As a central part of the mammalian brain, the prefrontal cortex (PFC) has been implicated in regulating cocaine-induced behaviors including compulsive seeking and reinstatement. Although dysfunction of the PFC has been reported in animal and human users with chronic cocaine abuse, less is known about how the PFC is involved in cocaine-induced behaviors. By using two-photon Ca²⁺ imaging to simultaneously record tens of intact individual networking neurons in the frontal association cortex (FrA) in awake male mice, here we report that a systematic acute cocaine exposure decreased the FrA neural activity in mice, while the chemogenetic intervention blocked the cocaine-induced locomotor sensitization. The hypoactivity of FrA neurons was critically dependent on both dopamine transporters and dopamine transmission in the ventromedial PFC (vmPFC). Both dopamine D1R and D2R neurons in the vmPFC projected to and innervated FrA neurons, the manipulation of which changed the cocaine-induced hypoactivity of the FrA and locomotor sensitization. Together, this work demonstrates acute cocaine-induced hypoactivity of FrA neurons in awake mice, which defines a cortico-cortical projection bridging dopamine transmission and cocaine sensitization.

作为哺乳动物大脑的核心部分，前额叶皮层 (PFC) 与调节可卡因诱导的行为有关，包括强迫性寻找和恢复。尽管在长期滥用可卡因的动物和人类使用者中已经报道了 PFC 功能障碍，但对于 PFC 如何参与可卡因诱发的行为知之甚少。通过使用双光子 Ca ²⁺成像同时记录清醒雄性小鼠额叶联合皮层 (FrA) 中数十个完整的个体网络神经元，在这里我们报告系统性急性可卡因暴露降低了小鼠的 FrA 神经活动，而化学遗传学干预阻断了可卡因诱导的运动敏化。FrA 神经元的活动减退严重依赖于腹内侧 PFC (vmPFC) 中的多巴胺转运体和多巴胺传递。vmPFC 中的多巴胺 D1R 和 D2R 神经元投射到并支配 FrA 神经元，其操作改变了可卡因诱导的 FrA 活动减退和运动致敏。总之，这项工作证明了清醒小鼠中 FrA 神经元的急性可卡因诱导的活动减退，