Orexins/hypocretins and resilience to stress

描述(由申请人提供)：长期暴露在重大生活事件形式的压力下，如丧亲、长期冲突或社会经济地位低，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，一些人对压力的影响很有弹性，而另一些人则更脆弱。确定潜在的复原力和/或脆弱性的底物可导致新的个体化治疗方法，以增强复原力或减轻脆弱性。我们的初步工作在成年雄性大鼠中发现了一个反复社会失败的模型，在这个模型中，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，这两个亚群在食欲素的表达上存在差异，食欲素是觉醒、觉醒和警觉的关键多肽。有弹性的种群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，即抑制食欲素系统的功能与对反复失败的影响的弹性有关。为了检验中心假说，本文提出了两个具体目标。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有韧性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将减少焦虑和抑郁样行为，并改变神经内分泌功能，将易受攻击的亚群转变为有弹性的表型。具体目标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部位。为了调节食欲素的释放，一项新兴的技术，DREADDS(专门由设计师药物激活或抑制的设计师受体)将被使用。DREADDS是一种直接的药理学方法，允许微创慢性抑制内源性增食欲素的释放，初步数据在我们的实验室证明了这种方法的可行性。总之，拟议的实验结果将为食欲素参与反复应激的弹性或脆弱性提供新的见解，潜在地突出了食欲素在调节对压力的影响的弹性中的关键作用。

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.