Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstraße 17, 1090, Vienna, Austria.
Core Facilities Genomics, Medical University of Vienna, Lazarettgasse 14, 1090, Vienna, Austria.
Mol Psychiatry. 2021 Jul;26(7):2886-2899. doi: 10.1038/s41380-020-00904-2. Epub 2020 Oct 12.
The signal transducer and activator of transcription 3 (STAT3) signalling pathway is activated through phosphorylation by Janus kinases in response to a diverse set of immunogenic and non-immunogenic triggers. Several distinct lines of evidence propose an intricate involvement of STAT3 in neural function relevant to behaviour in health and disease. However, in part due to the pleiotropic effects resulting from its DNA binding activity and the consequent regulation of expression of a variety of genes with context-dependent cellular consequences, the precise nature of STAT3 involvement in the neural mechanisms underlying psychopathology remains incompletely understood. Here, we focused on the midbrain serotonergic system, a central hub for the regulation of emotions, to examine the relevance of STAT3 signalling for emotional behaviour in mice by selectively knocking down raphe STAT3 expression using germline genetic (STAT3 KO) and viral-mediated approaches. Mice lacking serotonergic STAT3 presented with reduced negative behavioural reactivity and a blunted response to the sensitising effects of amphetamine, alongside alterations in midbrain neuronal firing activity of serotonergic neurons and transcriptional control of gene networks relevant for neuropsychiatric disorders. Viral knockdown of dorsal raphe (DR) STAT3 phenocopied the behavioural alterations of STAT3 KO mice, excluding a developmentally determined effect and suggesting that disruption of STAT3 signalling in the DR of adult mice is sufficient for the manifestation of behavioural traits relevant to psychopathology. Collectively, these results suggest DR STAT3 as a molecular gate for the control of behavioural reactivity, constituting a mechanistic link between the upstream activators of STAT3, serotonergic neurotransmission and psychopathology.
信号转导子和转录激活子 3（STAT3）信号通路通过 Janus 激酶的磷酸化而被激活，以响应各种免疫原性和非免疫原性触发。有几条不同的证据表明，STAT3 复杂地参与了与健康和疾病行为相关的神经功能。然而，部分由于其 DNA 结合活性的多效性效应以及随后对各种具有上下文依赖性细胞后果的基因表达的调节，STAT3 参与神经病理学基础的神经机制的确切性质仍不完全清楚。在这里，我们专注于中脑 5-羟色胺能系统，这是调节情绪的中枢枢纽，通过使用种系遗传（STAT3 KO）和病毒介导的方法选择性敲低中缝 STAT3 表达，来研究 STAT3 信号对小鼠情绪行为的相关性。缺乏 5-羟色胺能 STAT3 的小鼠表现出负性行为反应性降低和对安非他命致敏作用的反应迟钝，以及中脑 5-羟色胺能神经元的神经元放电活动和与神经精神障碍相关的基因网络的转录控制发生改变。中缝背核（DR）STAT3 的病毒敲低复制了 STAT3 KO 小鼠的行为改变，排除了发育决定的效应，并表明成年小鼠 DR 中 STAT3 信号的破坏足以表现出与精神病理学相关的行为特征。总之，这些结果表明 DR STAT3 作为控制行为反应的分子门，构成了 STAT3、5-羟色胺能神经传递和精神病理学的上游激活物之间的机制联系。
