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Neurological Control of Cardiac Function
Posted by Scott November 18th, 2008 | 5,253 words |

Recent developments in cardiovascular research have produced an emerging view of autonomic cardiac regulation that opposes traditional philosophies regarding the roles of various elements of the nervous system in ensuring proper cardiac function. This review outlines the current knowledge of the neuronal control of the heart, with a special emphasis on the role of the “heart brain” in cardiac regulation. The functions of the autonomic nervous system is discussed, as well the connections between the brain and the heart from an anatomical perspective, and the intrinsic cardiac pacemaker system and its ability to be regulated by various neurotransmitters is discussed from a molecular perspective. The intrinsic cardiac nervous system is described in detail, including the morphological, phenotypical, and potential functional differences of individual neurons within the heart. Additionally, comments are provided about the “heart brain” in relation to future pharmacological and other scientific research.

INTRODUCTION

Importance of understanding neuronal control of the heart

Few mammalian organ systems are as critical to immediate survival as the cardiovascular system; temporary malfunction of which provokes life-threading pathological states and can even induce sudden death. Cardiovascular disease is the leading cause of death in the Western hemisphere (Kannel, 2002), claiming over 600,000 lives each year (killing one person every 34 seconds) in the United States alone (Hoyert et al., 2006) (Figure 1). Approximately 80 million American adults (1 in 3) have at least one type of cardiovascular disease (Rosamond et al., 2007). Although malfunctions within the myocardium itself can result in heart failure, the performance of the nervous system is critical to the maintenance proper cardiac function. A healthy and functional heart will stop performing adequately if it is not properly regulated by the nervous system (Chen and Tan, 2007). Recent developments in cardiovascular research have produced an emerging view of cardiac regulation that opposes traditional philosophies regarding the roles of various elements of the nervous system in ensuring proper cardiac function (Armour, 2007). A comprehensive anatomical, functional, and physiological understanding of the heart’s neural network is critical for the ability to develop methods for the detection and treatment of any one of the plethora of cardiovascular diseases which impact humanity (Armour, 2008).

Maintenance of homeostasis via the autonomic nervous system

The autonomic nervous system (ANS) is the compilation of neurons dedicated to maintaining homeostasis throughout the body by controlling the functions of specific tissues. Its primary components include the parasympathetic nervous system (PSNS), sympathetic nervous system (SNS), and the enteric nervous system (ENS) (Furness, 2006) (Figure 2). The general role of the PSNS is to suppress tissue and organ function. This response is often referred to as the “rest and digest” response, and it serves as the primary branch of the ANS that is activated when the body is not experiencing a significant amount of stress. Conversely, the primary role of the SNS is to incite a stimulatory response in body tissues when it becomes activated. This response becomes most active in response to stress. Activation of the SNS response prepares the body for rigorous activity, such as that required to fight or flee from the stressor. This reflex is often referred to as the “fight or flight” response.

Although their functions appear to oppose each other, the sympathetic and parasympathetic branches of the ANS generally work together in a reciprocal fashion to maintain homeostasis (Levy, 1997; Chen and Tan, 2007), with the activity of one branch increasing as the other decreases. Both of these branches contain efferent motonerusons which deliver signals away from the central nervous system (CNS) and toward their target tissues, ultimately serving to control or modify muscle activity. Afferent neurons are those which receive sensory information from the tissue and deliver it to the CNS. Utilizing received from the afferent neurons, the CNS will determine which branch of the ANS to stimulate in order to maintain homeostasis. Ultimately, it is the information sensed and transmitted by the afferent neurons that determines the activity of the sympathetic and parasympathetic branches of the ANS in physiologic conditions (Kukanova and Mravec, 2006).

The ENS (the branch of the ANS devoted to maintaining proper function of the digestive tract) contains elements from the sympathetic and parasympathetic branches of the ANS. However, the ENS possesses the ability to perform a small degree of local information processing independent of the CNS (Catharina and Susanne, 2001 ), allowing it to sense local information (chemical or physical changes), process that information, and generate an appropriate response (Figure 3). One advantage of an organ possessing the ability to perform local information processing is lies in its ability to generate short latency reflexes to specific stimuli much more rapidly than reflexes involving the CNS (Wood, 2008).

