Cardiac Ganglion Neurons Research Articles

Topographical mapping of catecholaminergic axon innervation in the flat-mounts of the mouse atria: a quantitative analysis

The sympathetic nervous system is crucial for controlling multiple cardiac functions. However, a comprehensive, detailed neuroanatomical map of the sympathetic innervation of the heart is unavailable. Here, we used a combination of state-of-the-art techniques, including flat-mount tissue processing, immunohistochemistry for tyrosine hydroxylase (TH, a sympathetic marker), confocal microscopy and Neurolucida 360 software to trace, digitize, and quantitatively map the topographical distribution of the sympathetic postganglionic innervation in whole atria of C57Bl/6 J mice. We found that (1) 4–5 major extrinsic TH-IR nerve bundles entered the atria at the superior vena cava, right atrium (RA), left precaval vein and the root of the pulmonary veins (PVs) in the left atrium (LA). Although these bundles projected to different areas of the atria, their projection fields partially overlapped. (2) TH-IR axon and terminal density varied considerably between different sites of the atria with the greatest density of innervation near the sinoatrial node region (P < 0.05, n = 6). (3) TH-IR axons also innervated blood vessels and adipocytes. (4) Many principal neurons in intrinsic cardiac ganglia and small intensely fluorescent cells were also strongly TH-IR. Our work provides a comprehensive topographical map of the catecholaminergic efferent axon morphology, innervation, and distribution in the whole atria at single cell/axon/varicosity scale that may be used in future studies to create a cardiac sympathetic-brain atlas.

Abstract 9479: Defined Subsets of Sympathetic Neurons Innervate the Heart and Differentially Respond to Cardiac Pathology

Introduction: Sympathetic regulatory aspect of cardiac functions is governed by neural circuit originating from postganglionic sympathetic neurons (PGNs) that primarily reside in stellate ganglia. PGNs is comprised of a diversified neuronal population that innervate heart and other tissue beds. Hypothesis: We hypothesize that cardiac innervating stellate ganglionic neurons (SGNs) exhibit diversity and distinction from those innervating other organs. In the settings of cardiac pathology, distribution of cardiac neuronal subtypes is altered, yielding a dominant neuronal subtype. Methods: We utilized method of retrograde axonal transport from heart and paw using adeno-associated virus (AAV-GFP/tdTomato, 1+e12 gc/ml, 10μl) followed by single cell RNA sequencing (scRNAseq) to identify and resolve transcriptomic profiles of SGNs in normal (n=8) and heart-failure mice (n=4). Using NPY-hrGFP mice, we characterized membrane excitability for NPY high and NPY low neurons (n=11). We delineated impact of NPY on cardiac sympathoexcitation by injecting AAV5-Flex-taCasp3 in NPY-Cre mice (n=8) and afterwards electrically stimulating right stellate ganglia (RSG). Results: In our scRNAseq study, we identified 3 adrenergic neuronal subtypes (NA1a, NA1b, and NA3) innervate heart. These subtypes differentiated as NPY high (NA1a) and NPY low (NA1b and NA3) subpopulations. NPY high (4.250±0.90) showed higher number of action potentials compared to NPY low (1.818±0.18). Cardiac sympathoexcitation was diminished in NPY-ablated mice compared to controls in response to escalating intensities (1, 5, 10, 15, &amp; 20 Hz). Maximal heart-rate change was detected at 10 Hz (p = 0.0240) for NPY-ablated mice (91.061±12.62 bpm) vs. controls (27.017±11.88). Across mice, ~70% of cardiac neurons are NPY+. In dilated cardiomyopathy mice, NA1b is a predominant subtype, consists of increased expression of Kcnq2 (M-current) and significant enriched pathways neurodegenerative disorders and neurotrophic signaling. Conclusion: These findings provide novel insights into the unique properties of neurons responsible for cardiac sympathetic regulation, with implications for novel strategies to target specific neuronal subtypes for sympathetic blockade in cardiac disease.

Molecularly defined circuits for cardiovascular and cardiopulmonary control.

