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: 7467791
• 负责人: Gay R Holstein
• 金额: $ 34.06万
• 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 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7467791
• 关键词: Address; Admission activity; Adrenergic Receptor; Adult; Adverse effects; Affinity; Age; Am 80; American; Amino Acid Neurotransmitters; Anatomy; Antihypertensive Agents; Architecture; Autonomic nervous system disorders; Baroreflex; Binding; Biological Models; Blood Pressure; Brain; Brain Stem; Cardiovascular system; Cell physiology; Cells; Cessation of life; Chemicals; Citrulline; Clinical Research; Clonidine; Complex; Dendrites; Development; Direct Costs; Disease; Distal; Dizziness; Dopamine; Drug Delivery Systems; Elderly; Epinephrine; Fall prevention; Financial cost; Force of Gravity; Functional disorder; Glutamates; Goals; Homeostasis; Hospitals; Human; IAA-RP; Imidazole; Immunofluorescence Immunologic; Inferior; Injection of therapeutic agent; Injury; Interneurons; Joints; Label; Lead; Ligands; Link; Literature; Location; Mediating; Methods; Mixed Function Oxygenases; Motor; Movement; Neural Pathways; Neurons; Neurotransmitters; Nitric Oxide; Norepinephrine; Nuclear; Nucleus solitarius; Organ; Orthostatic Hypotension; Output; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Phaseolus vulgaris leucoagglutinin; Phenotype; Phenylethanolamine N-Methyltransferase; Population; Posture; Pressoreceptors; Presynaptic Terminals; Process; Public Health; Rattus; Rattus norvegicus; Reflex action; Regulation; Relative (related person); Reporting; Research; Signal Transduction; Site; Societies; Source; Spinal Cord; Sympathetic Nervous System; Synapses; System; Testing; Thoracic spinal cord structure; Tissues; Tracer; Trauma; Vertigo; Vestibular nucleus structure; base; blood pressure regulation; falls; gamma-Aminobutyric Acid; imidazoleacetic acid ribotide; immunoreactivity; interest; medial vestibular nucleus; moxonidine; neurochemistry; neuronal cell body; noradrenergic; receptor; research study; rilmenidine; young adult

DESCRIPTION (provided by applicant): It is currently understood that arterial baroreceptors control sympathetic nervous system tone, while vestibular end organs provide afferent input to a vestibulo-sympathetic reflex that normally augments the compensatory baroreflex. However, the chemical anatomy, connectivity and synaptology of the neural pathways underlying this integration remain largely unknown. The overall goal of the proposed project is to identify the neurotransmitters and modulators involved in mediating vestibulo-autonomic synaptic interactions. The four aims address the chemoanatomy and synaptology of these vestibular projections in adult rats and evaluate the overall hypothesis that different transmitter/modulator signatures and distinct synaptic architectural arrangements are utilized by vestibular projections to the caudal and rostral ventrolateral medulla (CVLM and RVLM, respectively). Aim 1 is to identify the locations of vestibulo-medullary and medullo- sympathetic projection neurons, determine the relative proportions of vestibular projections to CVLM and RVLM, identify the primary amino acid neurotransmitter(s) utilized by these pathways and determine whether these projections terminate on glutamatergic and/or GABAergic neurons in CVLM and RVLM. Aim 2 is to determine whether vestibular terminals in CVLM and RVLM co-express IAA-RP and/or L-citrulline. Aim 3 is to conduct a qualitative analysis of the main neurotransmitters and modulators of vestibulo-recipient cells in RVLM and CVLM, to test the hypothesis that glutamatergic vestibular afferents terminate on interneurons and on distal dendrites of GABAergic/IAA-RP-containing CVLM neurons, GABAergic and noradrenergic dendrites in RVLM, and directly on the somata of glutamatergic/IAA-RP-containing RVLM neurons with direct projections to the spinal cord. Aim 4 is to visualize and quantify parameters of vestibulo-sympathetic synaptology, and will test the hypothesis that the synaptology of vestibular terminals in RVLM involves complex interactions among multiple transmitter systems, whereas the synaptology of vestibulo-sympathetic terminals in CVLM reflects direct axo-dendritic contacts with CVLM output neurons. Throughout the project, the vestibulo-sympathetic pathways will be identified using anterograde and retrograde tract-tracing in tissue that will be further processed using additional immunofluorescent tags to identify transmitters and modulators of interest. Ultrastructural studies will employ immunogold labels to identify and quantify terminals and synaptic contacts. These studies will characterize the neurotransmitters, modulators and synaptic articulations utilized by vestibular projections to sympathetic pre-motor medullary neuron pools and will yield qualitative analyses and quantitative estimates of parameters of their synaptic architecture. This information does not currently exist in the literature, and is important for the development of evidence-based pharmacotherapeutics for the treatment of vestibulo-autonomic disorders such as orthostatic hypotension, as well as the development of more specific anti-hypertensive medications that do not elicit disabling vestibular side-effects such as dizziness and vertigo. 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, little is known about the neurochemical organization of vestibulo-sympathetic pathways. This project will provide fundamental information about the chemoanatomic and synaptic organization 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）：目前理解的是，动脉压力感受器控制交感神经系统张力，而前庭终末器官向前庭-交感神经反射提供传入输入，该前庭-交感神经反射通常增强代偿性压力感受器反射。然而，这种整合背后的神经通路的化学解剖学、连接性和突触学仍然在很大程度上未知。该项目的总体目标是确定参与介导前庭-自主神经突触相互作用的神经递质和调节剂。这四个目标解决的化学解剖学和突触这些前庭预测在成年大鼠和评估的整体假设，即不同的发射器/调制器的签名和独特的突触结构安排，利用前庭预测的尾侧和头侧腹外侧延髓（CVLM和RVLM，分别）。目的1是确定前庭-延髓和延髓-交感投射神经元的位置，确定前庭投射到CVLM和RVLM的相对比例，确定这些通路所利用的主要氨基酸神经递质，并确定这些投射是否终止于CVLM和RVLM中的多巴胺能和/或GABA能神经元。目的2是确定CVLM和RVLM中的前庭终末是否共表达IAA-RP和/或L-瓜氨酸。目的3：对RVLM和CVLM前庭受体细胞的主要神经递质和调节剂进行定性分析，以验证多巴胺能前庭传入终止于含有GABA能/IAA-RP的CVLM神经元的中间神经元和远端树突、RVLM中的GABA能和去甲肾上腺素能树突以及直接投射到脊髓的多巴胺能/IAA-RP的RVLM神经元的胞体的假设。目的4是可视化和量化参数的前庭交感神经突触学，并将测试的假设，前庭终端在RVLM的突触学涉及多个递质系统之间的复杂的相互作用，而前庭交感神经终端在CVLM的突触学反映了直接轴-树突接触CVLM输出神经元。在整个项目中，前庭交感神经通路将使用组织中的顺行和逆行追踪来识别，这些追踪将使用额外的免疫荧光标记来进一步处理，以识别感兴趣的递质和调节剂。超微结构研究将采用免疫金标记来识别和量化终端和突触接触。这些研究将表征前庭投射到交感运动前髓神经元池所利用的神经递质、调制剂和突触关节，并将产生其突触结构参数的定性分析和定量估计。该信息目前在文献中不存在，并且对于开发用于治疗前庭自主神经疾病（如直立性低血压）的循证药物治疗以及开发不会引起致残性前庭副作用（如头晕和眩晕）的更特异性降压药物非常重要。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，很少有人知道前庭交感神经通路的神经化学组织。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化学解剖学和突触组织的基本信息，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。