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： 压力可以引起长期的行为变化，导致精神疾病，如创伤后精神病。 应激障碍（PTSD）。其中一些变化包括避免未来可能会有压力的情况- 诱导或忽视自己的基本需求，如吃饭。在小鼠中，压力可以以类似的方式表现出来： 这是一种压力诱导的经历，老鼠不会在一个新的、明亮的环境中寻找食物或进食， 饥饿这种回避行为的现象被称为新奇抑制进食或hyponeophagia。 终纹床核（BNST）是杏仁核延伸区的一个区域， 对压力的反应。BNST神经活动也会在人类无法控制的压力下增强。 使用小鼠模型的压力可控性，我们的初步数据建立，无论是GABA和 BNST内的谷氨酸神经元活动在不可控制的应激期间增加，延长了先前的谷氨酸神经元活动。 上述发现在人类特定的BNST神经元。我们还发现，BNST神经元形成 下丘脑的关键脑区，在进食和压力调节中发挥作用：弓状核 核（ARC）和室旁核（PVH）。使用RNAscope原位 通过杂交，我们发现大多数多巴胺能BNST神经元共表达基因， 机械囊泡包装GABA和谷氨酸。本项目的目标是确定 GABA和谷氨酸从BNST神经元到ARC和PVH的共传递的突触功能在 压力诱导的回避。主要的假设是，有一个共同传播的增加， 对下游ARC和PVH神经元施加不可控制的压力后，GABA和谷氨酸。所以我们 假设GABA-谷氨酸BNST到下丘脑通路是不可控制的 压力导致回避行为。光遗传学、全细胞电生理学、行为学 压力分析和交叉病毒策略将被用于靶向和研究BNST电路， ARC和PVH。在目标1中，我们将评估BNST中GABA和谷氨酸释放的应激诱导变化 ARC和PVH。在目标2中，我们将操纵GABA和谷氨酸从BNST到ARC的传递 和PVH在不可控制的压力，并确定在新奇抑制喂养的变化。生成的数据 从这个拟议的项目可以确定新的机制，神经递质共传递， 用来减少压力对逃避的影响。