BACKGROUND A clinical hallmark of alcohol use disorder is persistent drinking despite potential adverse consequences. The ventromedial prefrontal cortex (vmPFC) and dorsomedial prefrontal cortex (dmPFC) are positioned to exert top-down control over subcortical regions, such as the nucleus accumbens shell (NAcS) and basolateral amygdala, which encode positive and negative valence of ethanol (EtOH)-related stimuli. Prior rodent studies have implicated these regions in regulation of punished EtOH self-administration (EtOH-SA). METHODS We conducted in vivo electrophysiological recordings in mouse vmPFC and dmPFC to obtain neuronal correlates of footshock-punished EtOH-SA. Ex vivo recordings were performed in NAcS D1 receptor-expressing medium spiny neurons receiving vmPFC input to examine punishment-related plasticity in this pathway. Optogenetic photosilencing was employed to assess the functional contribution of the vmPFC, dmPFC, vmPFC projections to NAcS, or vmPFC projections to basolateral amygdala, to punished EtOH-SA. RESULTS Punishment reduced EtOH lever pressing and elicited aborted presses (lever approach followed by rapid retraction). Neurons in the vmPFC and dmPFC exhibited phasic firing to EtOH lever presses and aborts, but only in the vmPFC was there a population-level shift in coding from lever presses to aborts with punishment. Closed-loop vmPFC, but not dmPFC, photosilencing on a postpunishment probe test negated the reduction in EtOH lever presses but not in aborts. Punishment was associated with altered plasticity at vmPFC inputs to D1 receptor-expressing medium spiny neurons in the NAcS. Photosilencing vmPFC projections to the NAcS, but not to the basolateral amygdala, partially reversed suppression of EtOH lever presses on probe testing. CONCLUSIONS These findings demonstrate a key role for the vmPFC in regulating EtOH-SA after punishment, with implications for understanding the neural basis of compulsive drinking in alcohol use disorder.

中文翻译：

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惩罚性乙醇自我管理的前额调控

背景酒精使用障碍的临床标志是尽管存在潜在的不良后果，但仍持续饮酒。腹内侧前额叶皮层 (vmPFC) 和背内侧前额叶皮层 (dmPFC) 被定位为对皮层下区域施加自上而下的控制，例如伏隔核壳 (NAcS) 和基底外侧杏仁核，它们编码乙醇 (EtOH) 的正价和负价-相关刺激。先前的啮齿动物研究表明这些区域参与了受惩罚的乙醇自我管理 (EtOH-SA)。方法我们在小鼠 vmPFC 和 dmPFC 中进行了体内电生理记录，以获得足震惩罚的 EtOH-SA 的神经元相关性。在接受 vmPFC 输入的表达 NAcS D1 受体的中等多刺神经元中进行离体记录，以检查该途径中与惩罚相关的可塑性。使用光遗传学光沉默来评估 vmPFC、dmPFC、vmPFC 投影对 NAcS 或 vmPFC 投影对基底外侧杏仁核的功能贡献，以惩罚 EtOH-SA。结果 惩罚减少了 EtOH 杠杆按压并引发了中止按压（杠杆接近后快速缩回）。vmPFC 和 dmPFC 中的神经元表现出对 EtOH 杠杆按压和中止的阶段性放电，但只有在 vmPFC 中，编码发生了从杠杆按压到惩罚中止的人口水平转变。闭环 vmPFC，但不是 dmPFC，惩罚后探针测试中的光沉默否定了 EtOH 杠杆按压的减少，但不是中止的减少。惩罚与 vmPFC 输入到 NAcS 中表达 D1 受体的中等多刺神经元的可塑性改变有关。对 NAcS 的光静默 vmPFC 投影，但不是基底外侧杏仁核，部分逆转抑制 EtOH 杠杆在探针测试中的压力。结论 这些发现证明了 vmPFC 在惩罚后调节 EtOH-SA 中的关键作用，对理解酒精使用障碍中强迫饮酒的神经基础具有重要意义。