Preganglionic Research Articles

Vagal preganglionic axons arborize in the myenteric plexus into two types: nitrergic and non-nitrergic postganglionic motor pools?

Vagal preganglionic neurons innervate myenteric ganglia. These autonomic efferents are distributed so densely within the ganglia that it has been impractical to track individual vagal axons through the myenteric plexus with tracer labeling. To evaluate whether vagal efferent axons evidence selectivity, particularly for nitrergic or non-nitrergic myenteric neurons within the plexus, we limited the numbers and volumes of brainstem dextran biotin tracer injections per animal. Reduced labeling and the use of immunohistochemistry generated cases in which some individual axons could be distinguished and traced in three dimensions (Neurolucida) within and among successive (up to 46) myenteric ganglia. In the myenteric plexus of all stomach regions, the majority (∼86%) of vagal efferents were organized into two distinct subtypes. One subtype (∼24% of dextran-labeled efferents, designated "primarily nitrergic") selectively contacted and linked-both within and between ganglia-nitric oxide synthase positive (nNOS+) neurons into presumptive motor modules. A second subtype (∼62% of efferents, designated "primarily non-nitrergic") appeared to selectively contact and link-both within and between ganglia-non-nitrergic enteric neurons into a second type of effector ensemble. A third candidate type (∼14% of labeled preganglionics), appeared to lack "nitrergic selectivity" and to contact both nNOS+ and nNOS- enteric neurons. In addition to the quantitative assessment of the efferent axons in stomach, qualitative observations of the proximal duodenum indicated similar selective vagal efferent projections, in proportions comparable with those evaluated in the stomach. Limited injections of tracer, three-dimensional (3-D) tracing of individual axons, and histochemistry of myenteric neurons might distinguish additional efferent phenotypes.NEW & NOTEWORTHY The present study highlights the following: 1) one type of vagal efferent axon selectively innervates nitrergic upper gastrointestinal myenteric neurons; 2) a second type of vagal efferent selectively innervates non-nitrergic gastrointestinal myenteric neurons; and 3) the two types of vagal efferents might modulate peristalsis reciprocally and cooperatively.

Emerging non-invasive therapeutic approaches targeting hypocholinergic neural systems in Parkinson's disease.

Emerging non-invasive therapeutic approaches targeting hypocholinergic neural systems in Parkinson's disease.

Sympathetic nerve entrapment point injection for intractable nausea and vomiting in pregnancy: a case report

Nausea and vomiting during pregnancy (NVP) occurs in up to 80% of pregnant women worldwide. Severe intractable NVP accompanied by acute starvation may threaten the health of the mother and fetus, and greatly reduce the quality of life during pregnancy. Symptoms that cannot be controlled with pharmacotherapy are difficult to relieve in severe NVP. Dysfunction of the autonomic and enteric nervous systems is an important component of NVP pathogenesis. It is thought to be controlled by the autonomic nervous system. In the present case, a 30-year-old married female came to the emergency department complaining of severe nausea and vomiting. Her symptoms had not improved with medication, such as Diclrectin® and intravenous metoclopramide. Tenderness was detected in the multifidus area on both sides of the T7 spinal cord level. Normal saline (3 cc) was injected into the multifidus areas at both tenderness points, and her symptoms improved 30 min after the injections because intervertebral pressure and constriction of the vasa nervorum were alleviated. This approach improved the compression of sympathetic preganglionic fibers and increased blood flow to the sympathetic nerves. Nausea and vomiting symptoms improved as the imbalance in the autonomic nervous system improved and vagal tone was normalized. Sympathetic nerve entrapment point injection should be considered an alternative treatment to control severe NVP not resolved by medication.

