Central Viscerosensory Circuits-Structure and Function

描述(申请人提供)：来自身体内部的感觉信号被传递到大脑区域，形成对压力的生理和行为反应，并影响情绪学习。这项R01竞争性更新申请中提出的研究将为下丘脑和边缘前脑的内脏感觉输入的功能组织和发展提供新的见解，重点是来自肠道的感觉信号。实验将检验有关去甲肾上腺素(NA)和胰高血糖素样肽-1(GLP-1)信号通路的结构和功能的机械假说，这些信号通路起源于迷走神经背侧复合体(DVC)，靶向下丘脑室旁核(PVN)、下丘脑外侧区(LHA)、终纹床核(BNST)和杏仁中央核(CEA)。要检验的假设被组织成三个具体的目标。目标1将使用顺行跨神经元病毒追踪来标记从胃到前脑的内脏感觉通路。一组实验将检验这一假设，即NA和非NA DVC神经元将胃内脏感觉信号传递到PVN、LHA、BNST和CEA的离散亚区。其他实验将检验这一假设，即大鼠在出生后的头两周内，胃内脏感觉输入到前脑的结构经历了显著的结构成熟。目的2确定下丘脑和边缘前脑对内感应激反应的DVC NA神经元的必要性。一项研究将检验这一假设，即DVC NA神经元对于某些内感应激源[即CCK、氯化锂和脂多糖(LPS)]抑制食物摄入是必要的，但对于这些应激源支持条件性味觉厌恶学习是不必要的。一项相关研究将验证这一假说，即CCK、LiCl和LPS是诱导PVN和LHA中CFos表达所必需的，而这些应激源不是诱导CEA中CFos表达所必需的。第三项研究将检验这一假设，即在出生后的头两周，大鼠体内系统性CCK、LiCl和LPS激活PVN、LHA、BNST和CEA中CFos表达的能力逐渐显现。目的3将使用电子显微镜来确定不同的NA和GLP-1阳性轴突终末是否会聚在PVN、LHA、CEA和BNST的共同突触后靶点上。实验结果将促进我们对内脏感觉输入下丘脑和边缘前脑如何影响各种情况的理解，如焦虑症、内脏不适、HPA应激轴调节失调、抑郁和条件性厌恶。

DESCRIPTION (provided by applicant): Sensory signals from within the body are delivered to brain regions that shape physiological and behavioral responses to stress and influence emotional learning. The research proposed in this R01 competing renewal application will provide new insights into the functional organization and development of viscerosensory inputs to the hypothalamus and limbic forebrain, with a focus on sensory signals from the gut. Experiments will test mechanistic hypotheses about the structure and function of noradrenergic (NA) and glucagon-like peptide-1 (GLP-1) signaling pathways that originate in the dorsal vagal complex (DVC) and target the paraventricular nucleus of the hypothalamus (PVN), lateral hypothalamic area (LHA), bed nucleus of the stria terminalis (BNST), and central nucleus of the amygdala (CeA). Hypotheses to be tested are organized into three Specific Aims. Aim 1 will use anterograde transneuronal virus tracing to label viscerosensory pathways from the stomach to the forebrain. One set of experiments will test the hypothesis that NA and non-NA DVC neurons relay gastric viscerosensory signals to discrete subregions of the PVN, LHA, BNST, and CeA. Other experiments will test the hypothesis that gastric viscerosensory inputs to the forebrain undergo significant structural maturation in rats during the first two weeks postnatal. Aim 2 will determine the necessity of DVC NA neurons for hypothalamic and limbic forebrain responses to interoceptive stress. One study will test the hypothesis that DVC NA neurons are necessary for certain interoceptive stressors [i.e., cholecystokinin (CCK), lithium chloride (LiCl), and lipopolysaccharide (LPS)] to inhibit food intake, but are unnecessary for these stressors to support conditioned taste aversion learning. A related study will test the hypothesis that DVC NA neurons are necessary for CCK, LiCl and LPS to induce cFos expression in the PVN and LHA, but are unnecessary for these stressors to induce cFos expression in the CeA. A third study will test the hypothesis that the ability of systemic CCK, LiCl, and LPS to activate cFos expression in the PVN, LHA, BNST, and CeA emerges gradually in rats during the first two weeks postnatal. Aim 3 will use electron microscopy to determine whether separate populations of NA and GLP-1-positive axon terminals converge on common postsynaptic targets in the PVN, LHA, CeA, and BNST. Experimental outcomes will advance our understanding of how viscerosensory inputs to the hypothalamus and limbic forebrain might impact diverse conditions such as anxiety disorders, visceral malaise, dysregulation of the HPA stress axis, depression, and conditioned aversions.