Major depressive disorder (MDD) is considered a 'circuitopathy', and brain stimulation therapies hold promise for ameliorating MDD symptoms, including hippocampal dysfunction. It is unknown whether stimulation of upstream hippocampal circuitry, such as the entorhinal cortex (Ent), is antidepressive, although Ent stimulation improves learning and memory in mice and humans. Here we show that molecular targeting (Ent-specific knockdown of a psychosocial stress-induced protein) and chemogenetic stimulation of Ent neurons induce antidepressive-like effects in mice. Mechanistically, we show that Ent-stimulation-induced antidepressive-like behavior relies on the generation of new hippocampal neurons. Thus, controlled stimulation of Ent hippocampal afferents is antidepressive via increased hippocampal neurogenesis. These findings emphasize the power and potential of Ent glutamatergic afferent stimulation-previously well-known for its ability to influence learning and memory-for MDD treatment.

中文翻译：

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刺激内嗅皮质-齿状回电路是抗抑郁的。

重度抑郁症（MDD）被认为是“电路病”，而脑刺激疗法有望改善包括海马功能障碍在内的MDD症状。尽管Ent刺激可以改善小鼠和人类的学习和记忆能力，但对上游海马回路（例如内嗅皮层（Ent））的刺激是否具有抗抑郁作用仍是未知的。在这里，我们显示了分子靶向性（心理社会压力诱导蛋白的Ent特异性敲低）和Ent神经元的化学生成刺激在小鼠中诱导了抗抑郁样作用。从机制上讲，我们表明Ent刺激诱导的抗抑郁样行为依赖于新的海马神经元的产生。因此，通过增加海马神经发生，对Ent海马传入的受控刺激是抗抑郁的。