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

项目摘要 我们正在研究灵活调节防御行为的神经回路，以适应一个人的需要。 个人的当前情况，基于环境条件和先前的厌恶经验。这 与NIH的使命相关的潜在人类健康益处。特别是，长期接触 无法控制的行为挑战（即压力）被认为有助于或直接触发 现有疗法不足以治疗的多种精神疾病。改善治疗方法， 需要了解厌恶性经历如何调节特定的神经回路， 防御行为，以及这些回路的异常调节如何导致精神疾病。皮质素 释放激素受体（CRHR）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，但它们所起作用的神经回路水平机制 没有明确定义。一个非常重要的区域是外侧隔（LS）， 并通过2型CRHR调节应激诱导的防御状态的严重程度 （CRHR 2）的表达。此外，对压力相关疾病患者的神经影像学研究表明， 在海马体中持续检测到异常，海马体是与LS密切相关的结构。 然而，应激诱导CRHR2依赖性防御性变化的确切方式， 行为通过特定的LS电路，和海马输入的潜在作用，尚未确定。一 解决这个问题的关键第一步是确定LSCrhr 2的体内神经活动模式 神经元的防御行为的标准测定（目标1，父母补助金）。这些录音显示 LSCrhr2神经元的功能多样性出乎意料，具有指示不同功能的多个活性谱。 此外，在LSCrhr 2群体中观察到的多种威胁相关信号在我们的记录中没有检测到 从海马神经元投射到LS（Aim 2，父母奖）。为了解决这些问题，Dionnet Bhatti 追求两个目标，这两个目标与母补助金中所述的目标高度相关，但又有所不同： 在目标1中，为了定义在单个LSCrhr 2神经元的活动中编码的变量，Dionnet Bhatti是 在一个复杂的，基于试验的仪器防御过程中， 行为任务此外，他正在使用功能性操作来测试这些活动模式的因果作用， 防御行为 在目标2中，Dionnet将检验下丘脑投射到LS编码检测的假设。 显著的威胁刺激，并需要防御行为。

Project Summary We are investigating the neural circuits that flexibly modulate defensive behavior to be appropriate to an individual’s current circumstances, based on environmental conditions and prior aversive experience. This has potential human health benefits relevant to the mission of the NIH. In particular, prolonged exposure to uncontrollable behavioral challenge (i.e. 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 aversive experiences modulate specific neural circuits to alter defensive behavior, as well as how abnormal modulation of these circuits leads to mental illness. Corticotropin releasing hormone receptors (CRHR) 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 defensive states via the type 2 CRHR (CRHR2) 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 CRHR2-dependent changes in defensive behavior via specific LS circuits, and the potential roles of hippocampal inputs, have not been determined. A key first step taken to address this question has been to define the in vivo neural activity patterns of LSCrhr2 neurons in standard assays for defensive behavior (Aim 1, parent grant). These recordings revealed unexpected functional diversity of LSCrhr2 neurons, with multiple activity profiles indicative of distinct functions. Moreover, multiple threat-related signals observed in the LSCrhr2 population were not detected in our recordings from hippocampal neurons that project to LS (Aim 2, parent award). To address these issues, Dionnet Bhatti is pursuing two aims that are highly relevant to but distinct from those described in the parent grant: In Aim 1, To define the variables encoded in the activity of individual LSCrhr2 neurons, Dionnet Bhatti is performing cellular resolution in vivo calcium imaging during a complex, trial-based instrumental defensive behavioral task. Further, he is using functional manipulations to test the causal role of these activity patterns in defensive behavior. In Aim 2, Dionnet will test the hypothesis that hypothalamic projections to the LS encode detection of salient threat stimuli and are required for defensive behavior.