Ventral CA1 perineuronal nets modulate morphine-associated contextual memory via vCA1–NAcC synaptic remodeling in male mice

Repeated opioid exposure forms reward-context associations that can drive persistent drug seeking. Perineuronal nets (PNNs), reticular extracellular matrices surrounding parvalbumin interneurons (PV-INs), regulate hippocampal plasticity and memory, but their role in morphine-associated contextual memory remains unclear. Here, we show that in male mice, repeated morphine conditioning increased PNN abundance in the ventral CA1 (vCA1), accompanied by attenuated PV-IN-mediated inhibition of vCA1 pyramidal neurons and enhanced hippocampal output to D1-type medium spiny neurons (D1-MSNs) in the nucleus accumbens core (NAcC). ChABC-mediated degradation of vCA1 PNNs diminished morphine conditioning-induced pyramidal neuronal plasticity, reduced glutamatergic transmission to NAcC D1-MSNs, and impaired morphine-conditioned place preference (CPP) memory acquisition. Importantly, chemogenetic inhibition of vCA1 PV-INs attenuated the circuit dysfunction and CPP memory deficits induced by ChABC treatment. These findings support a modulatory role for vCA1 PNNs in regulating local, PV-IN-mediated inhibitory circuit function and downstream hippocampal output during morphine CPP acquisition. The role of hippocampal perineuronal nets in morphine-associated contextual memory remains unclear. Here, authors show that vCA1 nets regulate morphine CPP acquisition via PV-IN-mediated inhibition and glutamatergic output to NAcC D1-MSNs.