Down-regulation of cholinergic signaling in the habenula induces anhedonia-like behavior

僵核内胆碱能信号的下调导致快感缺失样行为

长期以来我们都认为，大脑内胆碱能信号的失调与抑郁症相关。然而，缰核胆碱能信号对特定抑郁行为的功能影响尚不清楚。在这里，我们证明了胆碱能信号基因(CHAT, VACHT, CHT, CHRNA3, CHRNB3和CHRNB4)的表达水平在慢性束缚应激(CRS)大鼠抑郁模型中下调，大鼠表现出类似抑郁的行为，如快感缺乏和情绪绝望。此外，敲除老鼠habenula（僵核）中的CHAT足以引发类似快感缺乏的行为。慢性服用选择性5 -羟色胺再摄取抑制剂氟西汀并不能逆转CHAT敲低引起的类似快感缺乏的行为。为了确定habenular胆碱能信号是否与腹侧被盖区(VTA)的多巴胺神经元和中中背核(DRN)的血清素神经元的调节有关，我们使用了CHAT::cre转基因小鼠，表达专门被设计药物激活的设计受体(DREADD)。habenular胆碱能神经元的药理学激活可诱导腹侧背盖区多巴胺神经元的兴奋，降低DRN中5-羟色胺(5-HT)的免疫反应性。被诊断为重度抑郁症(MDD)的自杀者死后的habenula中也发现了Habenular 胆碱能基因的下调。

Dysfunction of cholinergic signaling in the brain has long been believed to be associated with depressive disorders. However, the functional impact of habenular cholinergic signaling on the specified depressive behaviors is not well understood. Here, we demonstrated that the expression levels of cholinergic signaling genes (CHAT, VACHT, CHT, CHRNA3, CHRNB3 and CHRNB4) were down-regulated in a chronic restraint stress (CRS) rat model of depression, in which rats display depression-like behaviors such as anhedonia and mood despair. Moreover, knockdown of CHAT in the rat habenula was sufficient to evoke anhedonia-like behavior. The anhedonia-like behavior induced by CHAT knockdown was not reversed by chronic administration of the selective serotonin reuptake inhibitor fluoxetine. To determine whether habenular cholinergic signaling is associated with regulation of dopamine neurons in the ventral tegmental area (VTA) and serotonin neurons in the dorsal raphe nucleus (DRN), we used CHAT::cre transgenic mice expressing the Designer Receptors Exclusively Activated by Designer Drugs (DREADD). Pharmacogenetic activation of habenular cholinergic neurons induces the excitation of dopamine neurons in the VTA and reduces the immunoreactivity of 5-hydroxytryptamine (5-HT) in the DRN. Habenular cholinergic gene down-regulation was recapitulated in the postmortem habenula of suicide victims diagnosed with major depressive disorder (MDD).

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