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.

项目摘要： 压力会引起持久的行为改变，导致精神病，例如创伤后 应激障碍（PTSD）。其中一些变化包括避免可能压力的未来情况 - 引起或忽略自己的基本需求，例如饮食。在小鼠中，压力可以以类似的方式表现出来：之后 一种引起压力的体验，小鼠不会在新颖，明亮的环境中探索食物或进食 饥饿。这种回避行为的现象被称为新颖的喂养或降压性。 Stria末端（BNST）的床核是延长的杏仁核的区域，可调节行为 对压力的反应。 BNST神经活动也随着人类无法控制的压力而增强。 使用压力源可控性的鼠标模型，我们的初步数据确定了GABA和 在无法控制的应力期间，BNST内的谷氨酸神经元活性增加 人类对特定的BNST神经元的发现。我们还发现BNST神经元形成 突触到关键的下丘脑大脑区域，在进食和压力调节中起作用：弧形 下丘脑（PVH）的核（ARC）和室室核。原位使用rnascope 杂交，我们发现大多数谷氨酸能BNST神经元共表达通用 囊泡的机械包装GABA和谷氨酸。这个拟议项目的目标是确定 GABA和谷氨酸的突触功能从BNST神经元转移到ARC和PVH中 压力引起的回避的背景。主假设是，共同传输的增加 在下游弧和PVH神经元无法控制的应力后，GABA和谷氨酸。因此，我们 假设GABA-GLUTAMATE BNST到下丘脑途径是不可控制的 压力会导致回避行为。光遗传学，全细胞电生理学，行为的组合 应力分析和交叉病毒策略将用于针对和研究BNST电路至 ARC和PVH。在AIM 1中，我们将评估BNST的应力诱导的GABA和谷氨酸释放的变化 神经元到ARC和PVH。在AIM 2中，我们将操纵GABA和谷氨酸从BNST到弧的传播 和PVH在无法控制的压力期间，并确定新颖性喂养的变化。生成的数据 从这个提议 用于减少压力对回避的影响。