The sympathetic and parasympathetic nervous systems powerfully regulate internal organs1, but the molecular and functional diversity of their constituent neurons and circuits remains largely unknown. Here we use retrograde neuronal tracing, single-cell RNA sequencing, optogenetics, and physiological experiments to dissect the cardiac parasympathetic control circuit in mice. We show that cardiac-innervating neurons in the brainstem nucleus ambiguus (Amb) are comprised of two molecularly, anatomically, and functionally distinct subtypes. One we call ACV (ambiguus cardiovascular) neurons (~35 neurons per Amb), define the classical cardiac parasympathetic circuit. They selectively innervate a subset of cardiac parasympathetic ganglion neurons and mediate the baroreceptor reflex, slowing heart rate and atrioventricular node conduction in response to increased blood pressure. The other, ACP (ambiguus cardiopulmonary) neurons (~15 neurons per Amb) innervate cardiac ganglion neurons intermingled with and functionally indistinguishable from those innervated by ACV neurons, but surprisingly also innervate most or all lung parasympathetic ganglion neurons; clonal labeling shows individual ACP neurons innervate both organs. ACP neurons mediate the dive reflex, the simultaneous bradycardia and bronchoconstriction that follows water immersion. Thus, parasympathetic control of the heart is organized into two parallel circuits, one that selectively controls cardiac function (ACV circuit) and another that coordinates cardiac and pulmonary function (ACP circuit). This new understanding of cardiac control has implications for treating cardiac and pulmonary diseases and for elucidating the control and coordination circuits of other organs.

Topographical Mapping of Catecholaminergic Axon Distribution and Morphology in the Flat‐Mounts of the Mouse Heart

The sympathetic nervous system plays a crucial role in the control of heart functions. However, the distribution and morphology of sympathetic postganglionic innervation of the heart has not been well elucidated, which has significantly impeded the understanding of the sympathetic neuroanatomical organization and control of the heart. Our goal is to provide a map of the topographical innervation of sympathetic postganglionic neurons in the whole heart of mice. In this study, we used Tyrosine hydroxylase (TH) as a marker for sympathetic axons and applied a combination of state‐of‐the‐art techniques, including confocal microscopy, Zeiss Imager microscopy, flat‐mount tissue processing and immunohistochemistry, Neurolucida 360 Tracing and integration of the tracing data onto a 3D heart scaffold. We found that 1) Multiple large extrinsic TH‐IR nerve bundles entered the heart and branched out into smaller axons which covered the whole left and right atria and ventricles, 2) These TH‐IR bundles branched out into smaller axon bundles and ramified into individual axons covering the whole left and right atria and ventricles. 3) The TH‐IR axons formed an extensive neural network in the epicardium and axons formed varicose synaptic endings within the cardiac muscle. 4) TH‐IR axons and terminals were densest in the sinoatrial (SA) and atrioventricular (AV) node regions. 5) TH‐IR axons innervated blood vessels and fat cells. 6) Many principal neurons in intrinsic cardiac ganglia and small intensely fluorescent (SIF) cells were TH‐IR. 7) However, TH‐IR axons do not appear to innervate any cardiac principal neurons and SIF cells. 8) TH‐IR axon innervation will be integrated into a 3D scaffold. Our work will provide a comprehensive topographical map of the catecholaminergic efferent axon distribution, innervation, and morphology of the whole heart at single cell/axon/synapse scale that will be used to create a cardiac sympathetic‐brain atlas. It will also provide an anatomical reference to evaluate the altered sympathetic cardiac control in pathological conditions. The first two authors contributed equally to this work.

Electrical properties and synaptic transmission in mouse intracardiac ganglion neurons in situ.

