Mechanism for differential recruitment of orbitostriatal transmission during actions and outcomes following chronic alcohol exposure.
Mechanism for differential recruitment of orbitostriatal transmission during actions and outcomes following chronic alcohol exposure.
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DOI：
10.7554/elife.67065
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发表时间：
2021-03-17
期刊：
影响因子：
7.7
通讯作者：
Gremel CM
中科院分区：
文献类型：
--
作者：
Renteria R;Cazares C;Baltz ET;Schreiner DC;Yalcinbas EA;Steinkellner T;Hnasko TS;Gremel CM
精神疾病通常会产生对神经活动有不同影响的症状。例如，在药物依赖中，功能失调的基于价值的决策和强迫性行为分别与眶额叶皮层（OFC）-基底神经节回路的低活性和高活性有关;然而，其潜在机制尚不清楚。在这里，我们发现，酒精暴露的小鼠有增强的活动在OFC终端在背侧纹状体（OFC-DS）相关的行动，但减少活动的相同终端期间的结果检索，相应的结果控制决策的损失。中断的OFC-DS终端活动是由于多巴胺1型受体的功能障碍的多刺投射神经元（D1 R SPN），导致增加逆行内源性大麻素信号在OFC-D1 R SPN突触减少OFC-DS传输。阻断CB 1受体恢复了OFC-DS在体内的活性，并挽救了对决策的基于结果的控制。这些研究结果表明，在酒精暴露的小鼠中，一种电路、突触和计算特异性的机制门控了OFC的活动。
Psychiatric disease often produces symptoms that have divergent effects on neural activity. For example, in drug dependence, dysfunctional value-based decision-making and compulsive-like actions have been linked to hypo- and hyperactivity of orbital frontal cortex (OFC)-basal ganglia circuits, respectively; however, the underlying mechanisms are unknown. Here we show that alcohol-exposed mice have enhanced activity in OFC terminals in dorsal striatum (OFC-DS) associated with actions, but reduced activity of the same terminals during periods of outcome retrieval, corresponding with a loss of outcome control over decision-making. Disrupted OFC-DS terminal activity was due to a dysfunction of dopamine-type 1 receptors on spiny projection neurons (D1R SPNs) that resulted in increased retrograde endocannabinoid signaling at OFC-D1R SPN synapses reducing OFC-DS transmission. Blocking CB1 receptors restored OFC-DS activity in vivo and rescued outcome-based control over decision-making. These findings demonstrate a circuit-, synapse-, and computation-specific mechanism gating OFC activity in alcohol-exposed mice.