other ganglia. He believed that activation of these “autonomic afferents” should lead to purely autonomic responses. However Langley’s own careful work demonstrated that there were no such neurons. Complex neuronal networks within and closely associated with the gastrointestinal tract regulate digestive, absorptive and excretory functions. This enteric nervous system is structurally and functionally organized into afferent neurons, interneurons and motoneurons, with characteristic projections and neurochemical profiles. There are some projections from afferent cell bodies within the enteric nervous system to neurons in autonomic ganglia that project back to the gut, but projections to other parts of the autonomic nervous system are sparse or absent. Thus, rather than “autonomic afferents” (or sympathetic or parasympathetic afferents) we prefer the term “visceral afferents”. The fundamentally important point is that integrative processes responsible for the organization of visceral function occur principally within the central nervous system (brain and/or spinal cord). Both somatic and visceral afferents result in complex, brain mediated, responses that include somatic and visceral function. Autonomic motor activity can be generated by both somatic and visceral inputs to the CNS, and visceral inputs to the CNS initiate responses that are both somatic and autonomic. Natural bodily functioning does not include “purely autonomic” or “purely somatic” responses, just as it does not include ‘purely sympathetic” or “purely parasympathetic” responses. The best way to illustrate this idea is by examples.
Nociceptive visceral afferents (pain from internal organs)
Probably all the viscera are innervated by the unmyelinated axons of dorsal root ganglia neurons that respond to a range of noxious stimuli, such as tissue inflammation, low pH, or ischaemia. When activated, these pain afferents produce a conscious perception of pain reasonably localized to the organ. These visceral afferent neurons can result in sympathetically-mediated responses (eg increased blood pressure), but they also activate somatic motor activity, such as spasm of the facial muscles (grimacing), as well as the abdominal (“doubling over with pain”) and the respiratory muscles (rapid breathing).
Baroreceptors and chemoreceptors
The baroreceptors measure blood pressure via specialised sensory endings in the carotid arteries, just before they enter the skull. Changes in baroreceptor activity, via afferents in IX (glossopharyngeal) and X (vagal) cranial nerves, activate brain centres that lead to altered sympathetic motor outflow to the heart and blood vessels. This response helps to maintain blood flow to the brain under a wide range of circumstances. We have little conscious awareness of these actions unless they fail to work properly, as when we feel lightheaded after standing up too quickly. Other specialized receptors (chemoreceptors) in the carotid sinus signal alterations in blood oxygen levels to the brain. As well as changes in blood pressure and heart rate, responses to low blood oxygen levels include increased breathing, and moving the head and face to clear the airway. Thus medical and nursing staff caring for babies have a rule: “the restless infant is hypoxic until proven otherwise”.
Control of accommodation and pupil diameter
Accommodation refers to the ability of the eye to focus on nearby objects by changing the shape of the lens. This is a parasympathetic motor function that is largely under conscious control, with sensory input arising from the visual system. Changes in pupil diameter regulate the amount of light reaching the retina and allow the eye to adapt to varying levels of ambient light. Pupil diameter is regulated by a combination of parasympathetic and sympathetic innervation of smooth muscle in the iris, in response to the global level of incident light. The overall level of illumination is detected by a special set of photosensitive ganglion cells in the retina. Thus a “somatic” stimulus causes an “autonomic response”. If the light is extra bright we may also screw up our eyelids (squint), and this is a “somatic” response.
Tears in the eyes
If we are sad or upset or, perhaps, incredibly relieved or deliriously happy, we may cry. Lacrimation, the production of tears, is mediated by purely parasympathetic motor activity. Normally there is a low level of tear production that lubricates the eye when we blink. Lacrimation also occurs in response to mechanical irritation of the eye (eg a grain of sand) or chemical irritation (eg a squirt of lemon juice). We also may “cry” following noxious mechanical stimulation of the face (eg a whack across the bridge of the nose). A psychological visual stimulus, for example a sad scene in a movie, may also initiate crying. In a heightened emotional state, or after particular kinds of strokes, we may cry in the absence of any immediate external stimulus. In all of these situations, the increased parasympathetic activity may be accompanied by characteristic patterns of somatic motor activity such as vocalisations (eg wailing) and facial expressions.
Auditory system input to cardiovascular system and cutaneous thermoregulators
Many types of auditory input can activate sympathetic output to the heart and blood vessels. A sudden unexpected sound may cause an increase in heart rate and vasoconstriction in the skin (we go pale with fright). Alternatively, music with special emotional resonance may “send shivers down our spines” and give us “goosebumps”. Goosebumps are generated by sympathetic activation of special smooth muscles associated with each hair follicle, an evolutionary remnant from a time when we presumably possessed a much more luxuriant pelage. Indeed, if we really do need to raise our body temperature, either because the environment is cold (detected by cutaneous thermoreceptors) or because we have a fever, generated from the thermoregulatory areas of the hypothalamus, we will shiver (a somatic motor response) and reduce blood flow to the skin (a sympathetic response). Sexual activity Sexual activity requires coordinated motor activity of parasympathetic, sympathetic and somatic motor pathways. In males, erection is maintained mostly by parasympathetic activity, whilst ejaculation is controlled mostly by sympathetic activity. In both these components, somatic motor activity is required to control muscles of the pelvic floor and the external sphincters, for example, as well as all the various body movements involved in intercourse. As is well known, erection can be elicited either by appropriate cutaneous mechanical stimulation, which activates a special set of cutaneous mechanoreceptors in genital skin, or by psychogenic means.
One of the best known but most misinterpreted autonomic motor patterns is the response to stress. Typically this involves an increase in sympathetic activity in selected pathways, such as those to the cardiovascular system, producing increased heart rate, skin blanching and perhaps high blood pressure, as well as an increased sympathetic output to the sweat glands, of the face, armpits and hands. This pattern of autonomic output is psychogenic (i.e. “brainogenic”) in origin, even if triggered by visual, auditory or tactile somatic inputs: is that a spider crawling up the back of my neck?
The archetypal “visceral afferents” are those arising from the gastro-intestinal tract. Different functional classes of these afferent nerves respond to distention of the gut; or to changes in the contents of the gut, Yet others respond to inflammation or damage to the gut wall. Motor outputs from the brain to the gut utilize parasympathetic or sympathetic pathways. With food poisoning, activation of gut afferents generates autonomic motor activity in addition to coordinated somatic motor activity. Vomiting involves activation of somatic motor pathways to the pharyngeal and abdominal muscles. Autonomic pathways include those regulating contraction and relaxation of the stomach and oesophagus, saliva secretion from the main salivary glands, and probably the cardiovascular system as well. Intriguingly, we can generate the same coordinated set of responses entirely from central pathways, such as when we view and emotionally disgusting event that literally “makes us sick”, or if we are “sick with worry”.
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