The intrinsic cardiac nervous system represents the final site of signal integration for neurotransmission to the myocardium to enable local control of cardiac performance. The electrophysiological characteristics and ganglionic transmission of adult mouse intrinsic cardiac ganglion (ICG) neurons were investigated using a whole‐mount ganglion preparation of the excised right atrial ganglion plexus and intracellular microelectrode recording techniques. The passive and active electrical properties of ICG neurons and synaptic transmission including synaptic response strength and efficacy as a function of stimulation frequency were examined. The resting membrane potential and input resistance of ICG neurons were −47.9 ± 4.0 mV and 197.2 ± 81.5 MΩ, respectively. All neurons had somatic action potentials with overshoots of >+15 mV and after‐hyperpolarizations having an average of 10 mV amplitude and ~45 ms half duration. Phasic discharge activities were recorded from the majority of neurons studied and several types of excitatory synaptic responses were recorded following inputs from the vagus or interganglionic nerve trunk(s). Most postganglionic neurons (>75%) received a strong, suprathreshold synaptic input and reliably followed high‐frequency repetitive nerve stimulation up to at least 50 Hz. Nerve‐evoked synaptic transmission was blocked by extracellular Cd2+, ω‐conotoxin CVIE, or α‐conotoxin RegIIA, a selective α3‐containing nicotinic acetylcholine receptor antagonist. Synaptic transmission and the electrical properties of murine ICG neurons contribute to the pattern of discharge which regulates chronotropic, dromotropic, and inotropic elements of cardiac function.

Exosomes derived from cardiac parasympathetic ganglionic neurons inhibit apoptosis in hyperglycemic cardiomyoblasts.

Diabetic cardiomyopathy is known to involve two forms of cardiac cell death: apoptosis and necrosis. However, it remains unknown whether hyperglycemia-induced apoptosis in the H9c2 cell culture system is inhibited by parasympathetic ganglionic neurons (PGN) derived exosomes (exos). We isolated PGN and sympathetic ganglionic neurons (SGN) from the right stellate ganglion in rats, and derived exos from these sources. H9c2 cells were divided into 4 groups: (1) Control, (2) H9c2 + Glucose (100mmol/L), (3) H9c2 + Glucose + PGN-exos, and (4) H9c2 + Glucose + SGN-exos. We determined cell proliferation and viability with an MTT assay kit, and assessed apoptotic cell death with TUNEL staining and ELISA. Data were further confirmed by analyzing the presence of pro-apoptotic proteins Caspase-3 and Bax, and anti-apoptotic protein Bcl-2. Glucose exposed H9c2 cells significantly reduced cell viability, which was improved by PGN-exos, but not by SGN-exos. Furthermore, increased apoptosis in hyperglycemia in H9c2 cells was confirmed with TUNEL staining and cell death ELISA which demonstrated significantly (p < 0.05) reduction with PGN-exos treatment, but not with SGN-exos. Moreover, high expression of pro-apoptotic proteins Caspase-3 and Bax was reduced following treatment with PGN-exos; however, SGN-exos were unable to reduce the expression. Significantly reduced anti-apoptotic protein Bcl-2 following glucose treatment was improved with PGN-exos. Therefore, our data suggest that hyperglycemia induces apoptosis in H9c2 cells and decreases cell viability, and that PGN-exos are able to inhibit apoptosis, improve cell viability, and restore levels of anti-apoptotic protein Bcl-2.

Intrinsic Cardiac Ganglionic Neurons Projecting to the SA node in the Rat and Pig Hearts: Retrograde Labeling and Neurolucida 3‐D Reconstruction

