Perineuronal nets in the rat medial prefrontal cortex alter hippocampal-prefrontal oscillations and reshape cocaine self-administration memories.

ABSTRACT

The medial prefrontal cortex (mPFC) is a major contributor to relapse to cocaine in humans and to reinstatement in rodent models of cocaine use disorder. Output from the mPFC is potently modulated by parvalbumin (PV)-containing fast-spiking interneurons, the majority of which are surrounded by perineuronal nets (PNNs). We previously showed that ABC treatment with chondroitinase ABC (ABC) reduced the consolidation and reconsolidation of a cocaine conditioned place preference (CPP) memory. However, self-administration memories are more difficult to disrupt. Here we report in male rats that ABC treatment in the mPFC attenuated the consolidation and blocked the reconsolidation of a cocaine self-administration memory. However, reconsolidation was blocked when rats were given a novel, but not familiar, type of retrieval session. Further, ABC treatment prior to, but not after, memory retrieval blocked reconsolidation. This same treatment did not alter a sucrose memory, indicating specificity for cocaine-induced memory. In naive rats, ABC treatment in the mPFC altered levels of PV intensity and cell firing properties. In vivo recordings from the mPFC and dorsal hippocampus (dHIP) during the novel retrieval session revealed that ABC prevented reward-associated increases in high-frequency oscillations and synchrony of these oscillations between the dHIP and mPFC. Together, this is the first study to show that ABC treatment disrupts reconsolidation of the original memory when combined with a novel retrieval session that elicits coupling between the dHIP and mPFC. This coupling after ABC treatment may serve as a fundamental signature for how to disrupt reconsolidation of cocaine memories and reduce relapse.Significance Statement Powerful memories are associated with drug-taking behavior over extended periods, and these memories can drive relapse to drugs of abuse. The medial prefrontal cortex (mPFC) is a major contributor to relapse in cocaine use disorder. In a well-established rodent model of cocaine use disorder, we identify how removal of key extracellular matrix structures called perineuronal nets (PNNs) within the mPFC reduces the ability to update a cocaine memory. We further show that the ABC treatment within the mPFC impairs the coupling of oscillations between the mPFC and dorsal hippocampus during the updating of cocaine memory. This impaired communication between mPFC and hippocampal circuitry may act as a signature for disrupting cocaine-related memories to help break the cycle of relapse.