ASYMPTOMATIC DYSREFLEXIA AFTER POSTURAL CHANGES IN AN INCOMPLETE SPINAL CORD INJURY: CONSIDERATIONS FOR EXERCISE PHYSIOLOGISTS

https://youtu.be/Z6gJb7-F5Gw BACKGROUND Autonomic dysreflexia (AD) is a potentially life threatening hypertensive syndrome prevalent among patients with chronic spinal cord injuries (SCI) at spinal segment T6 or above. AD is due to the loss of supraspinal control over sympathetic preganglionic neurons and is triggered by noxious stimuli below the level of injury. The treatment of AD is multifaceted, from conservative management to topical and oral antihypertensive medications. Understanding AD's rapid onset and severity are extremely important for exercise physiologists working with patients with SCI. CASE PRESENTATION A 67-year old male with chronic motor incomplete cervical SCI (i.e., ASIA C4 C) and persistent orthostatic hypotension (OH) was enrolled in a study to determine the effects of biofeedback on blood pressure (BP) modulation when an episode of asymptomatic AD occurred. Baseline and resting BP were recorded at 122/82, with a resting mean arterial pressure (MAP) of 96. The BP was continuously monitored using a telemetric device (Caretaker, Charlottesville, VA). Upon positional changes required to measure OH with a tilt table, the participant showed an antagonist response with a sudden increase in BP consistent with AD symptoms, reaching a maximum level of 199/121. The participant was asymptomatic during the AD episode. CASE MANAGEMENT/OUTCOME BP returned to baseline levels after the participant was transferred back to a seated position in the wheelchair without using other measurements or medications. The titl test was modified with the participant positioned in a semi supine position (30° incline) and then tilted to approximately 45and remained in this position for 3 minutes. DISCUSSION AD is prevalent among people with cervical or upper thoracic SCI, and often the episodes are asymptomatic. As a part of the training routine, many patients with SCI are placed in a supine position for passive stretching and exercising. We are presenting data on this episode of asymptomatic AD due to postural changes to bring awareness to exercise physiologists of this life threatening condition. Trainers should carefully check for signs of AD in this population and measure BP often during the training sessions if a continuous assessment of BP is unavailable. Seated is recommended over a supine or semi-supine position. This could be accomplished by using physical therapy wedge cushions to maintain blood pressure homeostasis.

PACAP and acetylcholine cause distinct Ca2+ signals and secretory responses in chromaffin cells.

The adrenomedullary chromaffin cell transduces chemical messages into outputs that regulate end organ function throughout the periphery. At least two important neurotransmitters are released by innervating preganglionic neurons to stimulate exocytosis in the chromaffin cell-acetylcholine (ACh) and pituitary adenylate cyclase activating polypeptide (PACAP). Although PACAP is widely acknowledged as an important secretagogue in this system, the pathway coupling PACAP stimulation to chromaffin cell secretion is poorly understood. The goal of this study is to address this knowledge gap. Here, it is shown that PACAP activates a Gαs-coupled pathway that must signal through phospholipase C ε (PLCε) to drive Ca2+ entry and exocytosis. PACAP stimulation causes a complex pattern of Ca2+ signals in chromaffin cells, leading to a sustained secretory response that is kinetically distinct from the form stimulated by ACh. Exocytosis caused by PACAP is associated with slower release of peptide cargo than exocytosis stimulated by ACh. Importantly, only the secretory response to PACAP, not ACh, is eliminated in cells lacking PLCε expression. The data show that ACh and PACAP, acting through distinct signaling pathways, enable nuanced and variable secretory outputs from chromaffin cells.

Effect of Physical Training on the Morphology of Parasympathetic Atrial Ganglia after Unilateral Vagotomy in Rats.

Cardiac denervation is a serious problem in a number of patients, including patients after heart transplantation. The status of the parasympathetic ganglia after crossing the preganglionic fibers of the vagus nerve has not been enough studied. The aim of our study was to assess the effect of physical training on the morphological parameters of the parasympathetic atrial ganglia and autonomic regulation of heart rate after right- and left-sided vagotomy in rats. Morphometric characteristics of the right atrial ganglia were evaluated using an immunohistochemical method after a study that included a three-time assessment of heart rate variability. It was found that right-sided vagotomy leads to both an increase in the volume of ganglion and autonomic dysfunction. No significant change in the number of nerve cells was found in animals with false and left-sided vagotomy while maintaining preganglionic innervation after the physical training, whereas exercises led to a decrease in the volume of nerve tissue of rats with right-sided denervation. It was also found that in animals with preserved vagal innervation, the volume of atrial ganglion tissue correlates with overall heart rate variability and a normalized parasympathetic component. Therefore, a positive effect from regular physical activity on parasympathetic regulation can be expected only if preganglionic vagal influence is preserved.