NEURONAL CONTROL OF CARDIAC FUNCTION

Anatomical connections between the brain and heart

The autonomic nervous system serves to maintain proper cardiac output by modifying heart function in response to changing cardiac indices and body demands. Signals from the sympathetic and parasympathetic branches of the ANS travel through intrathoracic ganglia (ITG) before reaching the heart. Somatas of preganglionic parasympathetic efferent neurons are located in the ventral lateral region of the nucleus ambiguous and the dorsal motor nucleus (McAllen and Spyer, 1976; Armour and Hopkins, 1984; Klabunde, 2005). These neurons project through the vagus nerve and form synapses with neurons located in multiple intrinsic cardiac ganglia (ICG) located in, on, or near the heart (Figure 4A and Figure 4C). The ICG serve as the ITG of the PSNS. Parasympathetic postganglionic motoneurons (those whose somatas compose are within ICG) innervate the myocardium directly.

Sympathetic preganglionic efferent neurons project primarily from the T1-T5 segments of the spinal cord and form synapses with sympathetic cardiac ganglia located in the sympathetic trunk near the spinal cord (Klabunde, 2005) (Figure 4B and Figure 4C). The stellate ganglion is the primary ganglion of the sympathetic trunk which modulates cardiac function via the SNS (Nozdrachev, 2003). Sympathetic postganglionic motoneurons (those with somatas located in the stellate ganglia) were traditionally believed to simply and directly innervate the myocardium to exert SNS control over the heart (Figure 3C). Recent morphological studies have suggested that these neurons also form synapses with neurons within the parasympathetic ICG (Kukanova and Mravec, 2006).

Afferent neurons convey chemical and physical milieu from the heart to the CNS. Afferents traveling through the vagus nerve enter the nucleus of the solitary tract in the medulla, where the signals may travel to the hypothalamus for advanced processing before an appropriate response (stimulation of inhibition of parasympathetic vagal tone) is determined. Similar afferent neurons convey sensory information from the heart to the spinal cord to stimulate or inhibit sympathetic tone.

Homeostatic indices maintained by neuronal signals

Cardiac functions are modulated by chemicals released as neurotransmitters from the neurites of neurons which belong to the ANS, in addition to circulating hormones. The ANS regulates cardiac function in response to signals it receives from cardiac afferent neurons. Such neurons include baroreceptors (which measure blood pressure), volume receptors (stretch receptors which measure blood volume), chemoreceptors (which measure blood chemical content and pH), and osmoreceptors (which measure plasma osmolarity) (Klabunde, 2005). The CNS responds by activating the appropriate branch of the ANS to stimulate or depress various cardiac features such as chronotropy (heartbeat rate), inotropy (ventricle contractility), dromotrophy (conduction velocity), or vascular features such as resistance (in the arteries and arterioles) or capacitance (in veins and venules).

Stimulation or suppression of various cardiac functions via nerve stimulation is accomplished by the release of two main classes of neurotransmitters from the neurites of autonomic neurons (Potter et al., 1980). Postganglionic efferent neurons of the PSNS are cholinergic, meaning that they release acetocholine (Ach) as their primary neurotransmitter. The release of Ach in the myocardium has a suppressive effect on cardiac function, reducing dromotropy and inotropy. Postganglionic efferent neurons of the SNS are adrenergic, meaning that they release norepinephrine (NE, sometimes referred to as noradrenaline) as their primary neurotransmitter. NE is synthesized from L-tyrosine (an amino acid) so it is also referred to as a catecholaminergic neurotransmitter. NE has a stimulatory effect on the heart, increasing dromotropy and inotropy.

ACh and NE generally have opposite effects when administered directly to the myocardium. The differential effects of cardiac functions (chronotropy, inotropy, and dromotrophy) in response to the ANS are due either to the release of Ach from PSNS postganglionic efferent neurons or NE release from SNS postganglionic efferent neurons. NE released from sympathetic terminals activates postjunctional adenoceptors (β1, β2, and α1) to stimulate cardiac function. Ach released from parasympathetic terminals activates prejunctional musinaric receptors (M2) on the sympathetic nerve terminals, inhibiting NE release, and leading to the suppression of cardiac function. The different mechanisms by which these two neurotransmitters regulate chronotropy will be discussed at the molecular level later in this document.

