Cocaine, Parvalbumin, and Perineuronal Nets

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PROJECT SUMMARY/ABSTRACT Cocaine use disorder remains a prevalent problem with no FDA-approved treatment and profound societal consequences. Cocaine-associated memories are strong and resistant to modification but are the basis of relapse in many individuals. Our long-term goal is to diminish cocaine-associated memories to reduce drug relapse. The self-administration model in rodents best reproduces strong cocaine-associated memory. We have found that the removal of perineuronal nets (PNNs) in the rat medial prefrontal cortex (mPFC) disrupts cocaine self-administration memories by interfering with reconsolidation of these memories. PNNs form mainly around parvalbumin (PV)-containing, fast spiking interneurons that powerfully regulate mPFC output, and mPFC output is well known to control drug-seeking behavior in both animals and humans. PV neurons maintain cortical excitatory:inhibitory balance and contribute to theta and gamma oscillations vital for communication across brain regions, yet almost nothing is known about how mPFC PV neurons contribute to cocaine memory reconsolidation. Our Preliminary Data show that PNN removal in the mPFC: (1) decreases PV neuron firing and increases excitability of pyramidal cells in drug-naïve rats; (2) profoundly disrupts the reconsolidation of a self-administration cocaine memory, including cue-induced reinstatement and progressive ratio responding; and (3) disrupts the synchrony of theta and gamma oscillations within the mPFC and between the mPFC and hippocampus in response to a cocaine cue. These findings are significant because they are expected to give novel insights into brain oscillatory patterns that may signify disrupted cocaine memory and how to modify these persistent drug-associated memories. We hypothesize that PNNs allow PV neurons to stabilize and maintain cocaine memories and that, without PNNs, these memories can be destabilized and profoundly disrupted. We will use PV-Cre knock-in rats crossed with tdTomato knock-in rats throughout to determine in Aim 1 how PNN removal alters mPFC PV neuron function and in Aim 2 how PNN removal alters mPFC circuit function during cocaine memory reconsolidation. In Aim 3, we will assess two mechanistic pathways by which PNN removal blocks reconsolidation, including Cre-dependent, specific suppression of PNNs and Cre-dependent inhibition of PV neuron activity with Gi-DREADDs. We will use both slice and in vivo electrophysiology, transcriptomics, tract tracing, immunohistochemistry, molecular, and chemogenetic approaches to identify key factors in PV neuron-mediated control of cocaine-seeking behavior during cocaine memory reconsolidation. Our studies are expected to generate significant advances in understanding how to diminish powerful memories that drive cocaine-seeking behavior.