Abstract 15802: Chemogenetic Activation of Intracardiac Cholinergic Ganglia Neurons Reduces the Incidence of Arrhythmias After an Acute Myocardial Infarction

Intracardiac cholinergic ganglia (ICG) neurons receive excitatory input from vagal pre-ganglionic fibers and are critical for the transmission of parasympathetic drive throughout the heart. During disease, electronic vagal stimulation improves cardiac function and reduces arrhythmias. However, vagal stimulation is not selective for efferent or cholinergic fibers and implanting an electronic device before unanticipated episodes of cardiac infarction is not clinically feasible. We addressed these limitations by testing the hypothesis that chemogenetic ICG activation immediately after an infarction would reduce arrhythmia incidence and improve ventricular function. Floxed DREADDs (AAV2-hSyn-DIOhM3D(Gq)-mcherry) were injected into the pericardial sac of neonatal rats that selectively express Cre recombinase in cholinergic neurons. At 8 weeks, hearts were excised for ex-vivo studies and excitatory hM3Dq DREADDs expressed in ICG cholinergic neurons were activated by clozapine-N-oxide (CNO). Heart rate (HR), LV developed pressure, and overall arrhythmia incidence were measured. In healthy hearts, CNO decreased HR for the duration of the experiment (247 ±10.56 to 189.35± 3.46 beats per minute, p<0.0001, n=5). To study ICG activation after infarction, hearts received CNO or saline after complete ligation of the left anterior descending coronary artery or partial obstruction of the left coronary artery. The ECG was analyzed to assess PR interval and arrhythmia incidence, including non-sustained and sustained VT and fibrillation. ICG activation increased PR interval from 39.13 ± 2.75 to 42.46 ± 3.07 ms (p=0.0097, n=5). ICG activation also reduced arrhythmia incidence after coronary artery ligation from 1.65 to 0.6467 arrhythmias per min (p=0.042, n=5), an outcome that is likely motivated by ICG neuron inhibition of adrenergic activity in addition to vasodilation and increased coronary flow. These studies demonstrate that cardiac cholinergic ICG activation following an MI quickly elevates cardiac parasympathetic drive, protecting against arrhythmias. Future studies will focus on measuring the inhibition of adrenergic activity by chemogenetic activation of cholinergic ICG neurons and local coronary flow increases.

PMON182 PACAP Receptor Expression in Sympathetic Ganglia of the Autonomic Nervous System

Abstract In obesity, energy intake exceeds energy expenditure and concomitantly increases risk of chronic diseases, including metabolic diseases such as diabetes. Therapeutics to correct dysregulations in energy balance are needed and one notable neuropeptide being studied is pituitary adenylate cyclase-activating polypeptide (PACAP), an overarching regulator of the stress response1,2. In the context of metabolism, PACAP has been shown to regulate adaptive thermogenesis, an energy burning process regulated by the sympathetic nervous system (SNS) in response to cold stress and overfeeding. While research suggests PACAP acts centrally at the level of the hypothalamus to regulate energy balance3-5, PACAP is also known to be expressed in the SNS. In preganglionic neurons innervating the adrenal medulla6, PACAP is co-localized with acetylcholine and regulates catecholamine synthesis and release. Recent neuronal tracing studies have shown that postganglionic fibres of the stellate ganglia innervate intrascapular brown adipose tissue (BAT), the main thermogenic tissue in mammals7. However, PACAP's role within the sympathetic nerves innervating and regulating energy metabolism in adipose tissues is not known. As such, our group is interested in characterizing PACAP and PACAP receptor expression in sympathetic nerves innervating and regulating energy metabolism in BAT (via the stellate ganglia) in response to metabolic stressors, such as cold stress. We hypothesize that PACAP is released from preganglionic nerves which binds PACAP receptors (PAC1, VPAC1, VPAC2) expressed in postganglionic nerves of the stellate ganglia. Here we report, for the first time, PAC1 and VPAC1 expression in the stellate ganglia with sex-specific differential gene expression based on housing temperature. Analysis of PAC1 splice variant expression identified at least two variants in tissues of the SNS (adrenal gland, superior cervical ganglia and the stellate ganglia). These results will support future functional studies characterizing PACAP regulation of catecholamine production in peripheral ganglia which will contribute to assessing G-protein coupled receptors (GPCRs) as potential therapeutic targets for obesity and metabolic disease.

