Manipulation of dorsal raphe serotonergic neurons modulates active coping to inescapable stress and anxiety-related behaviors in mice and rats.
Manipulation of dorsal raphe serotonergic neurons modulates active coping to inescapable stress and anxiety-related behaviors in mice and rats.
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DOI：
10.1038/s41386-018-0254-y
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发表时间：
2019-03
期刊：
影响因子：
--
通讯作者：
Kaneko S
中科院分区：
文献类型：
--
作者：
Nishitani N;Nagayasu K;Asaoka N;Yamashiro M;Andoh C;Nagai Y;Kinoshita H;Kawai H;Shibui N;Liu B;Hewinson J;Shirakawa H;Nakagawa T;Hashimoto H;Kasparov S;Kaneko S
严重抑郁症和焦虑症是全世界的社会和经济负担。血清素能信号转导与这些疾病的病理生理学有关，因此是药物治疗的关键靶点。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，能够有效和特异性转导小鼠和大鼠的多巴胺能神经元，以阐明多巴胺能神经元在两个物种的焦虑样行为和积极应对行为中的作用。免疫组织化学分析表明，慢病毒载体的上游序列的色氨酸羟化酶2基因有效地转导的多巴胺能神经元的特异性约为95%，在小鼠和大鼠。电生理记录显示，这些慢病毒载体诱导了用于精确控制多巴胺能神经元的光遗传学工具的充分表达。使用这些载体，我们表明，急性激活中缝背核的多巴胺能神经元增加积极应对不可避免的压力在大鼠和小鼠在一个时间锁定的方式，和急性抑制这些神经元增加焦虑样行为，特别是在大鼠。这些发现进一步我们的理解中缝背核神经元在不同物种的病理生理作用，这些神经元作为治疗靶点在抑郁症和焦虑症的作用。
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.
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DOI：
10.1126/science.1190721
发表时间：
2010-07-30
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Gourine AV;Kasymov V;Marina N;Tang F;Figueiredo MF;Lane S;Teschemacher AG;Spyer KM;Deisseroth K;Kasparov S
通讯作者：
Kasparov S
影响因子：
5.1
作者：
Benzekhroufa, K.;Liu, B-H;Kasparov, S.
通讯作者：
Kasparov, S.
影响因子：
3.4
作者：
Collinson, N;Dawson, GR
通讯作者：
Dawson, GR
影响因子：
25
作者：
Boyden, ES;Zhang, F;Deisseroth, K
通讯作者：
Deisseroth, K
影响因子：
2.7
作者：
Bertoglio, LJ;Carobrez, AP
通讯作者：
Carobrez, AP