Drugs of abuse hijack a mesolimbic pathway that processes homeostatic need

• 成果类型: Article
• 署名作者: Tan, Bowen; Browne, Caleb J.; Nobauer, Tobias; Vaziri, Alipasha; Friedman, Jeffrey M.; Nestler, Eric J.
• 署名单位: Howard Hughes Medical Institute; Rockefeller University; Icahn School of Medicine at Mount Sinai; University of Toronto; Centre for Addiction & Mental Health - Canada; Rockefeller University; Rockefeller University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-12870
• DOI: 10.1126/science.adk6742
• 发表日期: 2024-04-19
• 关键词: conditioned place preference; cortex neuronal ensembles; medial prefrontal cortex; nucleus-accumbens; delta-fosb; induced reinstatement; orbitofrontal cortex; mammalian target; cocaine-seeking; addiction

摘要

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 single-nucleus RNA sequencing, 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.