Mechanisms by which the cardiac pacemaker system operates

Rather than depending on the CNS to command every individual heart beats, the heart possesses its own intrinsic pacemaker system which allows it to beat spontaneously (See Brown et al., 1979 for an extensive review). The posterior wall of the right atrium houses the sinoatrial (SA) node (Figure 5), a portion of unique muscle tissue which spontaneously initiates heartbeats by rhythmically generating and releasing action potentials at a rate of 100-110 depolarizations per minute. Although other cells in the heart also possess the ability to generate rhythmic spontaneous action potentials, the SA node generates them the fastest and therefore serves as the primary pacemaker of the heart. Electrical signals generated by the SA node are conducted throughout the atria and to the atrioventricular (AV) node in the inferior-posterior region of the interatrial septum (Figure 5). The AV node slows the conduction of the SA-generated electrical impulse as it travels toward the ventricles. Action potentials leave the AV node slowly through the bundle of His and travel to Purkinje fibers which conduct the impulses throughout the ventricles at high velocity, ultimately leading to ventricular contraction (Figure 5). The SA node and AV node work together to promote proper cardiac function by initiating contraction of the atria and ventricles separately. Spontaneous depolarization of the SV node causes the atria to contract, pushing blood into the ventricles. The delay provided by the AV node and the bundle of His allows sufficient time for blood to enter the ventricles prior to their contraction.

The mechanism underlying the spontaneous generation of action potentials by the specialized cells in the SA node involves 3 main phases (Figure 6): upstroke (phase 0), repolarization (phase 3), and spontaneous depolarization (phase 4).

The upstroke phase (phase 0) is triggered when the membrane potential of pacemaker muscle cells rises over the threshold (approximately -40 mV). The threshold potential is that which allows voltage gated L-type calcium channels open, promoting the import of Ca2+ into the cells. Because the movement of Ca2+through these channels is not rapid, the speed of depolarization is much slower in cells of the SA node than other cardiac cells (such as Purkinje cells).

Depolarization triggers voltage operated potassium channels to open, allowing K+ to exit the cell, resulting in a repolarizing effect. Once the membrane potential increases to the point where it crosses the threshold (in the reverse direction), the voltage gated L-type calcium channels close. The membrane potential of the cells eventually reaches a state of maximum hyperpolarization (-60 mV), at which time the potassium channels close.

Phase 4 begins after the cells have become hyperpolarized. Due to a slow efflux of potassium from within the cells, the degree of polarization decreases until it reaches the threshold, at which time phase 0 begins again and initiates another action potential. A special pacemaker current (sometimes referred to as a “funny current”, or If) also assists in the gradual depolarization of polarized cardiac pacemaker cells (Accili et al., 2002 ). Although its exact mechanism is unknown, it is believed that a slow inward movement of sodium ions also results in the gradual depolarization of phase 4.

Mechanisms by which the ANS modifies chronotropy

Neurons of the ANS modify chronotropy by releasing specific neurotransmitters directly into the SA node (Brown et al., 1979,Klabunde, 2005). These neurotransmitters have inhibitory (Ach released by the PSNS) or stimulatory (NE released by the SNS) effects on the SA node. Neural control of the SA node involves either changing the rate at which pacemaker cells slowly depolarize in phase 4, altering the threshold to trigger rapid depolarization in phase 0, or altering the degree of hyperpolarization at the end of phase 3. It is important to note that some circulating hormones (such as adrenaline) can be excreted into the blood by various body tissues to modify cardiac functionality similarly, but direct input from the ANS provides a more rapid and finder degree of control of the myocardium.

When at rest, the parasympathetic branch of the ANS is the dominant autonomic influence over body tissues. Ach released by the PSNS decreases the depolarization rate of the SA node through a combination three molecular mechanisms. First, Ach binds to M2 receptors (a type of G-protein receptor) which eventually leads to the decrease of intracellular cAMP levels. Since cAMP promotes the open state of L-type calcium channels and increases If current, its absence decreases the rate at which the cell depolarizes (phase 4 and phase 0). Second, Ach may increase the concentration of intracellular cGMP (which inactivates L-type calcium channels, increasing the amount of time it takes to complete phase 3) through the NO-cGMP pathway (Booz, 2005; Domek-Łopacińska and Strosznajder, 2005). Finally, the binding of Ach to the M2 receptors may activate a special type of potassium channel (KAch) which serves to import potassium during phase 4, increasing the amount of time between action potentials. The PSNS exerts a continuous tone when the body is at rest, which serves to suppress chronotropy (as well as other cardiac functions) below its intrinsic level.

