Turning on and off the cerebellum in drug-induced memory

In the last years the field of neuroscience has shed light on the critical role of the cerebellum in drug addiction, particularly emphasizing its involvement in the associative learning processes linking drug use to contextual cues (Miquel et al., 2009, 2016, 2020; Moulton et al., 2014). Our prior research has demonstrated that the cerebellum undergoes notable changes in plasticity and neural activity during the acquisition of drug-induced odor memories (Carbo-Gas et al., 2014; Carbo-Gas et al., 2017, Gil-Miravet et al., 2021; Guarque-Chabrera et al., 2022). Here, we investigate the cerebellum's role in a biased cocaine-induced place preference (CPP). The first correlational experiment replicates and extends prior research, demonstrating significant neural activity changes the posterior cerebellum's vermis during the expression of drug-context memories using biased conditioned place preference (CPP). Enhanced neural activity in the granule cell layer of the dorsal posterior cerebellar vermis is observed in rats exhibiting preference for cocaine-associated cues, reinforcing the cerebellar cortex's involvement in shaping Pavlovian memories. In the second experiment, we used a chemogenetic strategy to activate or inhibit the posterior vermis during learning of cocaine-induced CPP. Activation of inhibitory interneurons of lobule VIII facilitated the acquisition of CPP, while their inhibition prevented it. These findings strongly suggest a key role of the posterior cerebellar vermis in regulating cocaine-induced Pavlovian learning. Moreover, they suggest that by increasing the inhibitory control over Purkinje cells, behavioral drug effects may be regulated, shedding light on its potential as a therapeutic target.