Central Viscerosensory Circuits - Structure and Function

临床研究越来越强调从尾侧脑干上行的脏器感觉通路，包括去甲肾上腺素能（NA）通路，在应激反应和情感/情绪状态中的重要性。NA信号失调与应激相关精神疾病的病理生理学有关，包括抑郁症和焦虑症。该研究将测试关于上行NA通路的结构和功能的假设，这些上行NA通路调节下丘脑室旁核（PVN）、杏仁核中央核（CeA）和终纹前外侧床核（alBST）相互连接区域内的神经活动。这些通路产生于孤立束核（NST）和延髓腹外侧核（VLM）脏器感觉区域的NA神经元，很少或没有直接来自脑桥蓝斑的贡献。揭示大鼠这些系统的功能组织具有临床意义，并可能有助于开发治疗压力相关情绪失调的新治疗方案。我们的工作假设是，生理（内感受）和认知/情绪压力源都改变了由髓质NA神经元传递到下丘脑和边缘前脑的内脏感觉信号，这些信号对形成情绪状态至关重要，如应激反应、动机行为和情绪学习所证明的那样。NST和VLM内的NA神经元具有分支轴突，可靶向多个下丘脑和边缘前脑靶点。Aim 1的逆行通道追踪实验将同时检测NA轴突侧支和由一种不适诱导剂氯化锂（LiCl）募集的上行通路。Aim 1中获得的解剖学数据将有助于解释Aim 2中获得的功能数据，其中NA输入PVN， CeA和/或alBST将在大鼠对三种不同挑战的行为和生理反应进行分析之前被选择性地破坏：(1)LiCl,(2)暴露于引起恐惧和焦虑的捕食者气味，三甲基噻唑啉（TMT）或(3)系统性育himine (YO)，一种强有力地增加整个大脑NA信号的药理学药物。Aim 3的平行实验将验证一个假设，即在中枢NA回路完好的大鼠中，CeA和alBST之间的直接交流对于LiCl、TMT和YO的行为和生理反应是必要的。该研究将揭示下丘脑和边缘前脑的脏器感觉NA输入的功能组织的新方面，这些输入在介导对情绪重大事件的生理和行为反应中发挥关键作用。大脑中的去甲肾上腺素能信号失调与压力相关的精神疾病有关，包括抑郁症和焦虑症。拟议的研究将测试关于调节下丘脑和边缘前脑相互连接区域内神经活动的去甲肾上腺素能通路的结构和功能的假设。实验结果可能会导致新的治疗方案的发展，以治疗压力相关的情绪病理。

DESCRIPTION (provided by applicant): Clinical research has increasingly emphasized the importance of ascending viscerosensory pathways from the caudal brainstem, including noradrenergic (NA) pathways, in stress responses and affective/emotional state. Dysregulated NA signaling is implicated in the pathophysiology of stress-related psychiatric illnesses, including depression and anxiety disorders. The proposed research will test hypotheses about the structure and function of ascending NA pathways that modulate neural activity within interconnected regions of the paraventricular nucleus of the hypothalamus (PVN), central nucleus of the amygdala (CeA), and anterolateral bed nucleus of the stria terminalis (alBST). These pathways arise from NA neurons in viscerosensory regions of the nucleus of the solitary tract (NST) and ventrolateral medulla (VLM), with little or no direct contribution from the pontine locus coeruleus. Revealing the functional organization of these systems in rats has clinical relevance, and may contribute to the development of new therapeutic options for treating stress-related emotional dysregulation. Our working hypothesis is that both physiological (interoceptive) and cognitive/emotional stressors alter viscerosensory signals that are relayed by medullary NA neurons to the hypothalamus and limbic forebrain, and that these signals are critical for shaping emotional state as evidenced by stress responsiveness, motivated behavior, and emotional learning. NA neurons within the NST and VLM have branching axons that target more than one hypothalamic and limbic forebrain target. Retrograde tract-tracing experiments in Aim 1 will simultaneously examine NA axonal collateralization and ascending pathway recruitment by a malaise- inducing agent, lithium chloride (LiCl). The anatomical data obtained in Aim 1 will facilitate interpretation of functional data obtained in Aim 2, in which NA inputs to the PVN, CeA, and/or alBST will be selectively destroyed before rats are assayed for behavioral and physiological responses to three distinct challenges: (1) LiCl, (2) exposure to a fear- and anxiety-inducing predator odor, trimethylthiazoline (TMT), or (3) systemic yohimbine (YO), a pharmacological agent that robustly increases NA signaling throughout the brain. Parallel experiments in Aim 3 will test the hypothesis that direct communication between the CeA and alBST is necessary for behavioral and physiological responses to LiCl, TMT, and YO in rats with otherwise intact central NA circuitry. The proposed research will reveal new aspects of the functional organization of viscerosensory NA inputs to the hypothalamus and limbic forebrain that play a critical role in mediating physiological and behavioral responses to emotionally significant events. Dysregulated noradrenergic signaling in the brain is implicated in stress-related psychiatric illnesses, including depression and anxiety disorders. The proposed research will test hypotheses about the structure and function of noradrenergic pathways that modulate neural activity within interconnected regions of the hypothalamus and limbic forebrain. Experimental outcomes could lead to the development of new therapeutic options for treating stress-related emotional pathologies.