A midbrain-cortical circuit mediated by a claustrum neuronal ensemble orchestrates drug-paired context memory processing.

Drug-associated environmental cues can trigger drug-seeking behavior and precipitate relapse. In this study, we determined that the claustrum (CL) connects the ventral tegmental area (VTA) with the medial prefrontal cortex (mPFC), forming the VTA-CL-mPFC circuit. Using a methamphetamine (METH) conditioned place preference (CPP) model in male mice, we found that manipulating the VTA-CL-mPFC circuit or CL neuronal ensemble receiving projections from VTA and projecting to mPFC (VTA-CL-mPFC) could disrupt the retrieval of METH-paired context memory, resulting in the blockage of the acquisition of METH CPP in male mice. During the process, dopamine release and dopamine 1-like receptor-mediated activation of CL neurons were required for the retrieval of METH-induced reward memory in male mice. These findings reveal a midbrain-cortical circuit orchestrated by CL neurons that plays an essential role in the retrieval of drug-paired environmental cue memory.