To increase heart function by escalating chronotropy during times of stress, the sympathetic branch of the ANS releases NE into the SA node. NE binds to the B1 (G-protein) receptors eventually leading to the activation of adenylate cyclase, promoting the synthesis of cAMP. Amplified levels of cAMP promote an increased tempo of depolarizations by promoting the open state of L-type calcium channels and increasing If current.

The traditional view of autonomic cardiac regulation suggests that the SNS and PSNS control the heart independently in a reciprocal fashion using the two primary mechanisms described. In addition to releasing neurotransmitters to the SA and AV nodes, postganglionic neurons from both branches of the ANS innervate the atria and ventricles to allow for the release of neurotransmitters within the muscle itself, modifying its contractibility as well as other properties. Although reciprocal control of the myocardium by the parasympathetic and sympathetic branches of the ANS is a simple and straightforward model of cardiac regulation, recent morphological, physiological, and immunohistochemical findings suggest that the SNS and PSNS work together to detect and regulate cardiac function accordingly (Chen and Tan, 2007).

INTRINSIC CARDIAC NERVOUS SYSTEM

Components of the intrinsic cardiac nervous system

The control mechanisms that regulate cardiac indices are very complex, and have only recently begun to be described in detail (Kukanova and Mravec, 2006). The general function and significance of myocardium innervation by postganglionic efferent neurons from both branches of the ANS has been known for some time. Although the ICG were observed within the myocardium, their role was traditionally believed to be simple relay stations, serving to receive parasympathetic signals from the CNS and convey them to the appropriate regions of the myocardium. However, some studies have shown that select populations of neurons located within the myocardium do not receive innervation from either branch of the ANS and do not send axons out of the heart, representing a class of neurons located entirely within the myocardium (Gray et al., 2004). These local circuit neurons (LCNs) have not only been observed to form synapses with other neurons within the same ICG, but have also been observed forming synapses with neurons in other cardiac ganglia. Recent data has emerged suggesting that the intracardiac neurons (ICNs) play a vital role in modulating heart function (Arora et al., 2003).

The complex interactions of neurons within the ICG suggests that they may contribute more to cardiac regulation than acting as simple relay stations. The presence of ICNs receiving inputs from the both (parasympathetic and sympathetic) branches of the ANS (Leger et al., 1999) as well as input from local afferent neurons (Gray et al., 2004) suggests that a considerable degree of local information processing may be occurring within the ICNs. This complicated network of ICNs (Figure 7) comprises the intrinsic cardiac nervous system (ICNS), and its suggested ability to perform local integrative processing and regulation of cardiac function has resulted in it being dubbed “little brain on the heart” (Armour, 2007).

Although the specific functionality of different ICG (or individual neurons within ICG) remains unknown, evidence points to the complex nature of this neural network (Kukanova and Mravec, 2006,Gray et al., 2004). The morphological and phenotypical differences of individual neurons commonly found within ICG (Leger et al., 1999; Richardson et al., 2003; Yasuhara et al., 2006; Horackova et al., 1999; Kennedy et al., 1998) suggest functional differences between these neurons, further supporting the concept of a “heart brain”. Although research may one day elucidate the exact function of individual neurons within the ICNS, most of the research conducted thus far has focused on identifying the different types of neurons it is composed of by studying their morphology or differential levels of protein expression.

Morphological and phonotypical differences among neuronal subpopulations

Utilizing immunohistochemical techniques combined with confocal microscopy, researchers have identified many different types of neurons within ICG by their morphological properties and/or the proteins they express. Two main morphological classes of neurons in the heart are principal neurons (PNs) and small intensely fluorescent (SIF) cells.

