Activation of Cerebellar Lobule VI PC^TH+–Med Pathway Selectively blocks METH-induced Conditioned Place Preference in mice

Abstract

The cerebellum is implicated in drug addiction. However, the cerebellar neuronal circuitry underlying addiction, especially classic pathway of Purkinje cells (PCs) to deep cerebellar nuclei (DCN), are largely unknown. Here, tracing experiments showed robust projections from the cerebellar lobule VI tyrosine hydroxylase (TH)-positive PCs (PCTH+) to CaMKII-positive glutamatergic neurons in medial cerebellar nucleus (MedCaMKII), forming PCTH+─MedCaMKII pathway. Then, mice were subjected to methylamphetamine (METH)-induced conditioned place preference (CPP), showing that METH exposure excited MedCaMKII and inhibited PCTH+. Silencing MedCaMKII by tettox suppressed the formation and expression of METH-induced CPP, but produced serious motor coordination deficits. Chemogenetic activation of lobule VI PCTH+─Med pathway during METH CPP training blocked the formation and expression of METH-induced CPP without affecting motor coordination, locomotor activity and sucrose reinforcements in mice. Our findings revealed a novel cerebellar lobule VI PCTH+ ─MedCaMKII pathway and pointed out is critical role in encoding METH-preferred behaviors.