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（由适用提供）：尽管重度抑郁症（MDD）的患病率增加了，并且继续投资于确定有效治疗方法，但大多数治疗方法只是减轻症状而不是解决原因。这种疾病通常需要长期治疗，并且通常包括许多副作用。压力和/或厌恶刺激通常是抑郁症的发作。动物也容易受到压力的影响。例如，啮齿动物中反复的社交失败压力会影响普遍存在和持久的行为变化，类似于MDD患者的症状，包括社交互动受损，动机缺乏动力，无助和痛苦。尽管与抑郁症相关的行为变化得到了充分研究，但关于神经回路的参与变化的了解相对较少。这，我们将在解剖和功能上剖析介导各种压力引起的行为的不同神经回路小鼠可以更好地了解人类患者的大脑参与MDD的机理变化，这将有助于设计革命性电路特定和特定阶段的诊断和治疗。为此，我们将研究奖励电路的主要组成部分之一，腹侧颗粒膜（VP）的神经元电路机制，这是由反复的社交失败压力与多种技术结合使用，以解决电路级别机制，包括选择遗传学，病毒式介导，介导的介导的示踪，电流，电源型，电源fivo，从而引起了抑郁行为。我们的初步发现表明，VP项目中的不同类型的神经元与可能涉及抑郁行为不同方面的不同目标结构。首先，我们将使用光遗传学和病毒追踪方法来定义VP电路在抑郁行为中的项目特定作用。其次，使用体内纤维光度法和新开发的病毒工具，我们将直接监测细胞类型中VP电路的神经活动的动力学在反复的社交失败压力之前和之后，在社会互动中实时进行体内，以及它们对抗抑郁药的反应。第三，使用离体电生理分析，我们将检查应力引起的电路特异性电生理和突触变化。拟议作品的实现将对MDD的研究和治疗都非常有益，这也将为以特定电路方式研究精神障碍提供一个基本的框架。