Central Viscerosensory Circuits-Structure and Function

描述（由申请人提供）：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。本R01竞争更新申请的研究将为下丘脑和边缘前脑的脏器感觉输入的功能组织和发展提供新的见解，重点关注来自肠道的感觉信号。实验将测试源自迷走背复合体（DVC）的去甲肾上腺素能（NA）和胰高血糖素样肽-1 （GLP-1）信号通路的结构和功能的机制假设，这些信号通路以下丘脑室旁核（PVN）、下丘脑外侧区（LHA）、终纹床核（BNST）和杏仁核中央核（CeA）为靶点。要检验的假设分为三个具体目标。目的1将使用顺行跨神经元病毒追踪来标记从胃到前脑的脏器感觉通路。一组实验将验证NA和非NA DVC神经元将胃脏器感觉信号传递到PVN、LHA、BNST和CeA的离散亚区这一假设。其他实验将验证这一假设，即在大鼠出生后的头两周，胃脏器感觉输入到前脑经历了显著的结构成熟。目的2将确定DVC NA神经元对下丘脑和边缘前脑对感受内应激反应的必要性。一项研究将验证这样一种假设，即DVC NA神经元对于某些内感受性应激源（即胆囊收缩素（CCK）、氯化锂（LiCl）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。相关研究将验证CCK、LiCl和LPS诱导PVN和LHA中cFos表达所必需的DVC NA神经元，而这些应激源诱导CeA中cFos表达所不需要的假设。第三项研究将验证一个假设，即在大鼠出生后的前两周，全身CCK、LiCl和LPS激活PVN、LHA、BNST和CeA中cFos表达的能力逐渐出现。Aim 3将使用电子显微镜来确定NA和glp -1阳性轴突末端是否在PVN、LHA、CeA和BNST中聚集在共同的突触后靶点上。实验结果将促进我们对下丘脑和边缘前脑的脏器感觉输入如何影响焦虑障碍、内脏不适、HPA应激轴失调、抑郁和条件厌恶等多种疾病的理解。

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.