Central GLP1 Signaling Pathways and Anxiety

项目总结/摘要 情感性焦虑的特征是行为抑制伴随认知唤醒和警觉， 反映了一种面向未来的情绪状态。焦虑是对感知到的威胁的适应性反应;然而， 慢性焦虑会使人衰弱，焦虑症是美国最常见的精神疾病类型。 States.在动物模型中识别威胁行为反应的神经回路是至关重要的 了解导致正常和病理性焦虑的神经生物学机制， 人类基础和临床研究都强调杏仁核中央核的重要性 (CEA)终纹前外侧床核（anterolateral bed nucleus of stria terminalis，alBST）在调节情绪和生理方面的作用 焦虑的组成部分。CEA和alBST紧密相连，共享许多共同的资源。 输入，包括从身体到大脑传递感觉反馈的尾脑干神经元的输入;这 反馈强烈调节情绪状态，包括威胁反应。这项研究将测试新的 关于CEA/alBST投射脑干神经元的组织和行为作用的假设， 表达胰高血糖素样肽-1（GLP 1）。大鼠急性应激后GLP 1神经元被激活表达cFos， CEA/alBST中的GLP 1受体信号增加唤醒/警觉和行为抑制/回避 类似于人类的焦虑。我们最近开发了一种转基因Sprague道利大鼠（Gcg-Cre），其中 Cre由孤束尾侧核的GLP 1神经元有效地和选择性地表达， 中间网状核（即，NTS/IRtGLP 1神经元）。使用经过验证的病毒工具和行为分析， 这种新的模式生物，我们将进行突触连接和功能作用的比较分析 雄性和雌性Gcg-Cre大鼠的NTS/IRtGLP 1à CEA/alBST回路，包括潜在性别的记录 差异由于GLP 1神经元在脑干的分布和GLP 1受体在边缘前脑的分布， 在大鼠和人类中似乎相似，这项基础科学项目的结果具有潜在的转化价值。 与理解人类焦虑的正常和病理症状的神经生物学基础相关。

PROJECT SUMMARY/ABSTRACT Affective anxiety is characterized by behavioral inhibition accompanied by cognitive arousal and vigilance, reflecting a future-oriented emotional state. Anxiety is an adaptive response to perceived threat; however, chronic anxiety is debilitating, and anxiety disorders are the most common type of mental illness in the United States. Identification of neural circuits that underlie behavioral responses to threat in animal models is essential for understanding neurobiological mechanisms that contribute to normative and pathological anxiety in humans. Basic and clinical research has emphasized the importance of the central nucleus of the amygdala (CEA) and the anterolateral bed nucleus of stria terminalis (alBST) in regulating affective and physiological components of anxiety. The CEA and alBST are heavily interconnected and share many common sources of input, including input from caudal brainstem neurons that convey sensory feedback from body to brain; this feedback strongly modulates emotional state, including threat responses. The proposed research will test new hypotheses regarding the organization and behavioral role of CEA/alBST-projecting brainstem neurons that express glucagon-like peptide-1 (GLP1). GLP1 neurons are activated to express cFos in rats after acute threat, and GLP1 receptor signaling in the CEA/alBST increases arousal/vigilance and behavioral inhibition/avoidance in rats, akin to anxiety in humans. We recently developed a transgenic Sprague Dawley rat (Gcg-Cre) in which Cre is efficiently and selectively expressed by GLP1 neurons in the caudal nucleus of the solitary tract and intermediate reticular nucleus (i.e., NTS/IRtGLP1 neurons). Using validated viral tools and behavioral assays in this new model organism, we will conduct comparative analyses of the synaptic connectivity and functional role of NTS/IRtGLP1à CEA/alBST circuits in male and female Gcg-Cre rats, including documentation of potential sex differences. Since the distribution of GLP1 neurons in brainstem and GLP1 receptors in limbic forebrain appears similar in rats and humans, results from this basic science project have potential translational relevance for understanding neurobiological bases of normal and pathological symptoms of anxiety in humans.