ROLE OF THE CEREBELLAR PROJECTION TO THE VENTRAL TEGMENTAL AREA IN COCAINE-ASSOCIATED CONDITIONED MEMORY

Although traditionally associated with motor coordination, the cerebellum is now recognized as a contributor to cognitive and affective functions, including the regulation of behaviors related to substance use disorder (SUD). Evidence indicates that cerebellar circuits participate in drug-associated memory formation and modulate activity within reward-related brain regions. A compensatory interaction between the cerebellum and the infralimbic cortex (IL) has been proposed, suggesting reciprocal control of drug-conditioned behaviors. However, the neural substrates mediating this interaction remain unclear. The ventral tegmental area (VTA), a central node of the mesocorticolimbic system, has emerged as a potential mediator.

Here, we examined the role of the deep cerebellar nuclei (DCNs)–VTA pathway in cocaine-induced conditioned place preference (CPP), a model of drug–context associative learning. Using chemogenetic approaches based on Designer Receptors Exclusively Activated by Drugs (DREADDs) and a Cre-dependent strategy, we selectively modulated DCN neurons and their projections to the VTA.

Adult C57BL/6J mice underwent stereotaxic surgery to receive excitatory or inhibitory DREADDs in the interposed and lateral cerebellar nuclei, along with a retrograde Cre-expressing virus in the VTA. DREADDs were activated by clozapine-N-oxide during eight days of CPP conditioning, and preference was assessed 24 hours later.

Chemogenetic inhibition of the DCNs–VTA pathway altered conditioned preference, supporting a role for cerebellar output to the VTA in drug-context memory formation. In contrast, pathway activation produced no clear effects. These findings identify cerebellar–mesolimbic circuits as a relevant substrate through which the cerebellum may influence addiction-related behaviors.