Adolescent Cerebellar Nuclei Manipulation Alters Reversal Learning and Perineuronal Net Intensity Independently in Male and Female Mice

The cerebellum, identified to be active during cognitive and social behavior, has multisynaptic connections through the cerebellar nuclei (CN) and thalamus to cortical regions, yet formation and modulation of these pathways are not fully understood. Perineuronal nets (PNNs) respond to changes in local cellular activity and emerge during development. PNNs are implicated in learning and neurodevelopmental disorders, but their role in the CN during development is unknown. Connectivity deficits, specifically between lateral CN (LCN) and cortical regions have been found in autism spectrum disorder with patients displaying reduced cognitive flexibility. To examine the role of LCN on cognition, neural activity was perturbed in both male and female mice using designer receptors exclusively activated by designer drugs (DREADDs) from postnatal day 21 to 35. We found that while an adolescent LCN disruption did not alter task acquisition, correct choice reversal performance was dependent on DREADD manipulation and sex. Inhibitory DREADDs improved reversal learning in males (5 d faster to criteria), and excitatory DREADDs improved female reversal learning (10 d faster to criteria) compared with controls. Interestingly, the DREADD manipulation in females regardless of direction reduced PNN intensity, whereas in males, only the inhibitory DREADDs reduced PNNs. This suggests a chronic adolescent LCN manipulation may have sex-specific compensatory changes in PNN structure and LCN output to improve reversal learning. This study provides new evidence for LCN in nonmotor functions and sex-dependent differences in behavior and CN plasticity.