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.

项目总结