Intrinsic cardiac ganglionic neurons (ICNs) within the heart are essential for regulation of cardiac function. ICNs include afferent, efferent neurons and interneurons and constitute a local integration center. In rat and pig hearts, there are multiple cardiac ganglia. Among these ganglia, the largest ganglionated plexus in the rat heart and the right atrial ganglionic plexus (RAGP) in the pig heart are near the sinoatrial node (SAN). However, it is not clear whether both plexi project to the SAN. In this study, retrograde tracer Fast DiI was injected into the SAN in rats (n=5) and a pig. SAN cells were identified by immunostaining for pacemaker channel HCN4. Fluorogold (FG) was injected (i.p.) to label all of the ICNs in rats. FG‐ and DiI‐labeled ICNs were identified and analyzed using a confocal microscopic system and a Neurolucida Tracing and Digitization System. Sixteen days after Fast DiI injection in rats, the animals were perfused with paraformaldehyde, and the whole‐mount atria were prepared. There were multiple ganglionated plexi and the DiI‐labeled neurons were mainly found in the largest ganglionated plexus near the SAN in all these rats. Twenty‐one days after Fast DiI injection in the pig, the animal was sacrificed, and the RAGP was removed and sectioned at 40 μm. Numerous DiI‐labeled neurons were found in the RAGP of this pig. Interestingly, these DiI‐labeled neurons were organized in five spatially‐separated columns perpendicular to the epicardial surface. Our data suggest that the largest ganglionated plexus in rat indeed projects mainly to the SAN, and the pig RAGP projects very heavily to the SAN. The functional significance of this large ganglionated plexus in rat and the five spatially‐separated columns of RAGP ICN projecting neurons in the pig will be elucidated in the future.Support or Funding InformationSupported by NIH SPARC grant OT2OD023848, NIH R15HL137143‐01A1.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Variable expression of GFP in different populations of peripheral cholinergic neurons of ChATBAC-eGFP transgenic mice.

Immunohistochemistry is used widely to identify cholinergic neurons, but this approach has some limitations. To address these problems, investigators developed transgenic mice that express enhanced green fluorescent protein (GFP) directed by the promoter for choline acetyltransferase (ChAT), the acetylcholine synthetic enzyme. Although, it was reported that these mice express GFP in all cholinergic neurons and non-neuronal cholinergic cells, we could not detect GFP in cardiac cholinergic nerves in preliminary experiments. Our goals for this study were to confirm our initial observation and perform a qualitative screen of other representative autonomic structures for the presences of GFP in cholinergic innervation of effector tissues. We evaluated GFP fluorescence of intact, unfixed tissues and the cellular localization of GFP and vesicular acetylcholine transporter (VAChT), a specific cholinergic marker, in tissue sections and intestinal whole mounts. Our experiments identified two major tissues where cholinergic neurons and/or nerve fibers lacked GFP: 1) most cholinergic neurons of the intrinsic cardiac ganglia and all cholinergic nerve fibers in the heart and 2) most cholinergic nerve fibers innervating airway smooth muscle. Most cholinergic neurons in airway ganglia stained for GFP. Cholinergic systems in the bladder and intestines were fully delineated by GFP staining. GFP labeling of input to ganglia with long preganglionic projections (vagal) was sparse or weak, while that to ganglia with short preganglionic projections (spinal) was strong. Total absence of GFP might be due to splicing out of the GFP gene. Lack of GFP in nerve projections from GFP-positive cell bodies might reflect a transport deficiency.

Parasympathetic dysfunction and antiarrhythmic effect of vagal nerve stimulation following myocardial infarction.

Myocardial infarction causes sympathetic activation and parasympathetic dysfunction, which increase risk of sudden death due to ventricular arrhythmias. Mechanisms underlying parasympathetic dysfunction are unclear. The aim of this study was to delineate consequences of myocardial infarction on parasympathetic myocardial neurotransmitter levels and the function of parasympathetic cardiac ganglia neurons, and to assess electrophysiological effects of vagal nerve stimulation on ventricular arrhythmias in a chronic porcine infarct model. While norepinephrine levels decreased, cardiac acetylcholine levels remained preserved in border zones and viable myocardium of infarcted hearts. In vivo neuronal recordings demonstrated abnormalities in firing frequency of parasympathetic neurons of infarcted animals. Neurons that were activated by parasympathetic stimulation had low basal firing frequency, while neurons that were suppressed by left vagal nerve stimulation had abnormally high basal activity. Myocardial infarction increased sympathetic inputs to parasympathetic convergent neurons. However, the underlying parasympathetic cardiac neuronal network remained intact. Augmenting parasympathetic drive with vagal nerve stimulation reduced ventricular arrhythmia inducibility by decreasing ventricular excitability and heterogeneity of repolarization of infarct border zones, an area with known proarrhythmic potential. Preserved acetylcholine levels and intact parasympathetic neuronal pathways can explain the electrical stabilization of infarct border zones with vagal nerve stimulation, providing insight into its antiarrhythmic benefit.