Melanocortin-4 receptors activate sympathetic preganglionic neurons and elevate blood pressure via TRPV1.

Melanocortin-4 receptors (MC4Rs) expressed by the central nervous system are essential regulators of energy homeostasis, and Mc4r mutation is the most common cause of human monogenic obesity. Notably, patients with obesity carrying Mc4r mutations are protected against obesity-induced hypertension, and MC4R agonists elevate blood pressure (BP). Although increased sympathetic tone by MC4Rs is suggested to underlie this phenotype, the detailed mechanisms remain unclear. Here, we investigate how MC4Rs regulate the sympathetic preganglionic neurons and find that MC4Rs activate these neurons via the protein kinase A-dependent activation of the transient receptor potential vanilloid 1 (TRPV1) channel. Importantly, we demonstrate that the inhibition of TRPV1 prevents MC4R-induced elevation of BP but does not affect MC4R-induced anorexia. We further show that TRPV1 is responsible for MC4R-dependent activation of the sympathetic preganglionic neurons by high-fat diet. Together, our results provide insight into how MC4Rs regulate sympathetic function.

Brainstem noradrenergic neurons: Identifying a hub at the intersection of cognition, motility, and skeletal muscle regulation.

Brainstem noradrenergic neuron clusters form a node integrating efferents projecting to distinct areas such as those regulating cognition and skeletal muscle structure and function, and receive dissimilar afferents through established circuits to coordinate organismal responses to internal and environmental challenges. Genetic lineage tracing shows the remarkable heterogeneity of brainstem noradrenergic neurons, which may explain their varied functions. They project to the locus coeruleus, the primary source of noradrenaline in the brain, which supports learning and cognition. They also project to pre-ganglionic neurons, which lie within the spinal cord and form synapses onto post-ganglionic neurons. The synapse between descending brainstem noradrenergic neurons and pre-ganglionic spinal neurons, and these in turn with post-ganglionic noradrenergic neurons located at the paravertebral sympathetic ganglia, support an anatomical hierarchy that regulates skeletal muscle innervation, neuromuscular transmission, and muscle trophism. Whether any noradrenergic neuron subpopulation is more susceptible to damaged protein deposit and death with ageing and neurodegeneration is a relevant question that answer will help us to detect neurodegeneration at an early stage, establish prognosis, and anticipate disease progression. Loss of muscle mass and strength with ageing, termed sarcopenia, may predict impaired cognition with ageing and neurodegeneration and establish an early time to start interventions aimed at reducing central noradrenergic neurons hyperactivity. Complex multidisciplinary approaches, including genetic tracing, specific circuit labelling, optogenetics and chemogenetics, electrophysiology, and single-cell transcriptomics and proteomics, are required to test this hypothesis pre-clinical.

