Orexin signaling mediates the antidepressant-like effect of calorie restriction
Orexin signaling mediates the antidepressant-like effect of calorie restriction
复制标题
DOI：
10.1523/jneurosci.5584-07.2008
复制
发表时间：
2008-03-19
影响因子：
5.3
通讯作者：
Nestler, Eric J.
中科院分区：
文献类型：
--
作者：
Lutter, Michael;Krishnan, Vaishnav;Nestler, Eric J.
在食物供应减少的时期，动物必须以促进生存的行为适应来应对。尽管许多精神症状包括饮食紊乱是疾病的一个组成部分，但人们对短期限制卡路里导致的行为变化背后的神经生物学知之甚少。目前，我们证明，在两种抑郁的啮齿动物模型中，10d的卡路里限制对应于体重减轻20%-25%，导致显著的抗抑郁药样反应，并且这种反应依赖于下丘脑神经肽增食欲素(下丘脑)。在卡路里限制后的强迫游泳测试中，野生型小鼠，而不是缺乏食欲素的小鼠，表现出更长的不动潜伏期和更少的完全不动。在慢性应激的社会失败模型中，限制卡路里摄入可以逆转野生型小鼠的行为缺陷，但不能逆转食欲素基因敲除小鼠的行为缺陷。此外，慢性社会失败应激通过对食欲素基因启动子的表观遗传修饰，导致食欲素原mRNA表达的持续下降，而卡路里限制则增强了社会失败后食欲素细胞的激活。综上所述，这些数据表明，食欲素在调节卡路里限制导致的类似抑郁症状减轻的过程中发挥着重要作用。
During periods of reduced food availability, animals must respond with behavioral adaptations that promote survival. Despite the fact that many psychiatric syndromes include disordered eating patterns as a component of the illness, little is known about the neurobiology underlying behavioral changes induced by short-term calorie restriction. Presently, we demonstrate that 10 d of calorie restriction, corresponding to a 20-25% weight loss, causes a marked antidepressant-like response in two rodent models of depression and that this response is dependent on the hypothalamic neuropeptide orexin (hypocretin). Wild-type mice, but not mice lacking orexin, show longer latency to immobility and less total immobility in the forced swim test after calorie restriction. In the social defeat model of chronic stress, calorie restriction reverses the behavioral deficits seen in wild-type mice but not in orexin knock-out mice. Additionally, chronic social defeat stress induces a prolonged reduction in the expression of prepro-orexin mRNA via epigenetic modification of the orexin gene promoter, whereas calorie restriction enhances the activation of orexin cells after social defeat. Together, these data indicate that orexin plays an essential role in mediating reduced depression-like symptoms induced by calorie restriction.