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

控制压力引起的持续焦虑状态的外侧间隔电路的基因解剖

• 批准号: 10748497
• 负责人: Thomas L. Schwarz
• 金额: $ 8.56万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10748497
• 关键词: Address; Affect; Agonist; Anxiety; Area; Basic Science; Behavior; Behavior Control; Brain; CRF receptor type 2; Cells; Chronic; Corticotropin-Releasing Hormone Receptors; Development; Disease; Dissection; Electrophysiology (science); Exhibits; Exposure to; Fright; Genetic; Glutamates; Goals; Health Benefit; Hippocampus; Human; Image; Individual; Infusion procedures; Knockout Mice; Knowledge; Lateral; Lead; Learning; Lesion; Maintenance; Major Depressive Disorder; Mental disorders; Mission; Molecular; Mus; National Institute of Mental Health; Neural Pathways; Neurons; Neurophysiology - biologic function; Output; Pathway interactions; Patients; Pattern; Phase; Phenotype; Physiological; Physiology; Population; Post-Traumatic Stress Disorders; Predisposition; Public Health; Receptor Activation; Research; Resolution; Rodent Model; Role; Severities; Signal Transduction; Slice; Stimulus; Stress; Stressful Event; Structure; Testing; Trauma; United States National Institutes of Health; Viral; With laterality; acute stress; antagonist; anterior hypothalamic nucleus; anxiety states; anxious; anxious behavior; cell type; drug action; effective therapy; experimental study; improved; in vivo calcium imaging; mind control; model organism; nerve supply; neural circuit; neural patterning; neuroimaging; novel; novel strategies; novel therapeutics; optogenetics; prevent; promote resilience; receptor; response; stress related disorder; stressor; success; tool; transmission process

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.

项目摘要 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。这具有与NIH使命相关的潜在人类健康益处。尤其， 人们认为暴露于无法控制的压力会导致或直接触发多个精神病的发作 现有疗法不足的疾病。改善此类疾病的治疗方法将需要 了解压力性经历通常如何吸引特定的神经回路以增加焦虑和 防御行为，以及这些电路的过度参与如何导致精神疾病。 皮质激素释放因子受体（CRFR）控制压力和生理反应对压力和生理反应 与创伤相关的精神疾病有关，但神经电路级的机制 尚未明确定义。一个至关重要的区域是侧隔（LS），它是有效的 通过无法控制的应激源激活，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，与压力相关疾病患者的神经影像学研究 始终检测到海马的异常，这种结构与 LS。但是，压力通过焦虑和 通过特定LS电路的防御行为以及海马输入的潜在作用尚未 决定。在这里，我们专注于通过解决两个根本重要的问题来填补知识的差距 关于小鼠的LS连接性和功能，这是一种模型生物体，其大脑具有高结构 和与人脑的分子相似性。 在AIM 1中，我们将确定在压力后，LS变化中表达CRFR2的神经元的活动如何 经验以及这些变化与压力引起的焦虑行为的严重程度有关。作为 神经活动的特定模式可能会促进韧性或对压力的敏感性，该目标具有潜力 为预防或治疗与压力相关的疾病的新方法提供信息。我们还将确定CRFR2如何 受体改变LS神经元的活性。这很重要，因为通过 对CRF受体作用的药物管理已经表现出一些希望，但成功率有限。一个 因此，对CRF受体如何控制脑活动的了解得出的了解可能导致 更有效的疗法。 在AIM 2中，我们将确定如何连接来自海马的特定输入，以响应 威胁，影响焦虑和与恐惧有关的行为。