An error in interpretation and real extraordinary electrocardiographic changes in patient with acute traumatic spondylolisthesis

BackgroundAcute cervical spinal trauma may lead to cardiac effects by influencing cardiac sympathetic preganglionic fibers. Some of these effects, which are vital, may occur in ECG.Case presentationA 52-year-old female patient admitted to the emergency department with acute traumatic spondylolisthesis at C6-C7 level and paraplegia. Positive QRS complex, ST segment depressions and prolongation of QTc interval were observed on ECG according to sudden autonomic disruption because of sympathetic nerve compression. It was mentioned that changes in QRS complex axis was normal which was dependent to the ECG display format of Cabrera sequence used differently from the classical system. After surgical correction, evident ST depressions were recovered and QTc intervalwas narrowed but still prolonged in control ECG.ConclusionsAutonomic dysfunction can lead to extraordinary electrocardiographic presentation including widespread ST depressions with prolonged QTc interval. However, when evaluating the changes in the ECG, attention should be paid to ECG display format to avoid errors in interpretation.

Ethanol inhibits pancreatic projecting neurons in the dorsal motor nucleus of the vagus

Alcohol use disorder (AUD) is a rapidly growing concern in the United States. Current trending escalations of alcohol use are associated with a concurrent rise in alcohol-related end-organ damage, increasing risk for further diseases. Alcohol-related end-organ damage can be driven by autonomic nervous system dysfunction, however studies on alcohol effects on autonomic control of end-organ function are lacking. Alcohol intake has been shown to reduce insulin secretions from the pancreas. Pancreatic insulin release is controlled in part by preganglionic parasympathetic motor neurons residing in the dorsal motor nucleus of the vagus (DMV) that project to the pancreas. How these neurons are affected by alcohol exposure has not been directly examined. Here we investigated the effects of acute ethanol (EtOH) application on DMV pancreatic-projecting neurons with whole-cell patch-clamp electrophysiology. We found that bath application of EtOH (50 mM) for greater than 30 min significantly enhanced the frequency of spontaneous inhibitory post synaptic current (sIPSC) events of DMV pancreatic-projecting neurons suggesting a presynaptic mechanism of EtOH to increase GABAergic transmission. Thirty-minute EtOH application also decreased action potential firing of these neurons. Pretreatment of DMV slices with 20 μM fluoxetine, a selective serotonin reuptake inhibitor, also increased GABAergic transmission and decreased action potential firing of these DMV neurons while occluding any further effects of EtOH application, suggesting a critical role for serotonin in mediating EtOH effects in the DMV. Ultimately, decreased DMV motor output may lead to alterations in pancreatic secretions. Further studies are needed to fully understand EtOH’s influence on DMV neurons as well as the consequences of changes in parasympathetic output to the pancreas.

Chemogenetic activation of noradrenergic A5 neurons increases blood pressure and visceral sympathetic activity in adult rats.

In mammals, the pontine noradrenergic system influences nearly every aspect of central nervous system function. A subpopulation of pontine noradrenergic neurons, called A5, are thought to be important in the cardiovascular response to physical stressors, yet their function is poorly defined. We hypothesized that activation of A5 neurons drives a sympathetically mediated increase in blood pressure (BP). To test this hypothesis, we conducted a comprehensive assessment of the cardiovascular effects of chemogenetic stimulation of A5 neurons in male and female adult rats using intersectional genetic and anatomical targeting approaches. Chemogenetic stimulation of A5 neurons in freely behaving rats elevated BP by 15 mmHg and increased cardiac baroreflex sensitivity with a negligible effect on resting HR. Importantly, A5 stimulation had no detectable effect on locomotor activity, metabolic rate, or respiration. Under anesthesia, stimulation of A5 neurons produced a marked elevation in visceral sympathetic nerve activity (SNA) and no change in skeletal muscle SNA, showing that A5 neurons preferentially stimulate visceral SNA. Interestingly, projection mapping indicates that A5 neurons target sympathetic preganglionic neurons throughout the spinal cord and parasympathetic preganglionic neurons throughout in the brainstem, as well as the nucleus of the solitary tract, and ventrolateral medulla. Moreover, in situ hybridization and immunohistochemistry indicate that a subpopulation of A5 neurons coreleases glutamate and monoamines. Collectively, this study suggests A5 neurons are a central modulator of autonomic function with a potentially important role in sympathetically driven redistribution of blood flow from the visceral circulation to critical organs and skeletal muscle.

