Orexins/hypocretins and resilience to stress

描述（由申请人提供）：长期暴露于重大生活事件的压力下，如丧亲、长期冲突或低社会经济地位，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，有些人能适应压力的影响，而另一些人则更脆弱。识别复原力和/或脆弱性的基础可能导致新的个性化治疗，以增强复原力或减轻脆弱性。我们的初步工作已经在成年雄性大鼠中确定了一个反复社交失败的模型，其中两个不同的亚群出现了不同的应对策略，一个具有弹性，另一个容易受到反复社交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，这两个亚群在食欲素的表达上存在差异，食欲素是觉醒、清醒和警觉的关键肽。适应力强的种群表现出较低的促食欲素表达。这些和其他数据导致了一个中心假设，即抑制食欲素系统功能与对反复失败影响的恢复能力有关。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易受伤害和适应力强的人群中因社会失败而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会减少焦虑和抑郁样行为，并改变神经内分泌功能，使脆弱的亚群向有弹性的表型转变。特异性目的2将结合功能神经解剖学和全细胞电生理方法确定食欲素的潜在作用位点。为了调节食欲素的释放，将使用一种新兴技术，即设计受体（被设计药物完全激活或抑制的设计受体）。DREADDs是一种定向药理学方法，允许微创慢性抑制刺激内源性食欲素释放，初步数据在我们的实验室证明了这种方法的可行性。综上所述，这些实验的结果将为食欲素在对反复压力影响的恢复力或脆弱性中的具体参与提供新的见解，这可能会突出它们在调节对压力影响的恢复力方面的关键作用。

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.