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Neurocardiology: a neurobiologist's perspective

2016; Wiley; Volume: 594; Issue: 14 Linguagem: Inglês

10.1113/jp271895

1469-7793

Wilfrid Jänig,

Sleep and Wakefulness Research

Pre- and postganglionic neurones of the autonomic nervous system are functionally differentiated according to their target tissues. Individual sympathetic pre- and postganglionic neurones can be activated or inhibited reflexly by appropriate physiological stimuli as has been shown in anaesthetized animals (mainly cats and rats) for neurones of the lumbar sympathetic outflow to skeletal muscle, skin and pelvic viscera and for neurones of the thoracic sympathetic outflow to the head and neck (Jänig, 2006; Jänig & McLachlan, 2013) and in humans for postganglionic neurones projecting in muscle or skin nerves (Jänig & Häbler, 2003; Wallin, 2013). The reflexes correspond to the effector responses that are induced by changes in activity of these neurones. The reflex patterns are characteristic and therefore represent the physiological 'fingerprints' for each type of sympathetic pathway. They are the functional expression of the neural circuits in spinal cord, brain stem and hypothalamus connected to the peripheral sympathetic pathways. The same types of reflex patterns have been observed in both preganglionic and postganglionic neurones. The neurones in most of these pathways (e.g. the vasoconstrictor, sudomotor, motility-regulating pathways, and other pathways) have ongoing activity whereas the neurones in other pathways are normally silent in anaesthetized animals (e.g. pilomotor and vasodilator pathways, pathways to sexual organs). It is likely that other target cells are similarly innervated by functionally distinct groups of sympathetic neurones that have not been systematically studied so far. These include heart (pacemaker, myocytes, coronary arteries), kidney (blood vessels, juxtaglomerular cells, tubules), urogenital tract, hindgut, spleen, and brown and white adipose tissue (Verberne & Sartor, 2010; Morrison, 2011, 2013). Several systematic studies have been made on the functional properties of parasympathetic pre- and postganglionic neurones. The principle of organization into functionally discrete pathways is likely to be the same as in the sympathetic nervous system, the main difference being that some targets of the sympathetic system are widely distributed throughout the body (e.g. blood vessels, sweat glands, erector pili muscles, fat tissue) whereas the targets of the parasympathetic pathways are more restricted (Jänig, 2006; Jänig & McLachlan, 2013). The centrally generated signals are faithfully transmitted from the preganglionic neurones to the postganglionic neurones in the autonomic ganglia and from the postganglionic neurones to the effector tissues at the neuroeffector junctions or at the sites where the varicosities of the postganglionic axons are in close proximity with the tissue (e.g. non-excitable tissues). This signal transmission is function-specific and the basis for the precise regulation of autonomic effector tissues by the brain. A few effector tissues also contain intrinsic neuronal networks that include the components for reflex control within the periphery. The most prominent is the enteric nervous system, which contains afferent neurones, interneurones and motoneurones that regulate various target tissues (smooth musculature, secretory epithelia, endocrine cells) and even modulate postganglionic sympathetic neurones in prevertebral ganglia. The preganglionic parasympathetic and sympathetic pathways regulate the activity of these intrinsic pathways in an integrative manner to determine organ function. Some peripheral afferents from the visceral organs project as far as prevertebral sympathetic ganglia and amplify postganglionic activity (e.g. Szurszewski, 1981; Jänig & McLachlan, 1987; McLachlan & Meckler, 1989). Peripheral neuronal reflex systems have been identified in the heart and pancreas, and possibly other organs. However, other than the important control of peristalsis and secretion in the gut (Furness, 2006; Furness et al. 2014), the operation of these peripheral reflex pathways in determining organ function remains largely unknown and needs further investigation. The peripheral autonomic (parasympathetic and sympathetic) systems consist of several separate neuronal channels transmitting the central messages to the autonomic target tissues. This conclusion is supported by morphological studies using tracers and by studies of neuropeptides co-localized in postganglionic and preganglionic neurones with the classical transmitters acetylcholine or noradrenaline (Gibbins, 1995, 2004). Peripheral circuits may also modulate the central activity patterns related to some visceral organs. The distinct reflex patterns generated in autonomic neurones by physiological stimulation of afferent neurones innervating visceral, skin or deep somatic tissues indicate that each autonomic pathway is connected to specific neural circuits in spinal cord, brain stem and hypothalamus that are involved in autonomic regulation. We have some knowledge about the central circuits involved in cardiovascular regulation and thermoregulation. However, the central circuits, including the spinal ones, are largely unknown for most peripheral final autonomic pathways (see Jänig, 2006; Llewellyn-Smith & Verberne, 2011; Paton & Spyer, 2013). The brain–heart axis is involved in the neural regulation of the heart via the autonomic cardiomotor (CM) pathways. This axis was