Mapping of STB/HAP1 Immunoreactivity in the Mouse Brainstem and its Relationships with Choline Acetyltransferase, with Special Emphasis on Cranial Nerve Motor and Preganglionic Autonomic Nuclei

Huntingtin-associated protein 1 (HAP1) is a core component of stigmoid body (STB) and is known as a neuroprotective interactor with causal agents for various neurodegenerative diseases. Brain regions rich in STB/HAP1 immunoreactivity are usually spared from cell death, whereas brain regions with negligible STB/HAP1 immunoreactivity are the major neurodegenerative targets. Recently, we have shown that STB/HAP1 is abundantly expressed in the spinal preganglionic sympathetic/parasympathetic neurons but absent in the motoneurons of spinal cord, indicating that spinal motoneurons are more vulnerable to neurodegenerative diseases. In light of STB/HAP1 neuroprotective effects, it is also essential to clarify the distribution of STB/HAP1 in another major neurodegenerative target, the brainstem. Here, we examined the expression and detailed immunohistochemical distribution of STB/HAP1 and its relationships with choline acetyltransferase (ChAT) in the midbrain, pons, and medulla oblongata of adult mice. Abundant STB/HAP1 immunoreactive neurons were disseminated in the periaqueductal gray, Edinger-Westphal nucleus, raphe nuclei, locus coeruleus, pedunculopontine tegmental nucleus, superior/inferior salivatory nucleus, and dorsal motor nucleus of vagus. Double-label immunohistochemistry of HAP1 with ChAT (or with urocortin-1 for Edinger-Westphal nucleus centrally projecting population) confirmed that STB/HAP1 was highly present in parasympathetic preganglionic neurons but utterly absent in cranial nerve motor nuclei throughout the brainstem. These results suggest that due to deficient putative STB/HAP1-protectivity, cranial nerve motor nuclei might be more vulnerable to certain neurodegenerative stresses than STB/HAP1-expressing brainstem nuclei, including preganglionic parasympathetic nuclei. Our current results also lay a basic foundation for future studies that seek to clarify the physiological/pathological roles of STB/HAP1 in the brainstem.

Neuronal nitric oxide synthase and calbindin expression in sympathetic preganglionic neurons following capsaicin treatment.

Along with well-known data on the neurochemical mechanisms of nociceptor activation, there are still no clear data regarding changes in the cellular composition and morphological characteristics of spinal preganglionic neurons (SPN) after capsaicin treatment. The mechanism of capsaicin toxicity differs in developing and mature nerve cells. This study aimed to determine the number of SPN in the autonomic nuclei on spinal cord (SC) sections and their cross-sectional area, the localization, percentage, and profile area of SPN containing neuronal nitric oxide synthase (nNOS) and calbindin (CB) in the thoracic SC of rats of different ages (from birth to 1-year-old) after capsaicin treatment. Neonatal capsaicin treatment generally decreased the cross-sectional area of the SPN pericarya. However, the cross-sectional area of the CB-immunoreactive (IR) SPN increased in the central autonomic area in rats aged 10-30 days old after capsaicin treatment. The number of SPN decreased only in the central autonomic area of rats aged <20 days. The proportion of nNOS-IR neurons remained steady and did not change during development. The cross-sectional area of nNOS-IR SPN in capsaicin-treated rats was less than that in control rats. The results obtained will promote further studies on the mechanisms of sensory processing in the SC and the development of the sympathetic nervous system.

Immunohistochemical characterization of nerve elements in porcine intrinsic laryngeal ganglia.

