Chemical Anatomy and Synaptology of Vestibulo-Sympathetic Pathways

前庭交感神经通路的化学解剖学和突触学

• 批准号: 8115655
• 负责人: Gay R Holstein
• 金额: $ 44.76万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8115655
• 关键词: Address; Adverse effects; Afferent Pathways; Anatomy; Antihypertensive Agents; Autonomic nervous system disorders; Axon; Baroreflex; Basic Science; Bilateral; Blood Pressure; Brain Stem; Cardiovascular system; Catecholamines; Cells; Chemicals; Clinical Research; Complex; Cytology; Data; Detection; Development; Dizziness; Drug Delivery Systems; Elderly; Experimental Models; FOS gene; Feedback; Gene Proteins; Glutamates; Goals; Immediate-Early Genes; Immunofluorescence Immunologic; Inferior; Interneurons; Intervention; Lead; Link; Neurons; Neurotransmitter Receptor; Neurotransmitters; Nuclear; Organ; Orthostatic Hypotension; Pathway interactions; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Phaseolus vulgaris leucoagglutinin; Phenotype; Population; Posture; Pressoreceptors; Rattus; Receptor Signaling; Reflex action; Regulation; Research; Research Project Grants; Sensory; Signal Pathway; Signal Transduction; Site; Specificity; Spinal Cord Column; Structure; Sympathetic Nervous System; Synapses; System; Testing; Vasomotor; Vertigo; Vestibular nucleus structure; blood pressure regulation; feeding; medial vestibular nucleus; nerve supply; neurochemistry; otoconia; postsynaptic; preference; programs; relating to nervous system; spinal reflex; vestibular pathway

DESCRIPTION (provided by applicant): The existence of a functional link between the vestibular system and blood pressure control has been known for nearly a century. It is currently thought that arterial baroreceptors participate in a regulatory circuit that maintains sympathetic tone through the baroreflex while signals from the vestibular end organs drive a faster mechanism that counteracts the effects of a change in posture. This latter circuit is often called the vestibulo-sympathetic reflex (VSR). Primary afferents of this pathway terminate on cells in the caudal vestibular nuclear complex (VNCc). These second order neurons, in turn, project to brainstem sites involved in cardiovascular regulation such as the rostral and caudal ventrolateral medullary regions (RVLM and CVLM, respectively). Cells in the RVLM are thought to integrate the vestibular input with baroreceptor and other sensory afferents and send excitatory projections to preganglionic sympathetic neurons in the intermediolateral cell column of the spinal cord. While the principal neurotransmitter of these presympathetic vasomotor RVLM cells is likely to be glutamate, numerous neuroactive molecules have been co-localized in these cells, including catecholamines of the C1 cell group. In addition, bulbospinal vasomotor RVLM cells receive monosynaptic GABAergic projections from the CVLM, which tonically inhibit the RVLM neurons. As a result, CVLM cells can be viewed as sympathoinhibitory interneurons in the vasomotor pathway. The long-term goal of our research program is to identify the neurotransmitters, receptors, and signaling pathways that participate in vestibulo- autonomic projections so they can be targeted specifically by pharmacotherapeutics to ameliorate vestibulo- autonomic disorders. The specific objective of this research project is to identify the structural and chemical anatomy of vestibular pathways that contribute to blood pressure regulation. The project has two aims that will be pursued using rats as the experimental model, bilateral sinusoidal galvanic vestibular stimulation to activate the vestibular nuclei, telemetric detection of blood pressure, anterograde and retrograde tract-tracing, and immunofluorescence detection of the immediate early gene protein product c-Fos together with pathway- specific neurotransmitters and modulators. Aim 1 will identify the sensitivity, topography, cytology, neurotransmitter(s), and modulator(s) of vestibular neurons of the VSR. This aim will test the overall hypothesis that VNCc cells of the VSR pathway have a morphological, hodological and/or chemoanatomical phenotype that is distinct from other VNCc neurons and the baroreflex pathway. Aim 2 will identify the innervation pattern(s), synaptology and postsynaptic partners of vestibulo-sympathetic axons in RVLM and CVLM. This aim will address our over-arching hypothesis by determining the neuronal and synaptic specificity of vestibular input to pre-sympathetic vasomotor circuitry. These hypotheses are fundamental to our long-term goal, since regions or cells where the VSR pathway is morphologically or chemoanatomically segregated from the baroreflex pathway are candidate sites for specific pharmacological intervention into the VSR. PUBLIC HEALTH RELEVANCE: Orthostatic hypotension and vestibular side effects of drugs targeting the sympathetic nervous system (e.g. anti-hypertensive medications) impact large populations, especially the elderly. However, remarkably little is known about the neurochemical organization of vestibulo-sympathetic pathways. This project will provide fundamental information about the structural and chemical anatomy of vestibular projections to cardiovascular neurons in the ventrolateral medulla, may suggest new drug therapies to ameliorate orthostatic hypotension and intolerance, and may lead to the development of more specific anti-hypertensive medications that do not elicit disabling vestibular side effects such as dizziness and vertigo.

