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.

人们认为，成瘾药物可在一定程度上通过“劫持”大脑奖赏系统来促进成瘾，但其背后的潜在机制仍未明确。本研究采用全脑FOS图谱（whole-brain FOS mapping）与活体单神经元钙成像（in vivo single-neuron calcium imaging）技术，发现成瘾药物能够增强伏隔核（nucleus accumbens, NAc）内的多巴胺感受神经元集群活动，并以细胞类型特异性（cell-type-specific）的方式，扰乱自然奖赏所引发的重叠神经元集群响应。结合FOS-Seq、CRISPR扰动（CRISPR-perturbation）与单细胞核RNA测序（snRNAseq），我们鉴定出Rheb作为一种分子底物，既可调控伏隔核内的细胞类型特异性信号转导，又能介导成瘾药物对自然奖赏摄取行为的抑制作用。通过对成瘾药物激活的伏隔核投射脑区进行图谱分析，本研究揭示了其对自然奖赏摄取行为的输入特异性影响。上述研究阐明了经典奖赏通路的动态分子与环路基础，在此通路中，成瘾药物会干扰机体对先天需求的满足。