Central Viscerosensory Circuits - Structure and Function

描述（由申请人提供）：临床研究越来越强调来自尾侧脑干的上行内脏感觉通路（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信号转导失调与压力相关的精神疾病（包括抑郁症和焦虑症）的病理生理学有关。拟议的研究将测试有关上行NA通路的结构和功能的假设，这些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）的互连区域内的神经活动。这些途径来自孤束核（NST）和延髓腹外侧区（VLM）内脏感觉区的NA神经元，脑桥蓝斑几乎没有直接贡献。揭示这些系统在大鼠中的功能组织具有临床意义，并可能有助于开发新的治疗方法来治疗压力相关的情绪失调。我们的工作假设是，生理（内感受性）和认知/情绪应激改变内脏感觉信号，由延髓NA神经元传递到下丘脑和边缘前脑，这些信号是塑造情绪状态的关键，证明了压力反应，动机行为和情绪学习。NST和VLM内的NA神经元具有靶向多于一个下丘脑和边缘前脑靶点的分支轴突。目的1中的逆行追踪实验将同时检查NA轴突侧支化和由不适诱导剂氯化锂（LiCl）引起的上行通路募集。目标1中获得的解剖学数据将有助于解释目标2中获得的功能数据，其中在测定大鼠对三种不同挑战的行为和生理反应之前，将选择性地破坏PVN、CeA和/或alBST的NA输入：（1）氯化锂，（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）全身育亨宾（YO），一种能增强整个大脑NA信号传导的药物。目的3中的平行实验将检验以下假设：CeA和alBST之间的直接通信对于在具有其他完整的中枢NA回路的大鼠中对LiCl、TMT和YO的行为和生理反应是必要的。拟议的研究将揭示内脏感觉NA输入到下丘脑和边缘前脑的功能组织的新方面，这些功能组织在介导对情感重大事件的生理和行为反应中发挥关键作用。大脑中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。拟议中的研究将测试有关去甲肾上腺素能通路的结构和功能的假设，这些通路调节下丘脑和边缘前脑相互连接的区域内的神经活动。实验结果可能会导致开发新的治疗选择，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.