Dorsal raphe projection inhibits the excitatory inputs on lateral habenula and alleviates depressive behaviors in rats
Dorsal raphe projection inhibits the excitatory inputs on lateral habenula and alleviates depressive behaviors in rats
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中缝背侧投射抑制外侧缰核的兴奋性输入并减轻大鼠的抑郁行为
DOI：
10.1007/s00429-018-1623-3
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发表时间：
2018
影响因子：
3.1
通讯作者：
Chen Jian Guo
中科院分区：
文献类型：
--
作者：
Zhang Hai;Li Kuan;Chen Hong Sheng;Gao Shuang Qi;Xia Zhi Xuan;Zhang Jie Ting;Wang Fang;Chen Jian Guo
5-羟色胺能（5-HT）系统功能低下与重度抑郁症（MDD）的症状密切相关，但其潜在的神经回路机制尚不完全清楚。侧habenula （LHb）在厌恶行为中起着至关重要的作用，在抑郁的情况下被激活。据报道，5-HT抑制LHb神经元的兴奋性，导致假设减少5-HT的传递会提高LHb的活性，从而介导抑郁症状。利用霍乱毒素亚基B逆行追踪，我们发现中缝背核（DRN）向LHb发送原发性5-HT投射。体外切片膜片钳记录显示，光刺激DRN输入LHb抑制了突触后微型兴奋性电流的频率，同时增加了LHb神经元的成对脉冲比，说明5-HT投射突触前抑制了LHb神经元的兴奋性。在慢性不可预测轻度应激（CUMS）大鼠抑郁模型中，光遗传刺激DRN-LHb投射可减轻CUMS模型的抑郁症状。同时，该回路的光抑制导致LHb中c-fos表达升高，并诱导抑郁样行为。本研究表明，5-HT从DRN向LHb的投射抑制了LHb神经元的兴奋性，5-HT传递的功能障碍通过LHb的激活诱导抑郁行为。我们的研究结果揭示了DRN-LHb回路的功能连通性及其抗抑郁作用，这可能为抑郁症的治疗提供新的靶点。
Hypofunction of the serotonergic (5-HT) system has close relationship with the symptoms in major depressive disorders (MDD), however, the underlying neural circuitry mechanisms are not fully understood. Lateral habenula (LHb) plays a crucial role in aversive behaviors and is activated in conditions of depression. It has been reported that 5-HT inhibits the excitability of LHb neurons, leading to the hypothesis that decreased transmission of 5-HT would elevate the activity of LHb and therefore mediates depressive symptoms. Using retrograde tract tracing with cholera toxin subunit B, we find that dorsal raphe nucleus (DRN) sends primary 5-HT projection to the LHb. In vitro slice patch-clamp recording reveals that opto-stimulation of DRN inputs to the LHb suppresses the frequency of miniature excitatory postsynaptic current, while increases paired pulse ratio in LHb neurons, indicating 5-HT projection presynaptically suppresses the excitability of LHb neurons. In chronic unpredictable mild stress (CUMS) rat model of depression, optogenetic stimulation of DRN–LHb projection alleviates the depressive symptoms in CUMS models. Meanwhile, opto-inhibition of this circuit results in elevated c-fos expression in LHb and induces depression-like behaviors. This study demonstrates that the 5-HT projection from DRN to LHb suppresses the excitability of LHb neurons, and hypofunction of 5-HT transmission induces depressive behavior via the activation of LHb. Our results reveal the functional connectivity of DRN–LHb circuit and its antidepressant action, which may provide a novel target for the treatment of depression.