Characterization of glutamatergic neurons in the rat atrial intrinsic cardiac ganglia that project to the cardiac ventricular wall

The intrinsic cardiac nervous system modulates cardiac function by acting as an integration site for regulating autonomic efferent cardiac output. This intrinsic system is proposed to be composed of a short cardio-cardiac feedback control loop within the cardiac innervation hierarchy. For example, electrophysiological studies have postulated the presence of sensory neurons in intrinsic cardiac ganglia (ICG) for regional cardiac control. There is still a knowledge gap, however, about the anatomical location and neurochemical phenotype of sensory neurons inside ICG. In the present study, rat ICG neurons were characterized neurochemically with immunohistochemistry using glutamatergic markers: vesicular glutamate transporters 1 and 2 (VGLUT1; VGLUT2), and glutaminase (GLS), the enzyme essential for glutamate production. Glutamatergic neurons (VGLUT1/VGLUT2/GLS) in the ICG that have axons to the ventricles were identified by retrograde tracing of wheat germ agglutinin–horseradish peroxidase (WGA–HRP) injected in the ventricular wall. Co-labeling of VGLUT1, VGLUT2, and GLS with the vesicular acetylcholine transporter (VAChT) was used to evaluate the relationship between post-ganglionic autonomic neurons and glutamatergic neurons. Sequential labeling of VGLUT1 and VGLUT2 in adjacent tissue sections was used to evaluate the co-localization of VGLUT1 and VGLUT2 in ICG neurons. Our studies yielded the following results: (1) ICG contain glutamatergic neurons with GLS for glutamate production and VGLUT1 and 2 for transport of glutamate into synaptic vesicles; (2) atrial ICG contain neurons that project to ventricle walls and these neurons are glutamatergic; (3) many glutamatergic ICG neurons also were cholinergic, expressing VAChT; (4) VGLUT1 and VGLUT2 co-localization occurred in ICG neurons with variation of their protein expression level. Investigation of both glutamatergic and cholinergic ICG neurons could help in better understanding the function of the intrinsic cardiac nervous system.

Autonomic cardiac nerves: literature review.

The aim of this paper was to summarise the knowledge about the autonomic cardiac innervation. It is generally known, that the cardiac nervous system consists of nerve plexoganglionic structures located mostly around the strategic regions of the heart. They consist of two main types of components: parasympathetic neurons, which exert an inhibitory effect, and sympathetic postganglionic nerve fibres, which stimulate the cardiac conduction system, and myocardial cells. However, many authors describe that cardiac ganglia contain various populations of neurons. The largest group are classical cholinergic neurons. The second group of cardiac neurons are cells of dual, cholinergic-adrenergic character. There is also subpopulation of small intensely fluoroscent cells of typically adrenergic phenotype. Moreover, many authors indicated the presence of various neurotransmitters in various combinations. In this way, the neurons in cardiac ganglia are a neurochemical complex beyond the classical vision of parasympathetic ganglia.

Atrial fibrillation increases sympathetic and parasympathetic neurons in the intrinsic cardiac nervous system.

Chronic atrial fibrillation (AF) leads to heterogeneous autonomic nerve innervation termed neural remodeling. The quantitative changes in neural density as a function of autonomic remodeling and its association with sustained AF has not been previously determined. Seven dogs (paced group) were chronically paced with electrodes sutured to the epicardium of left atrial appendages. Seven dogs (control animals) were not paced. All paced dogs developed sustained AF by 5 weeks of pacing. The fat pads on the atrial epicardium containing ganglionated plexuses (GP) were separated along with underlying myocardial tissue. Immunocytochemical techniques were used to identify the neurons immunoreactive to anti-tyrosine hydroxylase (TH) and anti-acetylcholine antibodies. After chronic AF, sympathetic and parasympathetic neurons in the atrial intrinsic cardiac ganglia increased significantly. In paced dogs, the density of sympathetic neurons was 3,022 ± 507 μm(2) /mm(2) in the right atrial GP (vs control P < 0.01), 8,571 ± 476 μm(2) /mm(2) in the ventral left atrial GP (vs control P < 0.0001)， 6,422 ± 464 μm(2) /mm(2) in the dorsal atrial GP (vs control P < 0.0001) and 5,392 ± 595 μm(2) /mm(2) in the inferior vena cava-inferior atrial GP (vs control P <0.0001), respectively. The density of parasympathetic neurons was 4,396 ± 877 μm(2) /mm(2) in the right atrial GP, 7,769 ± 465 μm(2) /mm(2) in the ventral left atrial GP， 7,016.47 ± 687 μm(2) /mm(2) in the dorsal atrial GP and 5,485 ± 554 μm(2) /mm(2) in the inferior vena cava-inferior atrial GP, respectively, which was higher than control cohorts in corresponding GP (P < 0.05). This study provides evidence for the remodeling in atrial intrinsic cardiac ganglia in the dogs with pacing induced AF. A significant increase of sympathetic and parasympathetic neurons was present in atrial intrinsic cardiac ganglia.

