The autonomic nervous system and the regulation of body functions

Somatomotor activity and adjustments of the body

All living organisms interact continuously with their environment. They receive multiple signals from the environment via their sensory systems and respond by way of their somatomotor system. Both sensory processing and motor actions are entirely under control of the central nervous system. Within the brain are representations of both extracorporeal space and somatic body domains, the executive motor programs and programs for the diverse patterns of behavior which are initiated from higher levels. The brain generates complex motor commands on the basis of these central representations; these lead to movements of the body in its environment against different internal and external forces. The tools for performing these actions are the effector machines, the skeletal muscles and their controlling somatomotoneurons.

The body's motor activity and behavior are only possible when its internal milieu is controlled to keep the component cells, tissues and organs (including the brain and skeletal muscles) maintained in an optimal environment for their function. This enables the organism to adjust its performance to the varying internal and external demands placed on the organism. In the short term the mechanisms involved include the control of:

• fluid matrix of the body (fluid volume regulation, osmoregulation),

• gas exchange with the environment (regulation of airway resistance and the pulmonary circulation),

• ingestion and digestion of nutrients (regulation of the gastrointestinal tract, control of energy balance),

• transport of gases, nutrients and other substances throughout the body to supply organs, including the brain to maintain consciousness (regulation of blood flow and blood pressure by the cardiovascular regulation),

• […]

In the preceding chapters I described that sympathetic and parasympathetic systems consist of many functionally separate pathways that supply the peripheral target organs. The neurons in these pathways have characteristic reflex discharge patterns, which are centrally generated. The final central output neurons are the preganglionic neurons in the spinal cord and in the brain stem. Integrative processes in general do not seem to occur between functionally distinct autonomic pathways but only within some non-vasoconstrictor pathways to viscera (see Chapter 4). The discharge patterns measured in postganglionic neurons are unlikely to be generated by qualitatively different discharge patterns in subpopulations of preganglionic neurons converging on the same postganglionic neuron, although we have no direct experimental proof for this. This does not collide with the finding that neurochemically different preganglionic neurons may converge on the same postganglionic neuron (Murphy et al. 1998). Thus, in the autonomic ganglia, the discharge patterns are not changed qualitatively, but may be modified quantitatively, i.e. enhanced by the converging synaptic input. At the neuroeffector junctions, temporal and spatial aspects of the neural signals transmitted to the effector cells contribute to transmission; furthermore, various non-neural signals may modulate the neuroeffector transmission pre- and postjunctionally.

This section will focus on some principles of the organization of central regulation of peripheral autonomic pathways integrated in the spinal cord, brain stem and hypothalamus.

The activity in spinal preganglionic neurons is the result of the summation of potential changes in the neuronal membrane arising from integrative processes in the spinal cord, brain stem, hypothalamus and forebrain. As in the somatomotor system (Lloyd 1960), the spinal cord itself is a major highway of interaction between the brain and the autonomic target organs. In this chapter, I will concentrate on the thoracolumbar spinal autonomic (sympathetic) systems and summarize what is known and discussed about the sacral spinal autonomic (parasympathetic) systems. I will give arguments supporting the idea that the spinal cord contains intrinsic autonomic systems and that the spinal autonomic systems are coordinated via function-specific autonomic interneurons and integrated in the regulation of autonomic effector organs. This integration involves synaptic events derived from segmental spinal, propriospinal and supraspinal sources. Thus, I will put forward the idea that the spinal autonomic systems are integrated in the regulation of activity in preganglionic neurons by supraspinal centers. This idea has been borrowed from our understanding of the physiology of regulation of the activity in somatic motoneurons in the generation of movements. Alternative ideas discussed here are that spinal autonomic circuits modulate descending signals in the regulation of the activity in the preganglionic neurons or that spinal autonomic circuits are not important during normal regulation of autonomic target organs via sympathetic and sacral parasympathetic systems.

Sacral parasympathetic systems are essential in the regulation of lower urinary tract, hindgut and reproductive organs.

Impulse activity in the preganglionic neurons is the result of integrative processes in the spinal cord and brain stem (see Chapters 9 and 10). Such top down signaling (i.e. central message) is not usually distorted in the ganglia of the final autonomic pathways. It is modified by synaptic input from peripheral neurons in a few autonomic pathways to the viscera (see Subchapters 5.7 and 6.5). The central message is distributed to a large population of postganglionic neurons but confined to the respective autonomic pathways. Thus, transmission of impulses from preganglionic neurons to postganglionic neurons occurs within the same final autonomic pathway, but not between autonomic pathways. In this chapter I will discuss some mechanisms by which centrally generated messages are transmitted from postganglionic neurons to the target cells (effectors).