Within ICG, PNs are more numerous and larger in size than SIF cells. Postganglionic efferent neurons of the PSNS are PNs, providing motor control over the myocardium. PNs are usually 20-40µm in diameter and are immunoreactive (IR) for proteins involved in the synthesis and transport of ACh (Yasuhara et al., 2006). SIF cells are believed to be sensory cells which receive local chemical or physical input (via short dendrites) and in response release neurotransmitters to neurons located nearby (via very short and thin axons), acting as LCNs (Figure 7). Small clusters of SIF cells with their somatas in direct physical contact with the somatas PNs have been observed in the ICG of mice (Figure 8). Unlike PNs, SIF cells are intensely IR for proteins involved in the synthesis and transport of catecholamines (Slavíková et al., 2003).

Since the ICG are composed of parasympathetic postganglionic efferent neurons which release ACh as their primary neurotransmitter, proteins involved with the synthesis and transport of ACh are found in the somatas of all PNs within ICG (Yasuhara et al., 2006). For example, choline acetyl transferase (ChAT; an enzyme which acetylates choline molecules to form ACh) is found within the bodies of all ICG PNs, but not in SIF cells. This evidence supports the notion that SIF cells do not release Ach, but PNs of the ICG do.

Tyrosine Hydroxylase (TH) is the rate limiting enzyme in the synthesis of catecholamines (stimulatory neurotransmitters primarily released by the SNS, such as NE and adrenaline). SIF cells are strongly IR to TH (Eränkö, 1978 ). Surprisingly, many of the neurons within some ICG are also IR to TH (Yasuhara et al., 2006) - a finding which opposes the traditional notion that cholinergic ICG act as simple relay stations for the PSNS. Intriguingly, TH-IR PNs within ICG are not TH-IR with the vesicular monoamine transporter (Weihe et al., 2005 ), a critical protein involved in the formation of synaptic vesicles containing NE. This finding is paradoxical; why do some PNs possess the ability to synthesize TH if they do not also possess the ability to use it as a neurotransmitter? Without the vesicular monoamine transporter, any cholaminergic products synthesized by TH are quickly degraded in the cytoplasm (Croft et al., 2005).

Other protein makers that have been found to only reside in a subpopulation of neurons within ICG are nitric oxide synthase (NOS) and calbindin. It was noted that no cells IR for NOS contained calbindin (and visa versa), suggesting that these two subpopulations of neurons possess different functions. There are many other studies which characterize the phenotypes of neurons within the ICG of mammals by performing immunohistochemical studies on individual proteins (Leger et al., 1999; Richardson et al., 2003; Yasuhara et al., 2006; Horackova et al., 1999; Kennedy et al., 1998), but to date the specific functions of these individual phenotypes of neurons within ICG is unknown. However, the complexity of the ICG (both in their connections with the ANS and LCNs, as well as the multitude of neuronal phenotypes found within) suggests that they possess the ability to perform complex information integration functionality.

Role of the “heart brain” in cardiac regulation

Many ICG contain neurons which receive input from the PSNS, SNS, SIF cells, and other ICG while also containing motoneurons which are able to act upon the myocardium directly (Gray et al., 2004). This complicated network of afferent, efferent, and local circuit connections (Figure 7) provides the anatomical and functional bases for a complex ICNS (Kukanova and Mravec, 2006). Multiple phenotypical and morphological studies have suggested that chemical and structural diversity supports the theory of the “heart brain”, where ICG possess ability to perform complex local information processing.

To test the function of ICG in situ, one study utilized an ablation device to selectively destroy individual intrinsic cardiac ganglia (Hou et al., 2007) in a canine model. Disabling the ICG (traditionally viewed as completely parasympathetic in nature) by ablation resulted in a reduction of modulation of cardiac function by the sympathetic branch of the ANS (activated via vasosympathetic stimulation). This evidence further supported theory that the ICG are more than just relay centers, but rather serve as “integration centers” that modulate the actions of the ANS by processing information from both branches of the ANS, as well as local information from LCNs.

The decreased size and complexity of the “heart brain” compared to the brain itself suggests that the CNS is still the dominant mechanism of large-scale information processing and control of cardiac function. However, for smaller issues raised throughout the normal cardiac cycle, different regions of the ICNS are most likely able to detect small perturbations and correct the problem without involving the CNS. This gives rise to a model of three different levels of cardiac reflexes which are activated on the bases of the magnitude of the stimulus and classified by the speed at which the reflex can occur (Armour, 2008).

