Adolescent cerebellar nuclei manipulation alters reversal learning and perineuronal net intensity independently in male and female mice.

Abstract

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)-cortical regions have been found in autism spectrum disorder (ASD) 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 21-35. 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 days faster to criteria) and excitatory DREADDs improved female reversal learning (10 days faster to criteria) compared to 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 non-motor functions and sex-dependent differences in behavior and CN plasticity.Significance statement The cerebellum is commonly known to be important for motor control; however, recent studies have revealed a role in cognition. Yet, it is unknown if the cerebellum modulates cognition in early development or the pathways by which this influence may be exerted. Using a chemogenetic approach, we manipulated the lateral cerebellar nuclei in adolescent male and female mice. Flexible cognition, measured through reversal learning of a touchscreen task was altered in a sex-dependent way. Perineuronal nets were found to be reduced in mice with a cerebellar nuclei DREADD inhibition and these mice demonstrated faster reversal learning. These findings highlight the importance of studying the cerebellar nuclei to gain new insights into early development.