The mechanism of neuroeffector transmission varies considerably between target tissues. This is a consequence of there being many different types of cells innervated by postganglionic neurons (see Table 1.2). However, neuroeffector transmission has been studied in only a few cases. Such studies clearly demonstrate that the neural impulse activity is transmitted to the effector cells in a rather specific way and this may apply to all autonomically innervated effector cells. This view does not preclude the idea that the activity in some autonomic effector cells is also modified by multiple non-neural influences and that these non-neural components may operate during ongoing regulation of the target tissues.

The autonomic nervous system carries the signals from the central nervous system to all organs and tissues of the body except skeletal muscle fibers. It is made up of preganglionic and postganglionic neurons linked together in functionally distinct pathways. The postganglionic terminals have specific relationships with their target tissue. As well as distributing centrally derived command signals, this system can also integrate reflex interactions between different parts of the peripheral nervous system, even without involving the spinal cord. All of these activities are specific for each organ system and attempts to generalize have often proved incorrect. The breadth and scope of involvement of this system in body function are obvious. The autonomic nervous system controls not only the quantity and quality of tissue perfusion in response to varying needs, and the maintenance of secretions for protection of the body's orifices and the lining of the gastrointestinal tract, but it also regulates the usually intermittent but complex functions of the abdominal viscera and pelvic organs, the mechanical aspects of the eye and the communication between the nervous system and the immune system. Many autonomic pathways are continuously active but they can also be recruited when the environmental and/or emotional situation demands it. This system is essential for homeostasis – hence the subtitle of this book.

Despite its enormous importance for the maintenance of normal physiology in all vertebrate species, and for the understanding of many clinical symptoms of disease, the autonomic nervous system has not, even transiently, been the center of attention in neuroscience research internationally over the past 40 years.

Sympathetic and parasympathetic premotor neurons are present in the lower brain stem (medulla oblongata and pons) in addition to those located more rostrally (see Chapter 8.4). Their cell bodies are located in the ventrolateral medulla (mainly rostral ventrolateral medulla), the ventromedial medulla, the caudal raphe nuclei and the A5 area of the ventrolateral pons (see Figures 8.15 and 8.17 and Tables 8.2 and 8.3). Premotor neurons form synapses with preganglionic neurons (and/or local interneurons associated with the preganglionic neurons) (Chapters 8, 9). How do autonomic premotor neurons in the lower brain stem function so as to contribute to the characteristic discharge patterns of the neurons of the peripheral autonomic pathways? Are they specialized for the behavioral repertoire of the organism? Are there discharge patterns similar to those seen in the neurons of the final autonomic pathways (see Chapter 4)?

On the basis of the knowledge we have about the central autonomic systems, I can partially answer these questions for some systems in the lower brain stem. These answers, incomplete as they may be, clearly indicate that we will be able to unravel the maze of the neural organization of autonomic systems in the lower brain stem in the near future. One of the first decisive and important steps to reach this aim, particularly for the cardiovascular system, was and still is to record the effects of microinjection of pharmacological agents into defined regions of the lower brain stem on effector responses (e.g., arterial blood pressure, heart rate, blood flow through an organ).

Postganglionic neurons are the final autonomic motoneurons. Their cell bodies are aggregated in peripheral autonomic ganglia. They receive synaptic input from preganglionic neurons and in some ganglia (notably sympathetic prevertebral ganglia) from peripheral neurons of the enteric nervous system and from peptidergic spinal afferent fibers. As already mentioned in Chapter 1, most sympathetic ganglia are located at distance from their target cells and parasympathetic ganglia are located close to their targets.

Sympathetic ganglia have fascinated investigators since ancient times. It was believed that these structures are “little brains,” which integrate, carry and distribute the “animal spirits” from the brain to the periphery, leading to coordinated actions of the peripheral target organs (the “sympathies”) in association with the activity of the brain (Fulton 1949; Pick 1970; Spillane 1981; Karczmar et al. 1986).

