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

项目摘要 我们正在研究神经回路，这些神经回路控制着防御行为的持续提升， 无法控制的压力。这具有与NIH的使命相关的潜在人类健康益处。特别是， 暴露于无法控制的压力被认为有助于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。改善这些疾病的治疗将需要 了解压力体验通常如何参与特定的神经回路以增加焦虑， 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 还没有明确定义。一个非常重要的区域是外侧隔（LS），这是潜在的 由无法控制的压力源激活，并通过2型调节压力诱导的焦虑状态的严重程度 啮齿动物模型中的CRFR（CRFR2）。此外，对压力相关疾病患者的神经影像学研究 一直在检测海马体的异常，海马体是一种与大脑皮层密切相关的结构。 LS.然而，压力诱导持续的CRFR2依赖性焦虑变化的确切方式， 通过特定的LS电路的防御行为，以及海马输入的潜在作用，还没有被 测定在这里，我们通过解决两个根本性的重要问题， 关于小鼠中的LS连接和功能，小鼠是一种模型生物，其大脑具有高结构性 和人类大脑的分子相似性 在目标1中，我们将确定应激后LS中CRFR2表达神经元的活性如何变化。 经验，以及这些变化是如何与压力引起的焦虑行为的严重程度。作为 特定的神经活动模式可能会促进对压力的恢复力或敏感性，这一目标具有潜在的 为预防或治疗压力相关疾病的新方法提供信息。我们还将确定CRFR2 受体改变LS神经元的活性。这是重要的，因为努力治疗与压力有关的精神疾病， 施用作用于CRF受体的药物已经显示出一些希望，但是成功有限。一个 因此，对CRF受体如何控制大脑活动的进一步了解可能会导致 更有效的治疗方法。 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， 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.