Major depression and anxiety disorders are a social and economic burden worldwide. Serotonergic signaling has been implicated in the pathophysiology of these disorders and thus has been a crucial target for pharmacotherapy. However, the precise mechanisms underlying these disorders are still unclear. Here, we used species-optimized lentiviral vectors that were capable of efficient and specific transduction of serotonergic neurons in mice and rats for elucidation of serotonergic roles in anxiety-like behaviors and active coping behavior in both species. Immunohistochemical analyses revealed that lentiviral vectors with an upstream sequence of tryptophan hydroxylase 2 gene efficiently transduced serotonergic neurons with a specificity of approximately 95% in both mice and rats. Electrophysiological recordings showed that these lentiviral vectors induced sufficient expression of optogenetic tools for precise control of serotonergic neurons. Using these vectors, we demonstrate that acute activation of serotonergic neurons in the dorsal raphe nucleus increases active coping with inescapable stress in rats and mice in a time-locked manner, and that acute inhibition of these neurons increases anxiety-like behaviors specifically in rats. These findings further our understanding of the pathophysiological role of dorsal raphe serotonergic neurons in different species and the role of these neurons as therapeutic targets in major depression and anxiety disorders.

中文翻译：

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操纵中缝背侧血清素能神经元可调节小鼠和大鼠对不可避免的压力和焦虑相关行为的主动应对。


严重的抑郁症和焦虑症是全世界的社会和经济负担。血清素信号传导与这些疾病的病理生理学有关，因此一直是药物治疗的重要目标。然而，这些疾病背后的确切机制仍不清楚。在这里，我们使用了物种优化的慢病毒载体，该载体能够有效且特异性地转导小鼠和大鼠的血清素能神经元，以阐明血清素能在两个物种的焦虑样行为和主动应对行为中的作用。免疫组织化学分析表明，具有色氨酸羟化酶 2 基因上游序列的慢病毒载体可有效转导小鼠和大鼠的血清素能神经元，特异性约为 95%。电生理记录表明，这些慢病毒载体诱导光遗传学工具的充分表达，以精确控制血清素能神经元。使用这些载体，我们证明中缝背核中血清素能神经元的急性激活增加了大鼠和小鼠以时间锁定的方式积极应对不可避免的压力，并且这些神经元的急性抑制尤其增加了大鼠的焦虑样行为。这些发现进一步加深了我们对中缝背侧血清素能神经元在不同物种中的病理生理学作用以及这些神经元作为重度抑郁症和焦虑症治疗靶点的作用的理解。