Immunohistochemical detection and gene expression of tyrosine hydroxylase and vesicular monoamine transporter type 2 in intrinsic cardiac ganglia of socially isolated rats

Social isolation induced a significant increase in resting heart rate and reduction in heart rate variability. Dysfunction of the intrinsic cardiac nervous system is implicated in the genesis of cardiovascular diseases. Previous evidence suggests that cardiac ganglia contain noradrenergic neurons. Thus, immunohistochemical expression of catecholaminesynthesizing enzyme tyrosine hydroxylase (TH) and vesicular monoamine transporter 2 (VMAT2) were analyzed, as well as the effects of social isolation stress on mRNA and protein levels of this enzyme and transporter in the intrinsic cardiac nervous system of adult rats. Our results indicate that cardiac ganglion neurons express TH and VMAT2 immunoreactivity. Chronic isolated stress of rats caused a decrease in TH mRNA and VMAT2 mRNA in the neurons of intrinsic cardiac ganglia. No significant alterations in the protein levels of TH and VMAT2 were observed in these neurons. These data indicate that the neurons of intrinsic cardiac ganglia express TH as well as VMAT2 but that social isolation stress does not change their protein levels.

Decreased adrenoceptor stimulation in heart failure rats reduces NGF expression by cardiac parasympathetic neurons

Postganglionic cardiac parasympathetic and sympathetic nerves are physically proximate in atrial cardiac tissue allowing reciprocal inhibition of neurotransmitter release, depending on demands from central cardiovascular centers or reflex pathways. Parasympathetic cardiac ganglion (CG) neurons synthesize and release the sympathetic neurotrophin nerve growth factor (NGF), which may serve to maintain these close connections. In this study we investigated whether NGF synthesis by CG neurons is altered in heart failure, and whether norepinephrine from sympathetic neurons promotes NGF synthesis. NGF and proNGF immunoreactivity in CG neurons in heart failure rats following chronic coronary artery ligation was investigated. NGF immunoreactivity was decreased significantly in heart failure rats compared to sham-operated animals, whereas proNGF expression was unchanged. Changes in neurochemistry of CG neurons included attenuated expression of the cholinergic marker vesicular acetylcholine transporter, and increased expression of the neuropeptide vasoactive intestinal polypeptide. To further investigate norepinephrine's role in promoting NGF synthesis, we cultured CG neurons treated with adrenergic receptor (AR) agonists. An 82% increase in NGF mRNA levels was detected after 1h of isoproterenol (β-AR agonist) treatment, which increased an additional 22% at 24h. Antagonist treatment blocked isoproterenol-induced increases in NGF transcripts. In contrast, the α-AR agonist phenylephrine did not alter NGF mRNA expression. These results are consistent with β-AR mediated maintenance of NGF synthesis in CG neurons. In heart failure, a decrease in NGF synthesis by CG neurons may potentially contribute to reduced connections with adjacent sympathetic nerves.

