Digestion of perineuronal nets in the ventral CA1 suppresses methamphetamine-induced conditioned place preference acquisition by modulating PV interneuron activity in female mice.

Methamphetamine (MA) addiction is characterized by persistent drug-associated memory and high relapse risk. Perineuronal nets (PNNs), which mainly surround PV interneurons, are specialized extracellular matrix structures involved in synaptic stabilization and memory regulation. Our previous studies have shown that PNNs in the medial prefrontal cortex (mPFC) are essential for MA-induced conditioned place preference (CPP) memory, but the role of hippocampal PNNs in MA-associated contextual memory remains unclear. Here, a CPP paradigm was employed in female mice to investigate the role and underlying mechanisms of hippocampal PNNs in MA-induced reward memory. During MA-induced CPP acquisition, the number of c-Fos and PNNs in the hippocampal CA1 was significantly increased. Digestion of PNNs using chondroitinase ABC (ChABC) or knockdown of the key PNNs component Aggrecan in the ventral CA1 (vCA1) but not dorsal CA1 (dCA1) suppressed the acquisition of MA-induced CPP and reduced the immunoreactivity of PV and c-Fos. In addition, chemogenetic inhibition of PV interneurons in the vCA1 of Pvalb-IRES-Cre mice using the hM4D(Gi) DREADD strategy also suppressed CPP acquisition, supporting a critical role for PV interneuron activity in this process. Together, our findings indicate that MA-induced increased PNNs in the vCA1 promote the formation of CPP memory by regulating PV interneuron activity. This study provides new evidence for the region-specific role of hippocampal PNNs in drug-associated memory and suggests that targeting vCA1 PNNs and PV interneurons may represent a potential therapeutic strategy for MA addiction.