Orexins/hypocretins and resilience to stress

食欲素/下丘脑分泌素和压力恢复能力

• 批准号: 8772468
• 负责人: SEEMA BHATNAGAR
• 金额: $ 21万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-25 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8772468
• 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; 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; behavioral impairment; coping; depressive symptoms; hypocretin; insight; locus ceruleus structure; low socioeconomic status; male; minimally invasive; novel; public health relevance; receptor; receptor internalization; relating to nervous system; research study; resilience; response; social; vigilance

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）：长期承受重大生活事件（例如丧亲之痛、长期冲突或社会经济地位低下）带来的压力与抑郁症、创伤后应激障碍和慢性疲劳综合症的发病率增加有关。然而，有些人能够抵御压力的影响，而另一些人则更脆弱。识别弹性和/或脆弱性的基础可能会导致新的个体化治疗方法，以增强弹性或减轻脆弱性。我们的初步工作确定了成年雄性大鼠反复社交失败的模型，其中出现了两种不同的亚群，它们具有不同的应对策略，一种具有弹性，另一种则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，食欲素是唤醒、觉醒和警惕的关键肽。有弹性的群体表现出较低的食欲素表达。这些数据和其他数据得出了一个中心假设，即食欲素系统功能的减弱与对反复失败的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弱势群体和复原力群体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，在失败期间抑制食欲素释放将减少焦虑和抑郁样行为，并改变神经内分泌功能，使脆弱亚群转向有弹性的表型。具体目标 2 将结合功能性神经解剖学和全细胞电生理学方法来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 DREADD（专门由设计药物激活或抑制的设计受体）。 DREADDs 是一种定向药理学方法，可以微创慢性抑制内源性食欲素释放的刺激，初步数据证明了我们实验室这种方法的可行性。总之，所提出的实验结果将为食欲素在重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，可能突出其在调节压力影响恢复力方面的关键作用。