First, short latency reflexes are those that are triggered by small perturbations, such as the development of a single arrhythmatic heart beat. The ICG adjacent to the cardiomyocytes may be able to detect the perturbation and correct it during the same heartbeat. Because the information processing center is so close to the heart, these reflexes only take 20-40 ms to potentiate.

The second level in the autonomic cardiac hierarchy involves intermediate latency reflexes. These reflexes are triggered by a more severe perturbation, and the information is processed by the ITG (such as the stellate ganglia). These ganglia display some memory characteristics, because a stimulus during a single arrhythmatic heartbeat can stimulate the corrective reflex through the next several subsequent heartbeats as well. Intermediate latency reflexes take approximately 100-200 ms to potentiate.

Finally, long term reflexes are those generally associated with the parasympathetic and sympathetic branches of the ANS emerging from the CNS. Such reflexes are also responsible for chronic conditions, such as hypertension. The CNS is responsible for these reflexes and modulates the tone of the SNS or PSNS as a result. However, due to the time it takes for information to travel distance from the heart to the CNS, be processed by higher centers in the brain, and travel back into the heart, the fastest possible reflex times are believed to be 125-300 ms.

Due to the increasing delay caused by cardiac information traveling to higher levels of the ANS, it is vital that small in-beat perturbations be processed locally, rather than by the CNS. This allows small cardiac perturbations (such as the onset of an arrhythmatic heart beat) to be fixed mid-beat by temporary control by the ICNS, while ultimate command of cardiac function still lies with the CNS. Although each portion of the heart is at all times modulated by the CNS, another advantage of possessing a “heart brain” is that the CNS does not have to be burdened by every small perturbation the heart experiences. Instead, small issues can be resolved locally, increasing the effectiveness and efficiency of the heart to respond to minor perturbations.

DISCUSSION

Relevance of the changing view of cardiac regulation

In recent years, the traditional view of cardiac regulation managed entirely and directly by the CNS has been replaced by an emerging view in which the “heart brain” serves as an integration and command center, incorporating information from the CNS, LCNs, and SIF cells to appropriately command the functionality of Cardiomyocytes (Figure 9). Now that the extreme complexity of the ICNS is becoming evident, clinical and pharmacological studies of the various elements within it will benefit from its elucidation. Although the efficacy of selectively targeting individual components of the ICNS for treatment in humans is still speculative, some studies have shown that the modification of individual cardiac ganglia can produce a positive effect in reducing atrial arrhythmias in dogs (Hou et al., 2007). Increased knowledge about the methods of communication between neurons at all levels of the cardiac neuroaxis may yield pharmacological treatments of pathological cardiac conditions based upon the stimulation or blockade of specific receptors of the CNS, ICNS, or one of the elements in between. From a pharmacological basis, the development of treatments for many pathological cardiac states will be aided if the proper mechanisms by which the entire cardiac neuroaxis regulates heart function are illuminated.

Direction of future research

Although recent studies have revealed much about the ICNS, there is still much left to be understood. Phenotypical differences in subpopulations of neurons within ICG have been extensively classified (Leger et al., 1999; Richardson et al., 2003; Yasuhara et al., 2006; Horackova et al., 1999; Kennedy et al., 1998), but there is still an enormous need to determine the functionality of these different types of neurons. Additionally, the overall morphology of the ICNS needs to be further described. This has been prevented by many studies which, while only attempting to identify phenotypical markers utilizing immunohistochemical methods, have produced severely limited results by sectioning cardiac tissue, yielding the analysis of the intercardiac and intracardiac connections impossible. Whole mount preparations, although more cumbersome to prepare and analyze, yield a wealth of information not only about neuronal phenotypes within an individual ganglion, but also the structure of connections within that ganglion as well as interconnections between other ganglia (Horackova et al., 1999).

