STAT3 in the dorsal raphe gates behavioural reactivity and regulates gene networks associated with psychopathology

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 focussed 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 locally lacking 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 immune system, serotonergic neurotransmission and psychopathology. We aimed to study the alterations in gene expression in the dorsal raphe of mice lacking the transcription factor STAT3 in serotonergic cells by high-throughput sequencing of the midbrain dorsal raphe.信号转导与转录激活因子3（STAT3）信号通路可响应多种免疫原性与非免疫原性刺激物，通过贾纳斯激酶（Janus kinases）的磷酸化作用被激活。多项独立证据表明，STAT3在健康与疾病状态下均与行为相关的神经功能存在复杂关联。然而，部分由于其DNA结合活性所介导的多效性效应，以及由此调控的多种基因表达所产生的情境依赖性细胞结局，STAT3在精神病理相关神经机制中的具体作用仍未完全阐明。 本研究以调控情绪的核心枢纽——中脑5-羟色胺能系统为研究对象，通过种系遗传（STAT3 KO）与病毒介导两种手段选择性敲低缝核STAT3的表达，探究小鼠中STAT3信号通路与情绪行为的相关性。局部STAT3缺失的小鼠表现出负面行为反应性降低，对苯丙胺的致敏效应反应钝化，同时伴随中脑5-羟色胺能神经元的放电活动改变，以及与神经精神障碍相关的基因网络转录调控异常。通过病毒介导敲低中缝背核（dorsal raphe, DR）的STAT3表达，可复制STAT3 KO小鼠的行为学改变，这排除了发育因素的影响，并提示成年小鼠中缝背核内STAT3信号通路的阻断，足以引发与精神病理相关的行为表型。 综上，本研究结果表明，中缝背核STAT3是调控行为反应性的分子开关，为免疫系统、5-羟色胺能神经传递与精神病理之间搭建了机制性桥梁。本研究旨在通过对小鼠中脑背缝核进行高通量测序，探究5-羟色胺能细胞缺失转录因子STAT3的小鼠背缝核内的基因表达改变。