BNST circuitry to hypothalamic regions in stress-induced avoidance

应激诱导回避中下丘脑区域的 BNST 电路

• 批准号: 10680197
• 负责人: Annie Ly
• 金额: $ 4.01万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-16 至 2026-08-15
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680197
• 关键词: Amygdaloid structure; Anterior; Anxiety; Appetitive Behavior; Aversive Stimulus; Behavior; Behavioral; Brain region; Cells; Clinical; Corticosterone; Data; Development; Eating; Electrophysiology (science); Energy Metabolism; Environment; Exhibits; Experimental Designs; FOS gene; Food; Foundations; Future; Genetic; Glutamates; Goals; Homeostasis; Human; Hunger; Hyperactivity; Hypothalamic structure; In Situ Hybridization; Lesion; Light; Mental disorders; Messenger RNA; Metabolic; Mus; Neurobiology; Neurons; Neurosecretory Systems; Neurotransmitters; Opsin; Organism; Output; Panic Disorder; Pathway interactions; Physiological; Physiological Adaptation; Plasma; Post-Traumatic Stress Disorders; Property; Psychopathology; Regulation; Risk Assessment; Risk Factors; Role; Site; Stress; Stressful Event; Structure of nucleus infundibularis hypothalami; Structure of terminal stria nuclei of preoptic region; Synapses; Training; Viral; Whole-Cell Recordings; approach behavior; avoidance behavior; behavioral response; biological adaptation to stress; cell type; experience; feeding; gamma-Aminobutyric Acid; genetic profiling; glutamatergic signaling; mouse model; neural; neurotransmitter release; novel; optogenetics; paraventricular nucleus; patch clamp; recombinase; response; restraint stress; stressor; transmission process; traumatic stress; vector

PROJECT SUMMARY: Stress can induce long-lasting behavioral changes that result in psychiatric illnesses, such as post-traumatic stress disorder (PTSD). Some of these changes include avoidance of future situations that may be stress- inducing or ignoring one’s own basic needs, such as eating. In mice, stress can manifest in similar ways: after a stress-inducing experience, mice will not explore for food or eat in a novel, brightly lit environment in spite of hunger. This phenomenon of avoidant behavior is known as novelty-suppressed feeding or hyponeophagia. The bed nucleus of the stria terminalis (BNST) is a region of the extended amygdala that regulates behavioral responses to stress. BNST neural activity is also enhanced in response to uncontrollable stress in humans. Using a mouse model of stressor controllability, our preliminary data establishes that both GABA and glutamate neuron activity within the BNST is increased during uncontrollable stress, extending the previously aforementioned finding in humans to specific BNST neurons. We have also found that BNST neurons form synapses onto key hypothalamic brain regions that play a role in feeding and stress regulation: the arcuate nucleus (ARC) and the paraventricular nucleus of the hypothalamus (PVH). Using RNAscope in situ hybridization, we discovered that the majority of glutamatergic BNST neurons co-express the genetic machinery to vesicularly package both GABA and glutamate. The goal of this proposed project is to determine the synaptic functionality of GABA and glutamate co-transmission from BNST neurons to ARC and PVH in the context of stress-induced avoidance. The principal hypothesis is that there is an increase in co-transmission of GABA and glutamate after uncontrollable stress on downstream ARC and PVH neurons. Therefore, we hypothesize that the GABA-glutamate BNST to hypothalamus pathways are necessary for uncontrollable stress to cause avoidant behavior. A combination of optogenetics, whole-cell electrophysiology, behavioral analyses of stress, and intersectional viral strategies will be used to target and investigate the BNST circuitry to ARC and PVH. In Aim 1, we will evaluate stress-induced changes in GABA and glutamate release from BNST neurons to ARC and PVH. In Aim 2, we will manipulate GABA and glutamate transmission from BNST to ARC and PVH during uncontrollable stress and identify changes in novelty-suppressed feeding. The data generated from this proposed project may identify novel mechanisms of neurotransmitter co-transmission that may be used to reduce the effects of stress on avoidance.

项目概要： 压力会引起持久的行为改变，从而导致精神疾病，例如创伤后应激障碍 应激障碍（PTSD）。其中一些变化包括避免未来可能造成压力的情况 诱导或忽视自己的基本需求，例如饮食。在小鼠中，压力可以以类似的方式表现出来： 这是一种诱发压力的经历，小鼠不会在新的、明亮的环境中探索食物或进食，尽管 饥饿。这种回避行为的现象被称为新奇抑制进食或食少症。 终纹床核 (BNST) 是延伸杏仁核的一个区域，负责调节行为 对压力的反应。 BNST 神经活动也会因人类无法控制的压力而增强。 使用应激源可控性小鼠模型，我们的初步数据表明 GABA 和 在无法控制的压力下，BNST 内的谷氨酸神经元活性增加，从而延长了先前的 上述在人类中对特定 BNST 神经元的发现。我们还发现 BNST 神经元形成 突触连接到在进食和压力调节中发挥作用的下丘脑关键大脑区域：弓状突触 下丘脑室旁核 (ARC) 和室旁核 (PVH)。使用 RNAscope 原位 杂交，我们发现大多数谷氨酸能 BNST 神经元共同表达遗传 囊泡包装 GABA 和谷氨酸的机器。该拟议项目的目标是确定 GABA 和谷氨酸从 BNST 神经元到 ARC 和 PVH 共同传递的突触功能 压力引起的回避的背景。主要假设是共同传播有所增加 下游 ARC 和 PVH 神经元受到无法控制的应激后的 GABA 和谷氨酸。因此，我们 假设 GABA-谷氨酸 BNST 到下丘脑的通路对于失控是必要的 压力导致回避行为。光遗传学、全细胞电生理学、行为学的结合 压力分析和交叉病毒策略将用于瞄准和研究 BNST 电路，以 ARC 和 PVH。在目标 1 中，我们将评估应激引起的 BNST 中 GABA 和谷氨酸释放的变化 ARC 和 PVH 神经元。在目标 2 中，我们将操纵 GABA 和谷氨酸从 BNST 到 ARC 的传输 和PVH在无法控制的压力期间识别新奇抑制喂养的变化。生成的数据 从这个拟议的项目中可能会确定神经递质共同传递的新机制 用于减少压力对回避的影响。