When the front fails, the rear wins. Cerebellar correlates of prefrontal dysfunction in cocaine-induced memory in male rats

Reciprocal pathways connecting the cerebellum to the prefrontal cortex provide a biological and functional substrate to modulate cognitive functions. Dysfunction of both medial prefrontal cortex (mPFC) and cerebellum underlie the phenotypes of several neumpsychiatric disorders that exhibit comorbidity with substance use disorder (SUD). In people with SUD, cue-action-reward associations appears to be particularly strong and salient, acting as powerful motivational triggers for craving and relapse. Studies of cue reactivity in human with SUD have shown cerebellar activations when drug-related cues are presented. Our preclinical research showed that cocaine-induced conditioned preference increases neural activity and upregulates perineuronal nets (PNNs) around Golgi interneurons in the posterior cerebellar cortex. In the present investigation, we aimed at evaluating cerebellar signatures of conditioned preference for cocaine when drug learning is established under mPFC impairment. We used lidocaine to temporarily inactivate in male rats either the Prelimbic (PL) or the Infralimbic (IL) cortices during cocaine-induced conditioning. The inactivation of the IL, but not the PL, encouraged the acquisition of preference for cocaine-related cues, increased posterior cerebellar cortex activity, and upregulated the expression of PNNs around Golgi interneurons. Moreover, IL impairment not only increased vGluT2- and vGAT-related activity around Golgi cells but also regulated PNNs differently on subpopulations of Golgi cells, increasing the number of neurogranin+ PNN-expressing Golgi cells. Our findings suggest that IL dysfunction may facilitate the acquisition of cocaine-induced memory and cerebellar drug-related learning hallmarks. Overall, IL perturbation during cocaine-induced Pavlovian learning increased cerebellar activity and drug effects. Importantly, cerebellum involvement requires a contingent experience with the drug, and it is not the effect of a mere inactivation of IL cortex.

Automated summary

Reciprocal pathways between the cerebellum and prefrontal cortex play a crucial role in modulating cognitive functions and psychiatric disorders related to substance use. Cue-action-reward associations in individuals with substance use disorder can trigger craving and relapse, with cerebellar activations observed during drug-related cue presentations. Inactivation of the Infralimbic cortex in rats during cocaine-induced conditioning led to increased preference for drug-related cues, enhanced cerebellar activity, and altered expression of perineuronal nets around Golgi interneurons, suggesting a potential role of cerebellar dysfunction in facilitating drug-induced memory acquisition.