Chemical Anatomy and Synaptology of Vestibulo-Sympathetic Pathways

项目总结 压力感受器反射是一种平衡反馈途径，负责维持稳定的血液流向大脑。 压力感受器信号被传递到孤束核，然后传递到延髓尾侧腹外侧 (CVLM)。CVLM向吻侧腹外侧区发出兴奋性投射和GABA能抑制投射 延髓(RVLM)，它反过来为脊髓中的节前交感神经元提供关键输入 控制交感神经活动的物质。压力感受性反射通路是多突触的，潜伏期相对较长， 并且是唯一的反应性的，调节血管收缩和心率以响应先前的心血管疾病 变化，如血压(BP)的变化。相反，前庭-交感神经反射(VSR) 调节主动、直接和快速的血压调节，在高血压发作时启动体内的血液再分配 运动或姿势调整，以确保无论头部如何都能保持一致的脑灌注 位置。VSR是由前庭末端器官的输入触发的，前庭末端器官将信号传递给 前庭尾侧核(VNC)投射到CVLM和/或RVLM。通过VNC激活这一通路 引起交感神经活动和血压的变化。我们最近发现，有两个肢体的 VSR，一种是GABA能的，被认为是抑制的，另一种是被认为是兴奋和 谷氨酸能。拟议研究的目标是确定这两者的具体连通性 使用一种新的方法激活单个末端器官的VSR的化学解剖学方面。测试整体 假设刺激引起的血压变化方向反映了不同的激活， VSR的这两个主要分支的连接和突触。该项目利用了空间优势 脉冲红外激光刺激前庭末梢器官的特异性 单个感受器区域。我们将检验以下假设：焦点刺激仅限于椭圆囊或球囊 激活在局部隔离的特定化学解剖学定义的VSR神经元亚型 在VNC内，并主要到RVLM或CVLM项目。此外，我们还将调查 球囊、球囊和后半规管联合激活VSR介导的降压作用。 将进行超微结构研究，以确认这一途径的详细解剖。总体而言，这个项目 阐述VSR反应的解剖学基础，并为确定其实用性和有效性奠定基础 红外线激光刺激作为治疗前庭自主神经障碍的下一代疗法，包括 神经源性直立性低血压和不耐受。

PROJECT SUMMARY The baroreflex is a homeostatic feedback pathway responsible for maintaining stable blood flow to the brain. Baroreceptor signals are conveyed to the solitary nucleus and then to the caudal ventrolateral medulla (CVLM). The CVLM sends both excitatory and GABAergic inhibitory projections to the rostral ventrolateral medulla (RVLM), which in turn provides the key input to preganglionic sympathetic neurons in the spinal cord that control sympathetic nerve activity. The baroreflex pathway is polysynaptic, has a relatively long latency, and is solely reactive, modulating vasoconstriction and heart rate in response to a prior cardiovascular vicissitude such as a change in blood pressure (BP). In contrast, the vestibulo-sympathetic reflex (VSR) mediates proactive, direct and rapid BP modulation, initiating blood redistribution in the body at the onset of movement or a postural adjustment in order to assure consistent cerebral perfusion regardless of head position. The VSR is triggered by input from the vestibular end organs, which convey signals to neurons in the caudal vestibular nuclei (VNc) that project to CVLM and/or RVLM. Activation of this pathway through VNc causes changes in sympathetic nerve activity and BP. We have recently found that there are two limbs of the VSR, one that is GABAergic and putatively inhibitory, and another that is putatively excitatory and glutamatergic. The goal of the proposed research is to determine the specific connectivity of these two chemoanatomic facets of the VSR using a novel approach to activate individual end organs. testing the overall hypothesis that the direction of BP change resulting from stimulation reflects the differential activation, connectivity and synaptology of these two main limbs of the VSR. The project takes advantage of the spatial specificity of pulsed infrared laser stimulation of the vestibular end organs in order to discretely activate individual receptor regions. We will test the hypotheses that focal stimulation restricted to the utricle or saccule activates specific chemoanatomically-defined subtypes of VSR neurons that are topographically segregated within the VNC and project primarily to either RVLM or CVLM. In addition, we will investigate the effects of combined utricular, saccular and posterior semicircular canal activation on BP mediated by the VSR. Ultrastructural studies will be conducted to confirm the detailed anatomy of this pathway. Overall, this project addresses the anatomical bases for VSR responses, and is foundational for establishing the utility and efficacy of infrared laser stimulation as a next-generation treatment for vestibulo-autonomic disorders including neurogenic orthostatic hypotension and intolerance.