BNST circuitry to hypothalamic regions in stress-induced avoidance

项目总结： 压力会导致长期的行为改变，从而导致精神疾病，如创伤后疾病 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- 诱导性的诱导或忽视自己的基本需要的，如饮食在老鼠身上，压力也可以以类似的方式表现出来：在 作为一种压力诱导的体验，老鼠不会在新奇的、明亮的环境中寻找食物或进食，尽管 饥饿。这种逃避行为的现象被称为新奇抑制进食或食欲不振。 终纹床核(BNST)是杏仁核延长部的一个区域，负责调节行为 对压力的反应。在人类中，BNST神经活动也会在应对不可控的压力时得到增强。 利用压力源可控性的小鼠模型，我们的初步数据表明，GABA和 在不可控的应激中，BNST内的谷氨酸神经元活性增加，延长了之前的 在人类中的上述发现与特定的BNST神经元有关。我们还发现，BNST神经元形成 与下丘脑在摄食和压力调节中起作用的关键区域的突触：弓状核 核团(ARC)和下丘脑室旁核(PVH)。在现场使用RNAScope 杂交后，我们发现大多数谷氨酸能BNST神经元共表达基因 对GABA和谷氨酸进行囊状包装的机械。这个提议的项目的目标是确定 BNST神经元向ARC和PVH传递GABA和谷氨酸的突触功能 应激诱导的回避的背景。主要的假设是有一个共同传播的增加 GABA和谷氨酸在ARC和PVH下游神经元受到不可控的应激后。因此，我们 假设GABA-谷氨酸BNST到下丘脑的通路是不可控的 压力会导致逃避行为。光遗传学、全细胞电生理学、行为学 应激分析和交叉病毒策略将被用于靶向和研究BNST回路 ARC和PVH。在目标1中，我们将评估应激诱导的BNST中GABA和谷氨酸释放的变化 ARC和PVH的神经元。在目标2中，我们将操纵GABA和谷氨酸从BNST到ARC的传递 和PVH在无法控制的压力下，并识别新颖性抑制进食的变化。生成的数据 从这项拟议的项目中可以确定神经递质共同传递的新机制，可能是 用来减少压力对回避的影响。

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.