描述（由申请人提供）：前庭系统和血压控制之间的功能联系的存在已经被知道了近世纪。目前认为，动脉压力感受器参与通过压力感受器反射维持交感神经张力的调节回路，而来自前庭终末器官的信号驱动更快的机制，抵消姿势变化的影响。后一种回路通常被称为前庭交感神经反射（VSR）。该通路的初级传入终止于尾侧前庭核复合体（VNCc）中的细胞。这些二级神经元又投射到参与心血管调节的脑干部位，如延髓头端和尾侧腹外侧区（分别为RVLM和CVLM）。RVLM中的细胞被认为将前庭输入与压力感受器和其他感觉传入整合，并向脊髓的中间外侧细胞柱中的节前交感神经元发送兴奋性投射。虽然这些前交感血管RVLM细胞的主要神经递质可能是谷氨酸，但许多神经活性分子已共同定位于这些细胞中，包括C1细胞群的儿茶酚胺。此外，球脊髓血管RVLM细胞接受来自CVLM的单突触GABA能投射，其紧张性地抑制RVLM神经元。因此，CVLM细胞可以被视为血管通路中的交感抑制性中间神经元。我们的研究计划的长期目标是确定参与前庭自主神经投射的神经递质、受体和信号通路，以便它们可以被药物治疗特异性地靶向以改善前庭自主神经障碍。该研究项目的具体目标是确定有助于血压调节的前庭通路的结构和化学解剖。该项目有两个目标，将使用大鼠作为实验模型，双侧正弦前庭电流刺激以激活前庭核，遥测血压，顺行和逆行追踪，以及立即早期基因蛋白产物c-Fos以及通路特异性神经递质和调节剂的免疫荧光检测。目的1：明确前庭反应区前庭神经元的敏感性、局部解剖学、细胞学、神经递质和调制因子。该目的将测试VSR通路的VNCc细胞具有不同于其他VNCc神经元和压力反射通路的形态学、hodological和/或化学解剖学表型的总体假设。目的二是明确RVLM和CVLM前庭交感神经轴突的神经支配模式、突触学和突触后伙伴。这一目标将解决我们的过度兴奋的假设，通过确定前庭输入的神经元和突触的特异性，前交感神经血管通路。这些假设是我们长期目标的基础，因为VSR通路在形态学或化学解剖学上与压力感受性反射通路分离的区域或细胞是特定药物干预VSR的候选位点。 公共卫生相关性：靶向交感神经系统的药物（例如抗高血压药物）的体位性低血压和前庭副作用影响大量人群，尤其是老年人。然而，对于前庭交感神经通路的神经化学组织知之甚少。该项目将提供有关前庭投射到延髓腹外侧心血管神经元的结构和化学解剖学的基本信息，可能建议新的药物疗法来改善直立性低血压和不耐受，并可能导致开发更具体的抗高血压药物，这些药物不会引起前庭副作用，如头晕和眩晕。