Orexin prevents depressive-like behavior by promoting stress resilience.
Orexin prevents depressive-like behavior by promoting stress resilience.
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食欲素通过促进压力恢复能力来预防抑郁样行为
DOI：
10.1038/s41380-018-0127-0
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发表时间：
2019-03
影响因子：
11
通讯作者：
Zhu JN
中科院分区：
文献类型：
--
作者：
Ji MJ;Zhang XY;Chen Z;Wang JJ;Zhu JN
下丘脑神经肽增食欲素与精神障碍的病理生理学有关，越来越多的临床证据表明增食欲素与抑郁症之间存在潜在的联系。然而，食欲素在抑郁症中的确切作用，特别是潜在的神经底物和机制，仍然不清楚。在这项研究中，我们揭示了从下丘脑食欲素能神经元到腹侧苍白球(VP)的直接投射，该结构因其在奖赏处理、应激反应和抑郁中的关键位置而受到越来越多的关注。我们发现，增食欲素直接兴奋GABA能VP神经元，并防止大鼠的抑郁样行为。两种增食欲素受体OX1R和OX2R及其下游的Na+-钙离子交换器和L型钙通道共同介导了增食欲素的作用。此外，VP中食欲素受体的药物阻断或基因敲除会增加强迫游泳试验和蔗糖偏好试验中的抑郁样行为。有趣的是，在新伴侣之间的社交互动测试中，阻断VP的食欲素能输入并没有影响社交亲近性，但在由社会等级引发的急性心理社会压力下，显著增强了社交回避。值得注意的是，在暴露于急性应激(包括强迫游泳、食物/水剥夺和社会等级应激)的动物中，VP中的食欲素水平显著增加，同时血清皮质酮增加，而不是在非应激情况下。这些结果表明，内源性食欲素能对VP的调节对于防止应激事件引起的抑郁反应尤为关键。这些发现明确了中枢食欲素能系统在通过促进压力弹性来预防抑郁症方面发挥的不可或缺的作用。
Hypothalamic neuropeptide orexin has been implicated in the pathophysiology of psychiatric disorders and accumulating clinical evidence indicates a potential link between orexin and depression. However, the exact role of orexin in depression, particularly the underlying neural substrates and mechanisms, remains unknown. In this study, we reveal a direct projection from the hypothalamic orexinergic neurons to the ventral pallidum (VP), a structure that receives an increasing attention for its critical position in rewarding processing, stress responses, and depression. We find that orexin directly excites GABAergic VP neurons and prevents depressive-like behaviors in rats. Two orexin receptors, OX1R and OX2R, and their downstream Na+–Ca2+ exchanger and L-type Ca2+ channel co-mediate the effect of orexin. Furthermore, pharmacological blockade or genetic knockdown of orexin receptors in VP increases depressive-like behaviors in forced swim test and sucrose preference test. Intriguingly, blockage of orexinergic inputs in VP has no impact on social proximity in social interaction test between novel partners, but remarkably strengthens social avoidance under an acute psychosocial stress triggered by social rank. Notably, a significantly increased orexin level in VP is accompanied by an increase in serum corticosterone in animals exposed to acute stresses, including forced swimming, food/water deprivation and social rank stress, rather than non-stress situations. These results suggest that endogenous orexinergic modulation on VP is especially critical for protecting against depressive reactions to stressful events. The findings define an indispensable role for the central orexinergic system in preventing depression by promoting stress resilience.
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影响因子：
16.2
作者：
Creed M;Ntamati NR;Chandra R;Lobo MK;Lüscher C
通讯作者：
Lüscher C
影响因子：
9.3
作者：
Dauvilliers Y;Lopez R;Ohayon M;Bayard S
通讯作者：
Bayard S
DOI：
10.1073/pnas.1609811114
发表时间：
2017-01-03
影响因子：
11.1
作者：
Knight, Erik L.;Mehta, Pranjal H.
通讯作者：
Mehta, Pranjal H.
影响因子：
2.5
作者：
Bengtson, CP;Lee, DJ;Osborne, PB
通讯作者：
Osborne, PB
影响因子：
2.9
作者：
DeVries, AC;Glasper, ER;Detillion, CE
通讯作者：
Detillion, CE