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: 7763786
• 负责人: Gay R Holstein
• 金额: $ 34.41万
• 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 2011-06-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7763786
• 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; 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; 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; evidence base; falls; gamma-Aminobutyric Acid; imidazoleacetic acid ribotide; immunoreactivity; interest; medial vestibular nucleus; moxonidine; neurochemistry; neuronal cell body; noradrenergic; public health relevance; 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(申请人提供)：目前的理解是动脉压力感受器控制交感神经系统的张力，而前庭末端器官提供前庭-交感反射的传入输入，通常增强代偿性压力反射。然而，这种整合背后的神经通路的化学解剖学、连通性和突触学在很大程度上仍不清楚。该项目的总体目标是确定参与调节前庭-自主神经突触相互作用的神经递质和调节剂。这四个目标研究了成年大鼠前庭投射的化学解剖学和突触学，并评估了前庭向延髓尾侧和头端腹外侧投射(分别为CVLM和RVLM)利用不同的递质/调制器信号和不同的突触结构安排的总体假设。目的一是确定前庭-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，确定这些通路使用的初级氨基酸神经递质(S)，并确定这些投射是否终止于CVLm和RVLm的谷氨酸能和/或GABA能神经元。目的2确定CVLm和RVLm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内前庭受体细胞的主要神经递质和调节物进行定性分析，验证谷氨酸能前庭传入物质终止于含GABA能/IAA-RP的CVLM神经元的中间神经元和远侧树突，RVLM内的GABA能和去甲肾上腺素能树突，以及直接投射到脊髓的含Glu能/IAA-RP的RVLM神经元的胞体。目的4是可视化和定量化前庭交感突触的参数，并验证RVLM的前庭终末的突触涉及多个递质系统之间的复杂相互作用的假设，而CVLM的前庭交感终末的突触反映了与CVLM输出神经元的直接轴-树接触。在整个项目中，将使用组织中的顺行和逆行追踪来识别前庭交感通路，这些组织将使用额外的免疫荧光标记进行进一步处理，以识别感兴趣的递质和调节器。超微结构研究将使用免疫金标记物来识别和量化终末和突触接触。这些研究将表征前庭投射到交感运动前延髓神经元池的神经递质、调节物和突触连接，并将对其突触结构的参数进行定性分析和定量估计。这一信息目前在文献中还不存在，对循证药物疗法的发展非常重要，用于治疗直立性低血压等前庭自主神经障碍，以及开发更具体的抗高血压药物，这些药物不会引起致残性前庭副作用，如头晕和眩晕。公共卫生相关性：针对交感神经系统的药物(如抗高血压药物)的直立性低血压和前庭副作用影响大量人群，尤其是老年人。然而，人们对前庭-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区心血管神经元的化学解剖和突触组织的基本信息，可能会建议新的药物疗法来改善直立性低血压和耐受性，并可能导致更具体的降压药物的开发，这些药物不会导致前庭功能丧失的副作用，如头晕和眩晕。