However, it turns out that the primary function of most peripheral sympathetic and parasympathetic pathways is to distribute messages to the periphery from relatively small pools of preganglionic neurons to relatively large pools of postganglionic neurons. This particularly applies to the neural regulation of autonomic body functions, which are chiefly under central control, e.g., regulation of systemic blood pressure, thermoregulation, gastrointestinal functions, evacuative functions (micturition, defecation), erection, salivation, pupil diameter etc.

Acetylcholine is released by all preganglionic axon terminals at their synapses in ganglia and the effects of nerve activity are antagonized by blockade of nicotinic acetylcholine receptors.

The brain continuously receives messages from internal organs of the body. These afferent messages are neuronal, hormonal, chemical and physical in nature (see Figure 1). The continuous afferent feedback to the brain confers information about the state of internal organs (e.g., the degree and composition of filling of the gastrointestinal tract), the state of parameters regulated homeostatically (e.g., the level of systemic arterial blood pressure; the concentration of glucose, oxygen and bicarbonate in the blood; the size of fat stores by the concentration of leptin), the activity of endocrine glands (by the concentration of circulating hormones secreted by these glands) and the state of peripheral protective mechanisms of the body (e.g., by activity in nociceptive afferents, by signals from immune tissues [cytokines acting directly on the brain or indirectly via vagal afferents]). The multiple afferent feedback signals to the brain from various organs and tissues of the body are essential to achieve the precision of the homeostatic short- and long-term regulations in which the autonomic nervous systems are involved. This afferent (sensory) feedback connects to all levels of the autonomic motor hierarchy, to the centers of the cerebral hemispheres, which are responsible for conscious sensations and cognitive inputs to the motor hierarchy, and to the behavioral state system (Swanson 2000, 2003; see Introduction and Figure 2; see Subchapters 11.4 and 11.6).

Details about these regulations and the functional specificity of the afferent signals with respect to the autonomic regulations will be discussed in Part III of this book.

In Chapter 1 I described the anatomical and physiological characteristics of the peripheral autonomic nervous system on the macroscopic level. The overall conclusion from this conservative approach is that the peripheral autonomic neurons are integrated in the neural regulation of many target cells of the body (see Table 1.2). In other words, peripheral autonomic pathways that transmit signals from the spinal cord and brain stem to the peripheral effector cells must have some functional specificity with respect to these effector cells, in the sympathetic and the parasympathetic nervous system. Otherwise it would be impossible to understand how the precise autonomic regulation that is the basis for the continuous adaptation of the body during various demands occurs. Implicit in this idea is that these peripheral autonomic pathways are connected to distinct neuronal circuits in the spinal cord, brain stem, hypothalamus and telencephalon.

In this and the next chapter I will give arguments, and describe in some detail, that principally each type of target cell that is innervated by autonomic neurons is influenced by one or two autonomic pathways and that these pathways transmit distinct messages to the periphery and are connected to distinct central circuits. This chapter describes the final autonomic pathway and its analysis. It concentrates particularly on the neurophysiological analysis. Morphological analysis of autonomic circuits will be described in Chapter 8 and elsewhere in the book.

In this chapter I describe the reflex patterns for different groups of autonomic neurons, in particular sympathetic neurons. For other groups of autonomic neurons that have not yet been investigated in this way, I will draw indirect conclusions by analogy to those that have been investigated. Using this approach we gather information about the functional specificity of different neurons, about the relation between activity in certain types of neurons and the responses of the target tissue as well as information about the principal organization of the central circuits that determine the discharge pattern of these neurons (see Chapters 8 to 11). Thus, the experimental data described in this chapter are an important cornerstone of this book: they show that each autonomic pathway exhibits a characteristic pattern of discharge and that this is dependent on the structure of the central circuits in the neuraxis and the synaptic connections of these circuits with the different groups of afferent input to the neuraxis. This type of analysis gives the ultimate underpinning for the concept that the autonomic nervous system consists of functionally distinct building blocks (Jänig and McLachlan 1992a, b). As I have emphasized in Chapter 3, this description does not show how these autonomic systems function during ongoing regulation of autonomic function. This will be discussed in Chapters 5 to 10.

A similar approach has been used for the analysis of the somatomotor system.

Before developing the general concepts of the function of the autonomic nervous system and describing its neurobiology I will describe some aspects of the anatomy and function of this system on the macroscopic level and explain the limitations of our present understanding. Furthermore, I will provide some definitions. This conventional approach is necessary to help to convey what is meant when we speak of how the peripheral autonomic nervous system behaves and to lay the groundwork for the description of the functions in which the autonomic nervous system is involved.

