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 我们正在研究控制以下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， 暴露在无法控制的压力下被认为是导致或直接引发多发性精神分裂症的原因 现有治疗方法不足以治疗的疾病。改善对这类疾病的治疗将需要 了解应激经历通常如何激活特定的神经回路来增加焦虑和 防御性行为，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)控制应激的行为和生理反应，并 与创伤相关的精神疾病有关，但它们的神经回路水平机制 都没有明确的定义。外侧隔(LS)是一个非常重要的区域，它是 被不可控的应激源激活，并通过2型调节应激诱导的焦虑状态的严重性 CRFR(CRFR2)在啮齿动物模型中的表达。此外，应激相关障碍患者的神经成像研究 一直检测到海马体的异常，海马体是一种与 LS.然而，应激导致焦虑和焦虑中CRFR2持续依赖的变化的确切方式 通过特定LS回路的防御行为，以及海马区输入的潜在作用，还没有得到 下定决心。在这里，我们通过解决两个根本上重要的问题来填补这一知识空白 关于小鼠的LS连通性和功能，一个其大脑共享高结构的模式生物 以及与人脑的分子相似性。 在目标1中，我们将确定在应激后LS中表达CRFR2的神经元的活动如何变化 经验，以及这些变化如何与压力诱导的焦虑行为的严重程度相关。AS 神经活动的特定模式可能会促进对压力的弹性或敏感性，这一目标具有潜在的 为预防或治疗压力相关疾病提供新的方法。我们还将确定CRFR2如何 受体改变LS神经元的活动。这一点很重要，因为通过以下方式治疗与压力相关的精神疾病 使用作用于CRF受体的药物显示了一些希望，但收效甚微。一个 因此，对CRF受体如何控制大脑活动的更好理解可能会导致 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，响应 威胁，并影响焦虑和恐惧相关的行为。