The present study investigated the chemical coding of neurons and nerve fibres in local laryngeal ganglia in pigs (n=5) using double-labelling immunohistochemistry. Virtually all the neurons were cholinergic in nature (ChAT- or VAChT-positive). Only very solitary, small nerve cells (presumably representing interneurons) stained intensely for adrenergic marker, DβH. Many neurons also contained immunoreactivity for NOS (91%), VIP (62.7%), NPY (24.7%), galanin (10%), SP (1.3%) and CGRP (5.3%). No neurons expressing somatostatin or Leu-enkephalin were observed. Nearly all the neuronal somata were densely supplied with varicose cholinergic nerve terminals, which presumably represented preganglionic axons, and some of them were also closely apposed with CGRP- and/or SP-positive varicose nerve endings, which were putative collaterals of extrinsic primary sensory fibres. In conclusion, this study has revealed that intrinsic neurons in the porcine larynx, like in many other mammalian species studied, should be classified as parasympathetic cholinergic neurons expressing biologically active substances, predominantly NOS and VIP. Furthermore, they are likely to receive inputs from not only preganglionic neurons but also primary sensory nerve cells. Finally, it appears that the information on the occurrence of the local laryngeal ganglia should be regularly included in textbooks dealing with the cranial portion of the parasympathetic nervous system in mammals.

Genetic encoding of an esophageal motor circuit.

SUMMARYMotor control of the striated esophagus originates in the nucleus ambiguus (nAmb), a vagal motor nucleus that also contains upper airway motor neurons and parasympathetic preganglionic neurons for the heart and lungs. We disambiguate nAmb neurons based on their genome-wide expression profiles, efferent circuitry, and ability to control esophageal muscles. Our single-cell RNA sequencing analysis predicts three molecularly distinct nAmb neuron subtypes and annotates them by subtype-specific marker genes: Crhr2, Vipr2, and Adcyap1. Mapping the axon projections of the nAmb neuron subtypes reveals that Crhr2nAmb neurons innervate the esophagus, raising the possibility that they control esophageal muscle function. Accordingly, focal optogenetic stimulation of cholinergic Crhr2+ fibers in the esophagus results in contractions. Activating Crhr2nAmb neurons has no effect on heart rate, a key parasympathetic function of the nAmb, whereas activating all of the nAmb neurons robustly suppresses heart rate. Together, these results reveal a genetically defined circuit for motor control of the esophagus.

EndoFLIP Topography: Motor Patterns in an Obstructed Esophagus

EndoFLIP Topography: Motor Patterns in an Obstructed Esophagus

Сучасні наукові погляди на склад та будову автономної нервової системи (огляд літератури)

The purpose of the study was to analyze literary sources to summarize modern scientific views on the structure and possible changes in the existing classification of the autonomic nervous system. Results and discussion. According to classical views, the anatomically and functionally autonomic nervous system is divided into sympathetic and parasympathetic parts, and the last one includes cranial and sacral centers. This classification, in addition to ontogenetic, anatomical and physiological justification, has historical roots and is associated with the research of J. Langley. For more than a century, such a classification of the autonomic nervous system was considered commonplace. However, modern views on this issue emphasize the mechanisms of development and molecular mechanisms of these systems. More attention was paid to such elements as gene expression, features of embryogenesis and development, as well as the general functions of neurons localized in these parts of the autonomic nervous system. In recent years, a group of researchers Espinosa-Medina et al. determined the differential genetic features and relationships of sympathetic and parasympathetic preganglionic and postganglionic neurons. The aim of the study was to compare the relationships and genetic characteristics of lumbar and sacral preganglionic neurons with cranial (parasympathetic) and thoracic (sympathetic) neurons. In general, 15 phenotypic and ontogenetic features are given that distinguish the pre- and postganglionic neurons of the cranial part of the parasympathetic part from the sympathetic neurons of the thoracolumbar region. Each of the features, according to Espinosa-Medina et al., proves that the sacral section must be considered as part of the sympathetic, and not the parasympathetic, section of the autonomic nervous system. This assumption is based on the study on mice at 11.5, 13, 165 days of embryonic development of several transcription factors common to both sacral and thoracolumbar preganglionic neurons, but absent in cranial preganglionic neurons. When revising the existing classification, cranial vegetative nervous structures are proposed to be considered parasympathetic, and spinal – sympathetic. However, a number of researchers were critical of the proposed changes to the existing classification. They consider the interpretation of the findings controversial, point to possibly misleading conclusions due to misinterpretations of the evidence, and suggest that the phenotypes of common thoracic and sacral preganglionic neurons may simply share a common spinal identity. Conclusion. In recent years, thanks to the latest research, there has been a rethinking and possible change in the ideas that have existed for a long time about the composition and structure of the autonomic nervous system. The proposed reclassification of the autonomic nervous system involves the assignment of the sacral region to its sympathetic, not parasympathetic part. Such a simplified two-component structure offers a new concept of neurophysiology, as well as the evolution and development of the autonomic nervous system. At the same time, a number of researchers give their arguments in favor of rejecting the proposed radical changes and saving the existing classification. In this regard, further studies are highly demanded, which could finally shed light on this issue

