The Neural Basis of Social Stress-induced Depression

社会压力诱发抑郁症的神经基础

基本信息

批准号：
9260946
负责人：
Byungkook Lim
金额：
$ 43.7万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-10 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9260946
关键词：
Accelerometer Address Adult Adverse effects Affect Alpha Cell Amygdaloid structure Anatomy Anhedonia Animals Antidepressive Agents Area Aversive Stimulus Behavior Behavioral Brain Cells Cognitive Data Depressive disorder Desire for food Diagnosis Disease Electrophysiology (science)Fiber Genetic Engineering Globus Pallidus Goals Habenula Human Hypothalamic structure Impairment Injection of therapeutic agent Investigation Investments Knowledge Lateral Link Major Depressive Disorder Mediating Mental Depression Mental disorders Methods Monitor Motivation Mus Neurons Parvalbumins Patients Pattern Phenotype Photometry Physiological Prevalence Property Psychomotor Impairments Research Rewards Rodent Role Sleep Social Interaction Stimulus Stress Structure Symptoms Synapses Techniques Testing Therapeutic Time Tracer United States Ventral Tegmental Area Viral Work anatomical tracing calcium indicator cell type cholinergic neuron depressed patient depressive behavior depressive symptoms effective therapy experience in vivo in vivo imaging neural circuit neuromechanism neuropsychiatric disorder neuropsychiatry novel strategies optogenetics patch clamp pleasure public health relevance reduce symptoms relating to nervous system response reward circuitry social social stress tool

项目摘要

DESCRIPTION (provided by applicant): Despite the increased prevalence of major depressive disorder (MDD) and the continued investment into identifying effective cures, most treatments merely alleviate symptoms rather than addressing causes. Long-term treatments are generally required for this disease and often include many side-effects. The onset of depression is often precipitated by stressful and/or aversive stimuli. Animals, too, are susceptible to the effects of stress. For example, repeated social defeat stress in rodents induces pervasive and long-lasting behavioral changes similar to the symptoms seen in patients with MDD including impaired social interaction, lack of motivation, helplessness and anhedonia. While the behavioral changes associated with depression have been well-studied, there is relatively little knowledge about the accompanying changes in the neural circuitry. Thus, we will anatomically and functionally dissect the distinct neural circuits mediating various stress-induced behaviors in mice to better understand the mechanistic changes in the brain accompanying MDD in human patients, which will help to devise revolutionary circuit-specific and stage-specific diagnosis and treatments. To accomplish this, we will examine the neural circuit mechanism of ventral pallidum (VP), one of the major components of reward circuitry, underlying depressive behaviors elicited by repeated social defeat stress in combination with a variety techniques to address circuit-level mechanisms, including optogenetics, viral mediated tracing, electrophysiology, and real time in vivo fiber photometry. Our preliminary findings showed that different types of neurons in VP project to different target structures which may be involved in different aspects of depressive behaviors. First, we will define the projection specific roles of VP circuity in depressive behaviors induced by repeated social defeat stress using optogenetics and viral tracing methods. Second, using in vivo fiber photometry and newly developed viral tools, we will directly monitor the dynamics of neural activity of VP circuitry in cell-type and projection specific manner in vivo in real time during social interaction before and after the repeated social defeat stress, and their response to anti-depressant treatment. Third, using ex vivo electrophysiology analysis we will examine the circuit-specific electrophysiological and synaptic changes induced by the stress. The accomplishment of the proposed works will be greatly beneficial to both the research and treatment of MDD, and will also provide a fundamental framework for studying mental disorders in circuit-specific manner.

描述（由申请人提供）：尽管重度抑郁症（MDD）的患病率不断增加，并且持续投资寻找有效的治疗方法，但大多数治疗方法只是缓解症状而不是解决病因，这种疾病通常需要长期治疗。抑郁症的发作通常是由压力和/或厌恶刺激引起的。例如，啮齿动物反复遭受社交失败压力会导致普遍而持久的压力。与重度抑郁症患者症状类似的行为变化，包括社交互动受损、缺乏动力、无助和快感缺乏虽然与抑郁症相关的行为变化已得到充分研究，但对随之而来的神经回路变化的了解相对较少。因此，我们将从解剖学和功能上剖析介导各种压力诱发行为的不同神经回路。小鼠更好地了解人类 MDD 患者大脑的机制变化，这将有助于设计革命性的特定回路和特定阶段的诊断和为了实现这一目标，我们将检查腹侧苍白球（VP）的神经回路机制，这是奖励回路的主要组成部分，是由反复失败的社会压力引起的潜在抑郁行为，并结合多种技术来解决回路层面的机制。，包括光遗传学、病毒介导的示踪、电生理学和实时体内纤维光度测定，我们的初步研究结果表明，VP 中不同类型的神经元投射到不同的目标结构，这些结构可能涉及抑郁行为的不同方面。使用光遗传学和病毒追踪方法定义 VP 回路在反复社交失败压力诱发的抑郁行为中的投射特定作用。其次，使用体内光纤光度测定和新开发的病毒工具，我们将直接监测 VP 回路神经活动的动态。细胞类型和投影特定方式第三，利用离体电生理学分析，我们将研究压力成就引起的电路特异性电生理和突触变化。所提出的工作将对MDD的研究和治疗大有裨益，并且还将为以特定回路的方式研究精神障碍提供一个基本框架。