Hypertrophy of Neurons Within Cardiac Ganglia in Human, Canine, and Rat Heart Failure: The Potential Role of Nerve Growth Factor

BackgroundAutonomic imbalances including parasympathetic withdrawal and sympathetic overactivity are cardinal features of heart failure regardless of etiology; however, mechanisms underlying these imbalances remain unknown. Animal model studies of heart and visceral organ hypertrophy predict that nerve growth factor levels should be elevated in heart failure; whether this is so in human heart failure, though, remains unclear. We tested the hypotheses that neurons in cardiac ganglia are hypertrophied in human, canine, and rat heart failure and that nerve growth factor, which we hypothesize is elevated in the failing heart, contributes to this neuronal hypertrophy.Methods and ResultsSomal morphology of neurons from human (579.54±14.34 versus 327.45±9.17 μm2; P<0.01) and canine hearts (767.80±18.37 versus 650.23±9.84 μm2; P<0.01) failing secondary to ischemia and neurons from spontaneously hypertensive rat hearts (327.98±3.15 versus 271.29±2.79 μm2; P<0.01) failing secondary to hypertension reveal significant hypertrophy of neurons in cardiac ganglia compared with controls. Western blot analysis shows that nerve growth factor levels in the explanted, failing human heart are 250% greater than levels in healthy donor hearts. Neurons from cardiac ganglia cultured with nerve growth factor are significantly larger and have greater dendritic arborization than neurons in control cultures.ConclusionsHypertrophied neurons are significantly less excitable than smaller ones; thus, hypertrophy of vagal postganglionic neurons in cardiac ganglia would help to explain the parasympathetic withdrawal that accompanies heart failure. Furthermore, our observations suggest that nerve growth factor, which is elevated in the failing human heart, causes hypertrophy of neurons in cardiac ganglia.

Transmission of impulses in the parasympathetic cardiomotor pathway to the sino-atrial node

In mammals and other vertebrates the pacemaker cells of the sino-atrial (SA) node are under powerful inhibitory control of parasympathetic postganglionic cardiomotor neurones. The preganglionic neurones are located in the nucleus ambiguus; some are also located in the dorsal motor nucleus of the vagus although their function in the regulation of pacemaker activity is unknown (Jones, 2001). Activation of these preganglionic cardiomotor neurones leads to activation of cholinergic postganglionic neurones in cardiac ganglia, which in turn results in inhibition of the pacemaker cells in the SA node and subsequently in a decrease of heart rate. It is universally propagated in textbook chapters and elsewhere that the synaptic transmission from parasympathetic preganglionic neurones to postganglionic neurones in the cardiac ganglia occurs with a high safety factor without modulation and that the inhibition of pacemaker cells by activation of cholinergic cardiomotor neurones is mainly generated by the opening of potassium channels via the second-messenger adenylate cyclase/cAMP pathway and by suppression of hyperpolarization-activated Na+/K+-channels. These assumptions need to be corrected in view of experimental data published previously and recently.

Processing of central and reflex vagal drives by rat cardiac ganglion neurones: an intracellular analysis

Cardiac vagal tone is an important indicator of cardiovascular health, and its loss is an independent risk factor for arrhythmias and mortality. Several studies suggest that this loss of vagal tone can occur at the cardiac ganglion but the factors affecting ganglionic transmission in vivo are poorly understood. We have employed a novel approach allowing intracellular recordings from functionally connected cardiac vagal ganglion cells in the working heart-brainstem preparation. The atria were stabilised in situ preserving their central neural connections, and ganglion cells (n = 32) were impaled with sharp microelectrodes. Cardiac ganglion cells with vagal synaptic inputs (spontaneous, n = 10; or electrically evoked from the vagus, n = 3) were identified as principal neurones and showed tonic firing responses to current injected to their somata. Cells lacking vagal inputs (n = 19, presumed interneurones) were quiescent but showed phasic firing responses to depolarising current. In principal cells the ongoing action potentials and EPSPs exhibited respiratory modulation, with peak frequency in post-inspiration. Action potentials arose from unitary EPSPs and autocorrelation of those events showed that each ganglion cell received inputs from a single active preganglionic source. Peripheral chemoreceptor, arterial baroreceptor and diving response activation all evoked high frequency synaptic barrages in these cells, always from the same single preganglionic source. EPSP amplitudes showed frequency dependent depression, leading to more spike failures at shorter inter-event intervals. These findings indicate that rather than integrating convergent inputs, cardiac vagal postganglionic neurones gate preganglionic inputs, so regulating the proportion of central parasympathetic tone that is transmitted on to the heart.

