Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Nat Commun. 2019 Aug 21;10(1):3768. doi: 10.1038/s41467-019-11641-8.
The etiology of major depressive disorder (MDD), the leading cause of worldwide disability, is unknown. The neurogenic hypothesis proposes that MDD is linked to impairments of adult neurogenesis in the hippocampal dentate gyrus (DG), while the effects of antidepressants are mediated by increased neurogenesis. However, alterations in neurogenesis and endophenotypes are not always causally linked, and the relationship between increased neurogenesis and altered behavior is controversial. To address causality, we used chemogenetics in transgenic mice to selectively manipulate activity of newborn DG neurons. Suppressing excitability of newborn neurons without altering neurogenesis abolish the antidepressant effects of fluoxetine. Remarkably, activating these neurons is sufficient to alleviate depression-like behavior and reverse the adverse effects of unpredictable chronic mild stress. Our results demonstrate a direct causal relationship between newborn neuronal activity and affective behavior. Thus, strategies that target not only neurogenesis but also activity of newborn neurons may lead to more effective antidepressants.
重度抑郁症（MDD）是导致全球残疾的主要原因，但其病因尚不清楚。神经发生假说认为，MDD 与海马齿状回（DG）中成年神经发生受损有关，而抗抑郁药的作用则是通过增加神经发生来介导的。然而，神经发生和表型的改变并不总是有因果关系的，并且增加的神经发生和改变的行为之间的关系存在争议。为了解决因果关系问题，我们使用转基因小鼠中的化学遗传学选择性地操纵新生 DG 神经元的活性。抑制新生神经元的兴奋性而不改变神经发生会消除氟西汀的抗抑郁作用。值得注意的是，激活这些神经元足以缓解抑郁样行为并逆转不可预测的慢性轻度应激的不良影响。我们的研究结果表明，新生神经元活性与情感行为之间存在直接的因果关系。因此，不仅针对神经发生而且针对新生神经元活性的策略可能会导致更有效的抗抑郁药。