Evidence for Cholinergic Collateral Projections between Sympathetic Neurons in the Murine Stellate Ganglia

Postganglionic neurons of the stellate ganglia (SG) are an integral component of sympathetic regulation of the heart. SG neurons receive preganglionic cholinergic inputs via T‐2 and send noradrenergic projections to the heart via the inferior cardiac nerve (iCN) to influence cardiac activity. SG neurons are thought to receive simple monosynaptic inputs from preganglionic neurons, but early studies have hinted that cholinergic collateral projections may be present in the SG. In culture, SG neurons form noradrenergic and cholinergic synapses between one another, suggesting that SG neurons express dual neurochemical phenotypes. This study tests the hypothesis that cholinergic collateral projections are present between sympathetic neurons of the intact SG in mice.Whole‐cell patch clamp recordings were made of intact SG neurons from male (N=8) and female (N=6) ChATTH+CreERT2/lox mice with and without tamoxifen treatment (N=7 ChAT KO mice and N=7 control mice, respectively). Tamoxifen treatment in ChATTH+CreERT2/lox mice induced the deletion of choline acetyltransferase (ChAT) in tyrosine hydroxylase positive (i.e. noradrenergic) cells. This strategy blocks putative acetylcholine synthesis in SG neurons while leaving preganglionic cholinergic synapses intact. To search for collaterals, the preganglionic nerve trunk, T‐2, was electrically stimulated to evoke excitatory postsynaptic currents (eEPSCs). The amplitude and jitter (i.e. variability in latency) of eEPSCs were examined. Additionally, the postganglionic nerve trunk, the iCN, was electrically stimulated to evoke retrograde action currents (rAC) and the presence of evoked synaptic currents was assessed. The amplitude and frequency of spontaneous EPSCs (sEPSCs) were also examined.ChAT KO significantly reduced the frequency of sEPSCs compared to control mice (1.21±0.559events/s vs. 0.13±0.048events/s, P&lt;0.05 from Student’s unpaired t‐test, N=5‐6 cells) while the amplitude was unaffected (74.4±26.10pA vs. 39.4±10.46pA, P&gt;0.05 from Student’s unpaired t‐test, N=5‐6 cells). This suggests that ChAT KO reduces the presynaptic activity of postganglionic noradrenergic neurons within the SG. In control mice, stimulation of T‐2 evoked high jitter eEPSCs, which was significantly reduced in ChAT KO mice (327.1±92.14μs vs. 39.2±15.69μs, P&lt;0.05 from Student’s unpaired t‐test, N=5‐6 cells) Additionally, the proportion of neurons that exhibited evoked synaptic currents following stimulation of the iCN was significantly reduced in ChAT KO mice (3/4 cells vs. 1/9 cells, P&lt;0.05 from χ² test).Chemical transmission at additional synapses accounts for the high jitter events observed in disynaptic pathways. High jitter responses following T‐2 stimulation and evoked synaptic responses after iCN stimulation in control neurons are both consistent with the collateral hypothesis. The loss of high jitter responses and evoked synaptic currents in ChAT KO mice also suggests these collateral projections are cholinergic. This suggests that collateral synaptic activity contributes to the increased frequency of sEPSCs in control mice. Understanding SG neurocircuitry is critical in deciphering changes in sympathetic activity in many pathophysiological conditions such as myocardial infarction and heart failure and may identify novel therapeutic targets for the treatment of autonomic imbalance.