ECM remodeling in the mPFC exacerbates cocaine-induced hyperactivity and impairs threat vigilance.

The extracellular matrix (ECM) plays a crucial role in addiction-related neuroplasticity. While chondroitinase ABC (chABC)-mediated ECM degradation has been shown to impair drug-conditioned place preference, its effects on cocaine-induced locomotor activity remain unknown. Using 3D motion capture combined with unsupervised behavioral clustering in a chronic cocaine exposure mouse model, we demonstrate that cocaine treatment significantly increases locomotor activity while impairing environmental threat perception. Mechanistically, we observed elevated Wisteria floribunda agglutinin (WFA) intensity in the prelimbic (PrL), with pronounced effects in the interstitial matrix and perineuronal nets (PNNs) surrounding parvalbumin-positive (PV+) neurons in layers 2/3 and 5. Surprisingly, despite successfully reducing WFA staining in both PNNs and interstitial matrix, chABC treatment unexpectedly exacerbated cocaine-induced hyperlocomotion and impaired threat detection behaviors. Small interfering RNA (siRNA)-mediated knock-down of Lox, but not Spp1 partially rescued chABC-aggravated threat perception deficits in cocaine-exposed mice. These findings demonstrate that chronic cocaine exposure induces significant ECM remodeling in the PrL, and that ECM degradation paradoxically worsens behavioral outcomes through specific molecular alterations. Our results highlight the complex, context-dependent role of ECM in addiction-related behaviors and suggest the need for more targeted approaches to ECM-based interventions for substance use disorders.