Chemical Anatomy and Synaptology of Vestibulo-Sympathetic Pathways

描述（由申请人提供）：前庭系统和血压控制之间的功能联系已经存在了近一个世纪。目前认为，动脉压力感受器通过压力反射参与维持交感神经张力的调节回路，而来自前庭末端器官的信号驱动一种更快的机制，抵消姿势变化的影响。后一种回路通常称为前庭交感反射（VSR）。该通路的初级传入终止于尾侧前庭核复合体（VNCc）的细胞上。这些二级神经元依次投射到参与心血管调节的脑干部位，如吻侧和尾侧髓腹外侧区（分别为RVLM和CVLM）。RVLM中的细胞被认为整合前庭输入与压力感受器和其他感觉传入，并向脊髓中外侧细胞柱的神经节前交感神经元发送兴奋性投射。虽然这些交感前血管运动性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在这些细胞中共定位，包括C1细胞组的儿茶酚胺。此外，球脊髓血管运动性RVLM细胞接受来自CVLM的单突触gaba能投射，从而强直地抑制RVLM神经元。因此，CVLM细胞可被视为血管舒缩通路中的交感抑制中间神经元。我们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，以便它们可以通过药物治疗特异性靶向来改善前庭自主神经疾病。本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。本项目以大鼠为实验模型，有两个目的：双侧前庭窦电刺激激活前庭核，遥测血压，顺行和逆行示踪，免疫荧光检测即时早期基因蛋白产物c-Fos及通路特异性神经递质和调节剂。目的1将确定VSR前庭神经元的敏感性、地形、细胞学、神经递质和调节剂。这一目的将检验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、药理和/或化学解剖学表型的整体假设。目的2将确定RVLM和CVLM中前庭-交感轴突的神经支配模式、突触学和突触后伙伴。这一目标将通过确定前庭输入到交感前血管舒缩电路的神经元和突触特异性来解决我们的总体假设。这些假设对我们的长期目标至关重要，因为VSR通路在形态学或化学解剖学上与压力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。

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.