Orexins/hypocretins and resilience to stress

描述（由申请人提供）：以重大生活事件（如丧亲之痛、长期冲突或社会经济地位低下）的形式长期暴露于压力下与抑郁症、创伤后应激障碍和慢性疲劳综合征的发病率增加有关。然而，有些人对压力的影响有弹性，而另一些人则更脆弱。识别潜在的弹性和/或脆弱性的基板可能会导致新的个性化治疗，以提高弹性或减轻脆弱性。我们的初步工作已经确定了一个模型，反复的社会失败的成年雄性大鼠中，两个不同的亚群出现不同的应对策略，一个是弹性和一个是容易受到反复的社会失败的行为和神经内分泌的后果。我们的初步数据还表明，这两个亚群在食欲素的表达上存在差异，食欲素是唤醒，觉醒和警惕的关键肽。弹性群体表现出较低的食欲素表达。这些数据和其他数据导致了一个中心假设，即食欲素系统功能的减弱与对反复失败影响的恢复力有关。提出了两个具体目标来检验中心假设。在具体目标1中，我们将确定抑制或刺激食欲素释放对脆弱和弹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，在失败过程中抑制食欲素的释放将减少焦虑和抑郁样行为，并改变神经内分泌功能，使脆弱的亚群转向弹性表型。具体目标2将使用功能神经解剖学和全细胞电生理学方法的组合来确定食欲素的潜在作用位点。为了调节增食欲素释放，将使用一种新兴技术，DREADD（专门由设计药物激活或抑制的设计受体）。DREADDs是一种直接的药理学方法，允许微创慢性抑制内源性食欲素释放的刺激，初步数据证明了这种方法在我们实验室的可行性。总之，从拟议的实验的结果将提供新的见解食欲素的具体参与的弹性或脆弱性的影响，反复强调潜在的突出他们的关键作用，在调解弹性的压力的影响。

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.