Normal cognitive and social development require posterior cerebellar activity

Abstract

Cognitive and social capacities require postnatal experience, yet the pathways by which experience guides development are unknown. Here we show that the normal development of motor and nonmotor capacities requires cerebellar activity. Using chemogenetic perturbation of molecular layer interneurons to attenuate cerebellar output in mice, we found that activity of posterior regions in juvenile life modulates adult expression of eyeblink conditioning (paravermal lobule VI, crus I), reversal learning (lobule VI), persistive behavior and novelty-seeking (lobule VII), and social preference (crus I/II). Perturbation in adult life altered only a subset of phenotypes. Both adult and juvenile disruption left gait metrics largely unaffected. Contributions to phenotypes increased with the amount of lobule inactivated. Using an anterograde transsynaptic tracer, we found that posterior cerebellum made strong connections with prelimbic, orbitofrontal, and anterior cingulate cortex. These findings provide anatomical substrates for the clinical observation that cerebellar injury increases the risk of autism.

Targeting inhibitory cerebellar circuitry to alleviate behavioral deficits in a mouse model for studying idiopathic autism

“…In the open field, there were no group differences in traveling distance, time in the center, rearing or self-grooming behaviors (p > 0.05; Supplementary Table S3). The same chemogenetic manipulation did not affect the behavioral readouts of WT animals either in the three-chamber or in the openfield tests ( Supplementary Table S3), compatible with an earlier finding that increasing PN firing in adult mice has no impact on their sociability [55]. Our results suggest that restoring the activity of the posterior cerebellum is imperative for rescuing the social impairment of the BTBR model.…”

NINscope: a versatile miniscope for multi-region circuit investigations

“…Leveraging the capabilities of our miniscope, we demonstrate functional interactions between the cerebellum and cortex in unrestrained mice wearing dual miniscopes. Complex spike activity in Purkinje cell dendrites correlated with cellular activity measured in the cortex during periods of movement, in line with previous anatomical and functional studies of cerebello-thalamo-cortical connectivity (Badura et al 2018;Bostan, Dum, and Strick 2013;Akkal, Dum, and Strick 2007;Hoover and Strick 1999;Gao et al 2018;Wagner et al 2019) . Moreover, activity correlated across regions typically preceded behavioral acceleration.…”

“…For us, an important motivation for building a lighter and smaller miniscope was the ability to record from two regions concurrently in unrestrained mice and in particular to obtain cellular resolution recordings of cerebellum and cerebral cortex. There is ample anatomical evidence for cerebello-thalamo-cerebral loops (Hoover and Strick 1999;Akkal, Dum, and Strick 2007;Bostan, Dum, and Strick 2013) and an increasing number of studies suggest that functional interactions within such loops are important for the proper expression of social, cognitive and motor (planning) behaviors (Badura et al 2018;Stoodley et al 2017;Gao et al 2018) . The ability to record from both cerebellum and cortex simultaneously in unrestrained mice opens up the possibility to study how these interactions play out during natural spontaneous behaviors.…”

A Novel FN-MdV Pathway and Its Role in Cerebellar Multimodular Control of Sensorimotor Behavior

“…Vermal PCs project to the fastigial nucleus (FN), which targets vast numbers of downstream brain regions 34,35 . Indeed, FN outputs have recently been implied to play various roles in both motor and nonmotor tasks [36][37][38][39][40][41] . Anatomical studies using retrograde transneuronal tracing with rabies virus from the eyelid muscle (orbicularis oculi) have revealed prominent labeling in IN and FN, suggesting a potential role of the vermis and FN in controlling eyelid movements 42,43 .…”