Orexins/hypocretins and resilience to stress

食欲素/下丘脑分泌素和压力恢复能力

基本信息

批准号：
8898220
负责人：
SEEMA BHATNAGAR
金额：
$ 25.2万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-25 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8898220
关键词：
Adult Amygdaloid structure Animal Model Anxiety Anxiety Disorders Arousal Behavior Behavioral Bereavement Cells Characteristics Chronic Chronic Fatigue Syndrome Conflict (Psychology)Data Designer Drugs Development Disease Electrophysiology (science)Emerging Technologies Event Exhibits Exposure to Health Hippocampus (Brain)Hypothalamic structure Impairment Incidence Individual Lead Life Mediating Membrane Mental Depression Mental disorders Modeling Mood Disorders Neuroanatomy Neurosecretory Systems Outcome Peptides Phenotype Physiological Population Post-Traumatic Stress Disorders Posture Prefrontal Cortex Rattus Relapse Relative (related person)Signaling Molecule Site Social Interaction Stress Structure of paraventricular nucleus of thalamus System Testing Wakefulness Work anxiety-like behavior coping depressive behavior depressive symptoms hypocretin individualized medicine insight locus ceruleus structure low socioeconomic status male minimally invasive novel receptor receptor internalization relating to nervous system research study resilience response social vigilance

项目摘要

DESCRIPTION (provided by applicant): Chronic exposure to stress in the form of major life events such as bereavement, prolonged conflict or low socioeconomic status is associated with increased incidence of depression, post-traumatic stress disorder and chronic fatigue syndrome. However, some individuals are resilient to the effects of stress while others are more vulnerable. Identifying the substrates underlying resilience and/or vulnerability could lead to novel individualized treatments for enhancing resilience or mitigating vulnerability. Our preliminary work has identified a model of repeated social defeat in adult male rats in which two distinct subpopulations emerge with different coping strategies, one that is resilient and one that is vulnerable to the behavioral and neuroendocrine consequences of repeated social defeat. Our preliminary data also show that these two subpopulations differ in the expression of orexins, peptides that are key for arousal, wakefulness and vigilance. The resilient population exhibits lower orexin expression. These and other data lead to the central hypothesis that dampened orexin system function is associated with resilience to the effects of repeated defeat. Two Specific Aims are proposed to test the central hypothesis. In Specific Aim 1, we will determine the effects of inhibition or stimulation of orexin release on behavioral and neuroendocrine outcomes produced by social defeat in the vulnerable and resilient populations. We hypothesize that inhibition of orexin release during defeat will decrease anxiety- and depressive-like behaviors and alter neuroendocrine function shifting the vulnerable subpopulation towards a resilient phenotype. Specific Aim 2 will determine the potential sites of actions of orexins using combination of functional neuroanatomical and whole cell electrophysiological approaches. To modulate orexin release, an emerging technology, DREADDs (designer receptors exclusively activated or inhibited by designer drugs) will be used. DREADDs is a directed pharmacological approach that allows minimally invasive chronic inhibition of stimulation of endogenous orexin release, preliminary data demonstrate the feasibility of this approach in our lab. Together, the results from the proposed experiments will provide novel insights into the specific involvement of orexins in resilience or vulnerability to the effects of repeated stress potentially highlighting teir key role in mediating resilience to the effects of stress.

描述（由申请人提供）：长期暴露于重大生活事件（例如丧亲，长期冲突或低社会经济状况）形式的压力与抑郁症发生率增加，创伤后应激障碍和慢性疲劳综合征的发生率增加有关。但是，有些人对压力的影响有韧性，而另一些人则更脆弱。识别基础弹性和/或脆弱性的底物可能会导致新颖的个性化治疗方法，以增强弹性或减轻脆弱性。我们的初步工作已经确定了一种在成年男性老鼠中反复社会失败的模型，在成年男性老鼠中，有两个不同的应对策略出现了两种不同的亚群，一种策略是有弹性的，一种容易受到反复社会失败的行为和神经内分泌后果的影响。我们的初步数据还表明，这两个亚群在Orexins的表达上有所不同，Orexins是唤醒，清醒和警惕的关键的肽。弹性人群表现出较低的OREXIN表达。这些数据和其他数据导致了一个核心假设，即抑制了奥列生酸蛋白系统功能与反复失败的影响有关。提出了两个具体目标来检验中心假设。在特定的目标1中，我们将确定抑制或刺激Olexin释放对脆弱和韧性人群中社会失败产生的行为和神经内分泌结果的影响。我们假设在失败过程中抑制奥雷链肌蛋白的抑制作用将降低焦虑和抑郁样的行为，并改变神经内分泌功能，将脆弱的亚群转移到弹性表型中。特定的目标2将使用功能性神经解剖学和全细胞电生理方法的组合来确定奥雷蛋白作用的潜在部位。为了调节Orexin释放，将使用Dreadds（Designer受体专门激活或被设计师药物抑制）。 Dreadds是一种定向的药理学方法，可极少侵入性的慢性抑制内源性Orexin释放的刺激，初步数据证明了这种方法在我们的实验室中的可行性。总之，提出的实验的结果将提供新颖的见解，以了解奥雷蛋白在韧性或脆弱性中对重复应力的影响的特定参与，这可能突出了TEIR在介导应力影响的弹性中的TEIR关键作用。