Drugs of abuse hijack a mesolimbic pathway that processes homeostatic need

Drugs of abuse are thought to promote addiction in part by "hijacking" brain reward systems, but the underlying mechanisms remain undefined. Using whole-brain FOS mapping and in vivo single-neuron calcium imaging, we found that drugs of abuse augment dopaminoceptive ensemble activity in the nucleus accumbens (NAc) and disorganize overlapping ensemble responses to natural rewards in a cell-type-specific manner. Combining FOS-Seq, CRISPR-perturbation, and snRNAseq, we identified Rheb as a molecular substrate that regulates cell-type-specific signal transduction in NAc while enabling drugs to suppress natural reward consumption. Mapping NAc-projecting regions activated by drugs of abuse revealed input-specific effects on natural reward consumption. These findings characterize the dynamic molecular and circuit basis of a common reward pathway, wherein drugs of abuse interfere with the fulfillment of innate needs.

滥用药物（Drugs of abuse）被认为在一定程度上通过“劫持”大脑奖赏系统促进成瘾，但其潜在机制仍未明确。本研究采用全脑FOS图谱绘制与在体单神经元钙成像技术，发现滥用药物可增强伏隔核（nucleus accumbens, NAc）内的多巴胺敏感性神经元集群活动，并以细胞类型特异性方式打乱天然奖赏诱导的重叠神经元集群响应。结合FOS-Seq测序、CRISPR基因扰动与单细胞核RNA测序（snRNAseq），我们鉴定出Rheb作为一种分子底物，可调控伏隔核内的细胞类型特异性信号转导，并介导滥用药物抑制天然奖赏摄入行为。对被滥用药物激活的投射至伏隔核的脑区进行图谱绘制，揭示了其对天然奖赏摄入的输入特异性调控效应。上述研究结果阐明了共同奖赏通路的动态分子与环路基础，即滥用药物会干扰机体先天需求的满足。