Reduced Orexin System Function Contributes to Resilience to Repeated Social Stress.
Reduced Orexin System Function Contributes to Resilience to Repeated Social Stress.
复制标题
DOI：
10.1523/eneuro.0273-17.2018
复制
发表时间：
2018-03
期刊：
影响因子：
3.4
通讯作者：
Bhatnagar S
中科院分区：
文献类型：
--
作者：
Grafe LA;Eacret D;Dobkin J;Bhatnagar S
暴露于压力会增加患抑郁症和创伤后应激障碍（PTSD）等情感障碍的风险。然而，这些疾病只发生在一部分人身上，那些更容易受到压力影响的人，而其他人则保持弹性。应对压力源所采取的应对方式，无论是被动应对还是主动应对，都分别与脆弱性和弹性有关。重要的神经基板，介导的反应，以紧张性是食欲素。这些神经肽在患有与压力有关的疾病（如抑郁症和创伤后应激障碍）的患者的脑脊液中发生改变。本实验使用啮齿动物的社会失败模型，产生积极应对大鼠和被动应对大鼠，我们以前已经显示出弹性和脆弱的配置文件，分别检查食欲素是否发挥作用，在这些压力诱导的表型。原位放射性标记和qPCR显示，积极应对大鼠的前食欲素原mRNA表达显着低于被动应对大鼠。这导致了一种假设，即较低水平的食欲素有助于对反复的社会压力的恢复力。为了验证这一假设，大鼠首先经历了5天的社会失败，以建立主动和被动的应对表型。然后，在每次社交失败之前，使用专门由设计药物激活的设计受体（DREADDs）抑制食欲素神经元额外三天。食欲素的抑制增加了社会互动行为和减少抑郁样行为在脆弱的大鼠群体。事实上，这些数据表明，降低食欲素促进了对社会失败的恢复力，可能是治疗压力相关疾病的重要目标。
Exposure to stress increases the risk of developing affective disorders such as depression and post-traumatic stress disorder (PTSD). However, these disorders occur in only a subset of individuals, those that are more vulnerable to the effects of stress, whereas others remain resilient. The coping style adopted to deal with the stressor, either passive or active coping, is related to vulnerability or resilience, respectively. Important neural substrates that mediate responses to a stressor are the orexins. These neuropeptides are altered in the cerebrospinal fluid of patients with stress-related illnesses such as depression and PTSD. The present experiments used a rodent social defeat model that generates actively coping rats and passively coping rats, which we have previously shown exhibit resilient and vulnerable profiles, respectively, to examine if orexins play a role in these stress-induced phenotypes. In situ radiolabeling and qPCR revealed that actively coping rats expressed significantly lower prepro-orexin mRNA compared with passively coping rats. This led to the hypothesis that lower levels of orexins contribute to resilience to repeated social stress. To test this hypothesis, rats first underwent 5 d of social defeat to establish active and passive coping phenotypes. Then, orexin neurons were inhibited before each social defeat for three additional days using designer receptors exclusively activated by designer drugs (DREADDs). Inhibition of orexins increased social interaction behavior and decreased depressive-like behavior in the vulnerable population of rats. Indeed, these data suggest that lowering orexins promoted resilience to social defeat and may be an important target for treatment of stress-related disorders.