Definitions and limitations

Langley (1900, 1903a, b, 1921) originally proposed the generic term autonomic nervous system to describe the system of nerves that regulates the function of all innervated tissues and organs throughout the vertebrate body except striated muscle fibers; that is, the innervation of the viscera, vasculature, glands, and some other tissues. This term is synonymous with the term vegetative nervous system, which has become obsolete in Anglo-American countries. However, the latter is still the preferred term in German (“vegetatives Nervensystem”; Jänig 2005a), French (“système végétative”), Italian (“systema neurovegetativo”), Spanish (“sistema nervioso vegetativo”) and Russian (“vegetativnaia nervnaia systema”). Langley (1921) divided the autonomic nervous system into three parts: the parasympathetic nervous system, the sympathetic nervous system and the enteric nervous system. This definition has stood the test of time and is now universally used in descriptions of the autonomic nervous system in vertebrates (Nilsson, 1983; Gibbins, 1994).

The final chapter will describe how integrative neural control of most body functions is vital to keep the body able to survive and act in its environment. The autonomic nervous system is involved in virtually all of these functions (see Tables 11.1 and 11.2). I want to make clear:

• that the power and range of this integrative control of body function in mammals are dependent on the mesencephalon, hypothalamus and cerebral hemispheres;

• that the mastermind of the integration of autonomic, somatomotor and endocrine systems is located in the telencephalon;

• that the functionally differentiated autonomic pathways are the slaves of this mastermind, and

• that the “wisdom of the body” is to be found within these regions of the brain.

I will strictly adhere to the autonomic systems, described in the preceding chapters, in this description and will emphasize some critical points. I do not intend to describe the mechanisms underlying these integrative control systems in detail (as this would require another book). The chapter will not cover (1) how stress involves the autonomic nervous system in body protection (see Goldstein [1995, 2000]; Chrousos [1998]; McEwen [2001a]) and (2) neural mechanisms underlying emotional and motivational processes (Le Doux 1996; Panksepp 1998; Davidson et al. 2003; Morris and Dolan 2004).

The chapter will start with some critical reflections on concepts about the functioning of the autonomic nervous system that were propagated by Walter Bradford Cannon and Walter Rudolf Hess and are still influential in physiology and medicine.

In Chapters 3 and 4 the idea of the functional organization of the “final autonomic pathways” that transmit the central information to the peripheral targets was described. This idea sets the limits for the ensuing discussion of transmission of impulses along the final autonomic pathways (i.e., in the autonomic ganglia and to the target cells) as it occurs in vivo. In this section I want to emphasize that the centrally generated signals are faithfully transmitted from the preganglionic neurons through autonomic ganglia to the postganglionic neurons and from the postganglionic axons to the effector cells at the neuroeffector junctions. I will describe the principles of this signal transmission and how it can be modulated by peripheral reflexes and humoral mechanisms. I will not, however, extensively discuss the details of synaptic transmission in autonomic pathways including the different types of receptors for the neurotransmitters, their pharmacology and postreceptor pathways and chemical neuroanatomy (see articles in Burnstock and Hoyle [1992]; Elfvin et al. [1993]; McLachlan [1995]; Skok [2002]).

In his chapter “The sympathetic and related systems of nerves” in Schäfer's Textbook of Physiology (1900) Langley defined for the first time the idea that the gastrointestinal tract has a nervous system of its own. He called this system the enteric nervous system (Langley 1900). He repeated this idea in his short monograph in 1921 where he clearly described the division of the autonomic nervous system into three parts: sympathetic, parasympathetic and enteric nervous system. This classification is still used today (Langley 1921). The existence of the plexuses of Auerbach (plexus myentericus) and Meissner (plexus submucosus) has been known since the second half of the nineteenth century. Langley recognized that this system can act to a large extent independently of the central nervous system. He separated the myenteric and submucosal ganglia from the sympathetic (and parasympathetic) nervous system and classified them as a third autonomic nervous system for the following reasons: (1) they have a distinct histology compared to the histology of the paravertebral and prevertebral sympathetic ganglia; (2) it was unclear at that time whether they are connected with the central nervous system by sympathetic and parasympathetic neurons and (3) the sympathetic postganglionic fibers either send collaterals to or form synapses with the neurons of the enteric nervous system (Langley 1900). Up to about 1970 rather little or no attention was given to the enteric nervous system of the gastrointestinal tract; in fact this system was practically ignored.