Genetic dissection of lateral septal circuitry that controls stress-induced persistent anxiety states

项目概要 我们正在研究控制防御行为持续升高的神经回路 无法控制的压力。这对人类健康具有潜在的益处，与美国国立卫生研究院的使命相关。特别是， 暴露于无法控制的压力被认为会导致或直接引发多种精神疾病的发作 现有疗法不足以治疗的疾病。改善此类疾病的治疗方法需要 了解压力经历通常如何影响特定的神经回路以增加焦虑和 防御行为，以及这些回路的异常参与如何导致精神疾病。 促肾上腺皮质激素释放因子受体 (CRFR) 控制对压力和压力的行为和生理反应 与创伤相关的精神疾病有关，但它们起作用的神经回路水平机制 尚未明确定义。一个极其重要的区域是侧中隔 (LS)，它对 由无法控制的压力源激活，并通过 2 型调节压力引起的焦虑状态的严重程度 啮齿动物模型中的 CRFR (CRFR2)。此外，对患有压力相关疾病的患者进行神经影像学研究 一直检测到海马体的异常，海马体是与大脑密切相关的结构 LS。然而，压力引起持续的 CRFR2 依赖性焦虑变化的精确方式和 通过特定 LS 回路的防御行为以及海马输入的潜在作用尚未被研究 确定。在这里，我们重点通过解决两个根本性的重要问题来填补这一知识空白 关于小鼠的 LS 连接和功能，小鼠是一种模型生物，其大脑具有高结构 以及与人脑的分子相似性。 在目标 1 中，我们将确定 LS 中表达 CRFR2 的神经元的活动在应激后如何变化。 经验，以及这些变化如何与压力引起的焦虑行为的严重程度相关。作为 特定的神经活动模式可能会增强对压力的适应力或敏感性，这一目标具有潜力 提供预防或治疗压力相关疾病的新方法。我们还将确定 CRFR2 如何 受体改变 LS 神经元的活性。这对于治疗与压力相关的精神疾病非常重要 服用作用于 CRF 受体的药物已显示出一些希望，但收效有限。安 因此，提高对 CRF 受体如何控制大脑活动的理解可能会导致 更有效的疗法。 在目标 2 中，我们将确定来自海马体的特定输入如何连接到 LS，并响应 威胁，并影响焦虑和恐惧相关的行为。

Project Summary We are investigating the neural circuits that control persistent elevations of defensive behaviors following uncontrollable stress. This has potential human health benefits relevant to the mission of the NIH. In particular, exposure to uncontrollable stress is thought to contribute to or directly trigger the onset of multiple psychiatric disorders for which existing therapies are inadequate. Improved treatments for such disorders will require an understanding of how stressful experiences normally engage specific neural circuits to increase anxiety and defensive behaviors, as well as how abormal engagement of these circuits leads to mental illness. Corticotropin releasing factor receptors (CRFR) control behavioral and physiological responses to stress and are implicated in trauma-related mental illnesses, but the neural circuit-level mechanisms by which they act have not been clearly defined. One critically important region is the lateral septum (LS), which is potently activated by uncontrollable stressors and regulates severity of stress-induced anxious states via the type 2 CRFR (CRFR2) in rodent models. Moreover, neuroimaging studies of patients with stress-related disorders have consistently detected abnormalities in the hippocampus, a structure that is strongly connected with the LS. However, the precise means by which stress induces persistent CRFR2-dependent changes in anxiety and defensive behaviors via specific LS circuits, and the potential roles of hippocampal inputs, have not been determined. Here, we focus on filling this gap in knowledge by addressing two fundamentally important issues concerning LS connectivity and function in the mouse, a model organism whose brain shares high structural and molecular similarity to the human brain. In Aim 1, we will determine how activity of CRFR2-expressing neurons in LS changes following a stressful experience, and how these changes are related to the severity of stress-induced anxious behavior. As particular patterns of neural activity may promote resilience or susceptibility to stress, this aim has the potential to inform new approaches to prevent or treat stress-related disorders. We will also determine how the CRFR2 receptor alters activity of LS neurons. This is important as efforts to treat stress-related mental illnesses by administering drugs that act on CRF receptors have shown some promise but have had limited success. An improved understanding of how CRF receptors control brain activity may therefore result in development of more effective therapies. In Aim 2, we will determine how a specific input from the hippocampus is connected to the LS, responds to threat, and influences anxiety and fear-related behaviors.