Chemical Anatomy and Synaptology of Vestibulo-Sympathetic Pathways

描述（由申请人提供）：近一个世纪以来，人们就已经知道前庭系统和血压控制之间存在功能联系。目前认为，动脉压力感受器参与调节回路，通过压力反射维持交感神经张力，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。后一种回路通常称为前庭交感神经反射（VSR）。该通路的初级传入神经终止于尾部前庭核复合体 (VNCc) 的细胞上。这些二级神经元依次投射到涉及心血管调节的脑干部位，例如延髓头侧和尾侧腹外侧区（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在一起，并向脊髓中间外侧细胞柱中的节前交感神经元发送兴奋性投射。虽然这些前交感神经血管舒缩 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定位于这些细胞中，包括 C1 细胞组的儿茶酚胺。此外，球脊髓血管舒缩 RVLM 细胞接收来自 CVLM 的单突触 GABA 能投射，从而强直性抑制 RVLM 神经元。因此，CVLM 细胞可以被视为血管舒缩通路中的交感神经抑制性中间神经元。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，以便药物治疗能够专门针对它们来改善前庭自主神经紊乱。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结构。该项目有两个目标，将使用大鼠作为实验模型来实现，双侧正弦电前庭刺激以激活前庭核，遥测血压检测，顺行和逆行纤维束追踪，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。目标 1 将确定 VSR 前庭神经元的敏感性、拓扑结构、细胞学、神经递质和调节剂。这一目标将检验以下总体假设：VSR 通路的 VNCc 细胞具有与其他 VNCc 神经元和压力感受反射通路不同的形态学、方法学和/或化学解剖学表型。目标 2 将确定 RVLM 和 CVLM 中前庭交感神经轴突的神经支配模式、突触和突触后伙伴。这一目标将通过确定前庭输入到前交感神经血管舒缩回路的神经元和突触特异性来解决我们的总体假设。这些假设对于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对 VSR 进行特定药理干预的候选位点。

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.