Cocaine memory reactivation induces functional adaptations of fast-spiking interneurons in the rat medial prefrontal cortex

Abstract

Perineuronal nets (PNNs) are specialized extracellular matrix structures that ensheathe parvalbumin-containing fast-spiking interneurons (PV FSIs) and play a key role in neuroplasticity. We previously showed that PNNs within the prelimbic prefrontal cortex (PL PFC) are required for the maintenance of cocaine-associated memories following cocaine memory reactivation. However, how cocaine memory reactivation affects PNNs, PV, and corresponding changes in PV FSI function are unknown. In this study, we characterized the electrophysiological properties of PV FSIs and corresponding changes in PNN and PV intensity within the PL PFC prior to and after cocaine memory reactivation. Adult male Sprague-Dawley rats were trained to acquire cocaine-conditioned place preference (CPP) and, following cocaine-CPP memory reactivation (30 m, 2 h, and 24 h post-reactivation), we measured PNN intensity (determined by Wisteria floribunda agglutinin [WFA] staining) as well as PV intensity using immunohistochemistry. The intensity of PV staining was reduced at all time points following memory reactivation with no changes in WFA intensity. Using whole-cell electrophysiology we found a reduction in the number of action potentials at 30 m and 2 h that returned to control levels by 24 h. The attenuation in firing was accompanied by a presumed compensatory increase in excitatory synaptic transmission, which was corroborated by an increase in VGluT1 puncta apposing PV/PNN neurons. Collectively, our results indicate that cocaine memory reactivation decreases PV intensity, which may play a role in decreasing excitation of PV FSIs. Thus, the inhibitory tone onto pyramidal neurons may be decreased following memory reactivation, resulting in an increase in PFC output to promote cocaine-seeking behaviors.

Impact of Perineuronal Net Removal in the Rat Medial Prefrontal Cortex on Parvalbumin Interneurons After Reinstatement of Cocaine Conditioned Place Preference

“…All behavioral training and testing were performed during the animals' light phase. CPP chambers from Med Associates consisted of three distinguishable compartments separated by manual guillotine doors as previously described (Jorgensen et al, 2020 ). Locomotion and chamber preference were automatically detected by infrared photocell beams throughout the three chambers and recorded using Med Associates software.…”

“…After 72 h post injection, one group of rats was euthanized to obtain pre-reinstatement measurements prior to cocaine-induced reinstatement (pre-reinstatement group), while three additional groups were given a cocaine-induced reinstatement session and euthanized at various time points (t = 2 h for electrophysiology, and t = 2 h, 6 h, or 48 h for IHC analyses). These time points for IHC were chosen based on our previous study showing an impact of cocaine CPP memory retrieval in the drug-free state at 2 h and, in some cases, at 24 h after memory retrieval (Jorgensen et al, 2020 ). Thus, we added a 48 h time point to see if effects persisted past 24 h. We additionally chose the 6 h timepoint in the current study based on observations that the reconsolidation window is ~6 h (Nader et al, 2000 ).…”

“…Thus, we added a 48 h time point to see if effects persisted past 24 h. We additionally chose the 6 h timepoint in the current study based on observations that the reconsolidation window is ~6 h (Nader et al, 2000 ). For electrophysiology studies, we focused on the 2 h timepoint based on our previously observed changes in PV neuron firing after CPP memory retrieval (Jorgensen et al, 2020 ). Reinstatement consisted of a cocaine injection (10 mg/kg, i.p.)…”

“…We previously demonstrated that enzymatically degrading PNNs in the dorsal mPFC (mainly prelimbic PFC) with chondroitinase ABC (Ch-ABC) reduced the acquisition and reconsolidation of cocaine-induced conditioned place preference (CPP) in rats (Slaker et al, 2015 ). In a follow-up study, we tested whether PNNs and their underlying PV neurons were altered after a cocaine memory retrieval session in which rats were placed back into the CPP environment in a drug-free state (Jorgensen et al, 2020 ). The intensity of PV rapidly decreased beginning 30 min after the CPP test, and this decrease was retained for up to 24 h, with no change in the intensity or number of PNNs in the mPFC (Jorgensen et al, 2020 ).…”

“…In a follow-up study, we tested whether PNNs and their underlying PV neurons were altered after a cocaine memory retrieval session in which rats were placed back into the CPP environment in a drug-free state (Jorgensen et al, 2020 ). The intensity of PV rapidly decreased beginning 30 min after the CPP test, and this decrease was retained for up to 24 h, with no change in the intensity or number of PNNs in the mPFC (Jorgensen et al, 2020 ). Additionally, the intrinsic excitability of PNN-surrounded PV cells was decreased and accompanied by increases in excitatory input, as determined by an increased frequency of mEPSCs and VGluT1 puncta apposing PV/PNN cells.…”