The interconnected wirings between medial prefrontal cortex and claustrum and their governing roles in the methamphetamine reward memory in male mice.

Bidirectional communication between medial prefrontal cortex (mPFC) and claustrum (CL) plays a critical role in drug reward memory, particularly for conditioned drug-associated cues. However, their precise circuitry remains unclear. Here, using viral tracing, chemo-&opto-genetics and patch-clamp, alongside methamphetamine (METH) conditioned place preference (CPP) model, we dissected the connectivity pattern between mPFC and CL in male mice. Two relatively independent pathways of top-down mPFC-CL and bottom-up CL-mPFC were identified, each comprising both direct excitatory and indirect inhibitory projections. The mPFC-CL pathway predominantly mediates inter-hemispheric communication, while the CL-mPFC pathway mainly supports intra-hemispheric connections. Under physiological conditions, strong feedforward inhibition (FFI) via local GABAergic interneurons suppresses excitatory transmission between mPFC and CL. During METH CPP, FFI is weakened, resulting in enhanced excitatory signaling. The mPFC-CL pathway was engaged during reward memory encoding, whereas the CL-mPFC pathway mediated memory retrieval. These findings suggest potential therapeutic interventions for METH reward memory.