Abstract
Substance use disorder is a complex disease created in part by maladaptive learning and memory mechanisms following repeated drug use. Exposure to drug-associated stimuli engages prefrontal cortex circuits, and dysfunction of the medial prefrontal cortex (mPFC) is thought to underlie drug-seeking behaviors. Growing evidence supports a role for parvalbumin containing fast-spiking interneurons (FSI) in modulating prefrontal cortical microcircuit activity by influencing the balance of excitation and inhibition, which can influence learning and memory processes. Most parvalbumin FSIs within layer V of the prelimbic mPFC are surrounded by specialized extracellular matrix structures called perineuronal nets (PNN). Previous work by our group found that cocaine exposure altered PNN-surrounded FSI function, and pharmacological removal of PNNs reduced cocaine-seeking behavior. However, the role of FSIs and associated constituents (parvalbumin and PNNs) in cocaine-related memories was not previously explored and is still unknown. Here, we found that reactivation of a cocaine conditioned place preference memory produced changes in cortical PNN-surrounded parvalbumin FSIs, including decreased parvalbumin intensity, increased parvalbumin cell axis diameter, decreased intrinsic excitability, and increased excitatory synaptic input. Further investigation of intrinsic properties revealed changes in the interspike interval, membrane capacitance, and afterhyperpolarization recovery time. Changes in these specific properties suggest an increase in potassium-mediated currents, which was validated with additional electrophysiological analysis. Collectively, our results indicate that cocaine memory reactivation induces functional adaptations in PNN-surrounded parvalbumin neurons, which likely alters cortical output to promote cocaine-seeking behavior.