already present in vertebrates some 500 million years ago in elasmobranch and teleost fishes. The heart of elasmobranchs is under parasympathetic (vagal) CM control and the heart of teleosts under both parasympathetic and sympathetic CM control (Nilsson, 2011; Jänig, 2013). This shows that the regulation of the heart by the brain is phylogenetically old, as is the case for the foregut, but probably went through various changes in the central and peripheral nervous system, although the basic principles of the organization of the peripheral CM pathways remained the same throughout the vertebrate kingdom (transmitters and their receptors, excitatory effects, inhibitory effects, etc.). This shows that the brain–heart axis is biologically rather important. However, our knowledge about the mechanisms underlying the functioning of this axis under biological conditions remains still amazingly poor in view of the fact that the pathophysiology of the neural regulation of the heart and its consequences for therapy has a high representation in medicine. Knowledge about these peripheral and central mechanisms is the gate to understanding the pathophysiology underlying various diseases related to the heart in humans (Floras, 2012; Golombek, 2012; Robertson & Sato, 2012; Bajpai & Camm, 2013; Francis & Cohn, 2013; Hainsworth & Claydon, 2013; Samuels, 2013). Thus, research in neurocardiology should primarily focus on the neurobiology of the regulation of the heart, covering the field from neuroeffector transmission to telencephalic control of the heart. Here I will discuss research questions related to the brain–heart axis. This discussion is based on my personal opinion and does not imply any priority of the type of basic research involved and of the level of integration at which the neural control of the heart occurs. However, it should be kept in mind that the 'neural machineries' of the peripheral CM pathways (neuroeffector transmission, transmission and integration of impulse activity in cardiac and possibly stellate ganglia) are fully integrated in the central integrative processes, so that the peripheral neural machineries are 'used' by the brain as tools to regulate the functioning of the heart. Do functionally separate sympathetic CM pathways exist, e.g. to the SAN or AVN and to the myocytes? Is the sympathetic pathway to the coronary arteries (cardiovasoconstrictor neurones) separate from the sympathetic pathway(s) to the SAN, AVN or myocytes? If functionally separate sympathetic pathways to the heart do exist this should be reflected in functionally characteristic discharge patterns as functional markers for different populations of sympathetic neurones supplying the heart (Jänig, 2006; Jänig & McLachlan, 2013). This neurophysiological work should be combined with morphological work (intracellular labelling of functionally identified postganglionic neurones with reconstruction of their dendrites and axons). Intracellular recording from postganglionic neurones using the WHBP with attached spinal cord (McAllen et al. 2011) and in vitro experimentation using the SAN and other parts of the heart with attached nerves should be done. Which sympathetic neuronal subtype mediates the detrimental effects on the heart in pathophysiological conditions such as atrial or ventricular fibrillation, myocardial ischaemia, myocardial infarction, sudden cardiac death and the like? Is it possible that the changes in the coronary innervation regulating blood flow is important in these pathological conditions? In humans and higher vertebrates, expression of emotions signals the state of behaviour to conspecifics, being involved in the regulation of social behaviour, whereas the feeling of emotions is involved in internal signalling and regulation of their own behaviour. The generation and modulation of the emotions are believed to be dependent on the state of the body tissues, in particular visceral organs and deep somatic tissues (e.g. skeletal muscle), and therefore on the functions and on the spatio-temporal patterns of the activity in the afferent feedback from these body tissues to their central representations. The afferent neurones have small-diameter myelinated or unmyelinated axons and encode in their activity the mechanical, thermal, metabolic and inflammatory states of the body tissues. They project to lamina I of the spinal or trigeminal dorsal horn (spinal/trigeminal afferent neurones, Craig, 2003b) or to the NTS (vagal afferent neurones). Both lamina I and NTS are the interoceptive interface between body tissues and brain. Their tract neurones project, in addition to various nuclei in brain stem and hypothalamus, via specific thalamic nuclei (the posterior part of the ventromedial nucleus (VMpo) for the lamina I tract neurones and the basal part of the ventromedial nucleus (VMb) for the tract neurones in the NTS) to the dorsal posterior insular cortex. This cortex is according to Craig the primary interoceptive cortex or limbic sensory cortex (Craig, 2003a,b, 2015, 2016). Activity in these afferent feedback systems is also or mainly dependent on the activity in the efferent (autonomic, somatomotor) systems innervating the body tissues. Thus, efferent systems, body tissues and afferent interoceptive feedback form body loops which are hypothesized to be essential in the development (after birth), generation, maintenance and modulation of emotional expression as well as emotional feelings (James, 1884; Damasio, 1999, 2003). What is fact and what fiction? I thank Elspeth McLachlan for her valuable comments and suggestions.