Role of endocannabinoid signaling in a septohabenular pathway in the regulation of anxiety- and depressive-like behavior.
Role of endocannabinoid signaling in a septohabenular pathway in the regulation of anxiety- and depressive-like behavior.
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DOI：
10.1038/s41380-020-00905-1
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发表时间：
2021-07
影响因子：
11
通讯作者：
Liu QS
中科院分区：
文献类型：
--
作者：
Vickstrom CR;Liu X;Liu S;Hu MM;Mu L;Hu Y;Yu H;Love SL;Hillard CJ;Liu QS
增强内源性大麻素信号产生抗焦虑和抗抑郁样作用，但涉及的神经回路仍然知之甚少。内侧缰核（MHb）是一种遗传学上保守的上丘脑结构，是焦虑和抑郁样行为的有力调节器。在这里，我们表明，一个强大的内源性大麻素信号系统调制MHb和它的唯一确定的GABA输入，内侧隔和核的斜角带（MSDB）之间的突触传递。与RNAscope原位杂交，我们表明，合成或降解内源性大麻素2-花生四烯酸甘油（2-AG）或anandamide的关键酶在MHb和MSDB中表达，大麻素受体1（CB 1）在MSDB中表达。在MHb神经元的电生理记录显示，内源性释放的2-AG逆行抑制GABA输入MSDB。这种内源性大麻素介导的去极化诱导的抑制（DSI）是有限的单酰基甘油脂肪酶（MAGL），但不是由脂肪酸酰胺水解酶。解剖和光遗传学电路映射表明，MSDB GABA神经元单突触投射到腹侧MHb的胆碱能神经元。为了测试这种MSDB-MHb内源性大麻素信号传导的行为意义，我们通过将病毒递送的Cre重组酶注射到Cnr 1 loxP/loxP或MgllloxP/loxP小鼠的MSDB中来诱导CB 1或MAGL的MSDB特异性敲除。相对于对照小鼠，MSDB特异性敲除CB 1或MAGL双向调节腹侧MHb中的2-AG信号传导，并导致对焦虑和抑郁样行为的相反影响。因此，抑郁症的突触GABA释放MSDB腹侧MHb通路可能代表一个潜在的机制，内源性大麻素发挥抗焦虑和抗抑郁样作用。
Enhancing endocannabinoid signaling produces anxiolytic- and antidepressant-like effects, but the neural circuits involved remain poorly understood. The medial habenula (MHb) is a phylogenetically-conserved epithalamic structure that is a powerful modulator of anxiety- and depressive-like behavior. Here, we show that a robust endocannabinoid signaling system modulates synaptic transmission between the MHb and its sole identified GABA input, the medial septum and nucleus of the diagonal band (MSDB). With RNAscope in situ hybridization, we demonstrate that key enzymes that synthesize or degrade the endocannabinoids 2-arachidonylglycerol (2-AG) or anandamide are expressed in the MHb and MSDB, and that cannabinoid receptor 1 (CB1) is expressed in the MSDB. Electrophysiological recordings in MHb neurons revealed that endogenously-released 2-AG retrogradely depresses GABA input from the MSDB. This endocannabinoid-mediated depolarization-induced suppression of inhibition (DSI) was limited by monoacylglycerol lipase (MAGL) but not by fatty acid amide hydrolase. Anatomic and optogenetic circuit mapping indicated that MSDB GABA neurons monosynaptically project to cholinergic neurons of the ventral MHb. To test the behavioral significance of this MSDB-MHb endocannabinoid signaling, we induced MSDB-specific knockout of CB1 or MAGL via injection of virally-delivered Cre recombinase into the MSDB of Cnr1loxP/loxP or MgllloxP/loxP mice. Relative to control mice, MSDB-specific knockout of CB1 or MAGL bidirectionally modulated 2-AG signaling in the ventral MHb and led to opposing effects on anxiety- and depressive-like behavior. Thus, depression of synaptic GABA release in the MSDB-ventral MHb pathway may represent a potential mechanism whereby endocannabinoids exert anxiolytic and antidepressant-like effects.
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