Exercise with angina and cramp?

Exercise with angina and cramp?

Immunohistochemistric study of the intra-cardiac ganglia of the pig heart

Heart contains a variety of neurons known to influence cardiac functions. Little is known about the neurochemistry of these neurons. In this study, neurochemistry of intra cardiac neurons of the intrinsic cardiac ganglia was investigated. The technique used allows studying the morphology of the ganglionated nerve plexus found within the atria and great cardiac vessels as well as of individual neurons. The epicardial surface of pig hearts obtained postmortem using immunohistochemically staining in conjunction with confocal microscopy neurons in the cardiac intrinsic ganglia immunoreactive for PGP 9.5 identified in the epicardial fat pad around the aortic artery and pulmonary vein. Immunocytochemistry with the marker Protein gene product PGP9.5 was used to study the presence of neurons within clusters of intrinsic cardiac ganglia. Briefly, Tissues were fixed with neutral buffered formalin. Then, they were dissected, dehydrated, cleared, washed and incubated overnight at room temperature with PGP 9.5 (1/1000 in phosphate buffered saline with 0.2 Triton X-100). The slides were washed in PBS and incubated with a mixture of Cy3 labeled Donkey anti-rabbit antibody IgG for 2 hour at room temperature. The slides were evaluated and photographed with a confocal microscope. The results of this study indicate a moderate level of chemical diversity within the intra cardiac neurons of the pig such chemical diversity may reflect functional specialization of neurons in the intra cardiac ganglia. A distinct population of ganglia was seem to arise from in the endocardial plexus of the atria and was predominantly protein gene product 9.5 positive. The small black depressions on the neurons represented satellite cells. Neurons of the intrinsic cardiac ganglia are distributed more widely than has been described in experimented animals. Intra cardiac ganglia formed a complex plexus around the origin of pulmonary veins and were connected by nerve fibers. All neurons included in intrinsic cardiac ganglia contained immunoreactivity to PGP 9.5. Neurons express PGP 9.5 immunoreactivity, suggesting that catecolamine may be present in autonomic nerves in the heart.

The p75 neurotrophin receptor, semaphorins, and sympathetic traffic in the heart

the sympathetic and parasympathetic branches of the autonomic nervous system control cardiac function through the coordinated activity generated by neurons within the intracardiac autonomic ganglia and central nervous system (3). Activation of the sympathetic efferent projections to the heart increases heart rate, modifies the pattern and conduction velocity of the impulse through the heart, and augments both atrial and ventricular contractility while hastening myocardial relaxation. In the vasculature, the sympathetic nervous system (SNS) reduces venous capacitance and constricts resistance vessels, increasing blood pressure. Conversely, the parasympathetic nervous system (PSNS) decreases heart rate and cardiac impulse conduction. More recent evidence has suggested that the PSNS may also affect ventricular function, indirectly by countering β-adrenergic action or directly via inhibition of L-type Ca2+ channels (34). A transient imbalance between these two branches can lead to increased heart rate and blood pressure when cardiac output is increased. When subnormal cardiac PSNS activity concomitant with sympathetic hyperactivation persists, such as after myocardial infarction, this disequilibrium may increase the risk for cardiac adverse events, including arrhythmias, hypertension, cardiac hypertrophy, and, ultimately, heart failure. This condition is called “autonomic neural remodeling” and can greatly contribute to the induction of ventricular fibrillation, thus increasing the patient's susceptibility to sudden cardiac death (41, 47). It is plausible that neurotrophic factors, target organ-secreted proteins essential for the development and differentiation of neurons, are involved in the remarkable neuroplasticity exhibited by the SNS in the adult life, including autonomic remodeling after infarction and/or in the onset and progression of congestive heart failure (17, 30, 32).