Conclusion

The cardiac neuroaxis is far more intricate than traditionally assumed. ICG are to be thought of as more than simple relay stations conveying signals from the CNS to the heart. The interconnected ICG (whose neurons can receive input from the CNS as well as LCNs and SIF cells) form the “heart brain” (Fig 7), which performs the role of an integration and command station. Although always ultimately regulated by the sympathetic and parasympathetic branches of the ANS, the heart is actually controlled by this complicated network of ICG, which processes input from the PSNS, SNS, ITG, and LCNs, process the signals it receives, and commands the myocardium accordingly. The high degree of intrinsic autonomic control able to be performed without interaction with the CNS may even suggest that the cardiac nervous system should be the added alongside the parasympathetic, sympathetic, and enteric nervous system as a fourth primary branch of the ANS.

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MANY IMAGES WILL NOT BE DISPLAYED DUE TO COPYRIGHT ISSUES

Figure 1: Cardiovascular disease is at the top of the list of leading causes of death in the United States in 2003.

Adapted from Hoyert et al., 2006

Figure 2: Simplified schematic depicting efferent projections of the sympathetic (left) and parasympathetic (right) branches of the autonomic nervous system and the target tissues that they innervate.

Notice the complexity of the ENS represented by multiple subpopulations of neurons within the gastrointestinal tract.

(1) Eye, (2) Lacrimal glands, (3) Intracranial arteries, (4, 5) Salivary glands, (6) Airways, (7) Brown fat, (8) Heart, (9) Liver, (10) Spleen, (11) Pancreas, (12) Gallbladder, (13) Adrenal gland, (14) Tubular gastrointestinal tract, (15) Kidney, (16) Urinary bladder, (17) Genital organs, (18) Prevertebral ganglia and plexuses, (19, 20) Sympathetic chains (paravertebral ganglia and their interconnections). Spinal cord levels: C, cervical; T, thoracic; L, lumbar; S, sacral.

Adapted from Furness, 2006

Figure 3: Schematic representation of enteric reflexes. Although the enteric nervous receives inputs from the PSNS and SNS branches of the ANS from the CNS, it also possesses the ability to sense, process, and generate rapid responses independent of the CNS.

Adapted from Catharina and Susanne, 2001

Figure 4: Cardiac innervation by the ANS. A. The PSNS projects from the brainstem to ICG near the heart via the vagus nerve. B. The SNS projects from the spinal cord to the sympathetic trunk, then the sympathetic ganglion projects to the heart. C. A simplified schematic displaying both primary efferent branches of the ANS.

Figure 5: A simplified representation of the main tissues involved in generating and conducting electrical impulses generated by the intrinsic cardiac pacemaker system.

Figure 6: 4 main phases of polarization within cardiomyocytes of the SA node.

Fig 7: Simplified schematic of neurons within an ICG. Arrows indicate direction of signal transmission.

(A) Axon of parasympathetic preganglionic neuron

(B) Parasympathetic postganglionic neuron

(D) Sympathetic neuron

(E) Axon from neuron localized in another ICG

(F) SIF cell

(G) Axon innervating another ICG

(H) Sensory LCN

(HG) ICG

Adapted from Kukanova and Mravec 2006

Figure 8: Confocal image depicting SIF cells (arrowheads) in physical contact with PNs (arrow) on the periphery of an ICG in a mouse. (Scale bar 20 µm; Yellow is TH-IR; blue-gray is background fluorescence)

Figure 9: Schematic representation of the traditional vs. emerging view of cardiac regulation by the ANS.

Solid lines – efferent pathways

Broken lines – afferent pathways

DRG – dorsal root ganglia

HG – ICG

NG – nodose ganglia

PSG – parasympathetic ganglia

SG – sympathetic ganglia

ABBREVIATIONS:

ACh Acetocholine

ANS Autonomic Nervous System

ChAT Choline Acetyl Transferase

CNS Central Nervous System

ICG Intrinsic Cardiac Ganglia

ICNs Intracardiac Neurons

ICNS Intrinsic Cardiac Nervous System

IR Immunoreactive

TH Tyrosine Hydroxylase

ITG Intrathoracic Ganglia

LCNs Local Circuit Neurons

NE Norepinephrine

NOS Nitric Oxide Synthase

PNs Principal Neurons

PSNS Parasympathetic Nervous System

SIF Small Intensely Fluorescent

SNS Sympathetic Nervous System