Cerebellar modulation of the reward circuitry and social behavior: Deep cerebellar nuclei implicated in addictive behavior and autism spectrum disorder, cognitive affective syndrome, and schizophrenia

Cerebellar modulation of the reward circuitry and social behavior. Ilaria Carta et al. Science Jan 18 2019:Vol. 363, Issue 6424, eaav0581. DOI: 10.1126/science.aav0581

The cerebellum and reward-driven behavior
Damage to the cerebellum manifests itself in various forms of cognitive impairment and abnormal social behavior. However, the exact role the cerebellum plays in these conditions is far from clear. Working in mice, Carta et al. found direct projections from the deep cerebellar nuclei to the brain's reward center, a region called the ventral tegmental area (see the Perspective by D'Angelo). These direct projections allowed the cerebellum to play a role in showing a social preference. Intriguingly, this pathway was not prosocial on its own. Cerebellar inputs into the ventral tegmental area were more active during social exploration. Depolarization of ventral tegmental area neurons thus represents a similar reward stimulus as social interaction for mice.

Abstract
INTRODUCTION: Although the cerebellum has long been considered to be a purely motor structure, recent studies have revealed that it also has critical nonmotor functions. Cerebellar dysfunction is implicated in addictive behavior and in mental disorders such as autism spectrum disorder (ASD), cognitive affective syndrome, and schizophrenia. The cerebellum is well poised to contribute to behavior because it receives a wide array of cortical and sensory information and is subject to control by a number of neuromodulators. To perform its function, the cerebellum is believed to integrate these diverse inputs to provide the rest of the brain with predictions required for optimal behavior. Although there are many pathways for this to occur in the motor domain, fewer exist for the nonmotor domain.

RATIONALE: There are no direct pathways emanating from the cerebellum that have been shown to serve nonmotor functions. We hypothesized that the cerebellum may contribute to motivated behavior by a direct projection to the ventral tegmental area (VTA), a structure that is critical for the perception of reward and control of social behaviors. Such a projection would explain why functional imaging experiments indicate that the cerebellum plays a role in addiction and would provide one potential mechanism by which cerebellar dysfunction might contribute to the symptoms of mental disorders.

RESULTS: In mice, we found that monosynaptic excitatory projections from the cerebellar nuclei to the VTA powerfully activate the reward circuitry and contribute to social behavior. Using anatomical tracing, we showed that axonal projections from the cerebellar nuclei form synapses with both dopaminergic and nondopaminergic neurons in the VTA. The cerebello-VTA (Cb-VTA) projections were powerful and their optogenetic stimulation robustly increased the activity of VTA neurons both in vivo and in vitro. Behavioral tests to examine reward processing showed that stimulation of the Cb-VTA projections was sufficient to cause short-term and long-term place preference, thereby demonstrating that the pathway was rewarding. Although optogenetic inhibition of Cb-VTA projections was not aversive, it completely abolished social preference in the three-chamber test for sociability, which suggests that the cerebellar input to the VTA is required for normal social behavior. A role for the cerebellum in social behavior was also indicated by correlation between calcium activity in these axons and performance in the three-chamber test. However, optogenetic activation of the Cb-VTA inputs was not prosocial, hence the pathway was not sufficient for social behavior.

CONCLUSION: The Cb-VTA pathway described here is a monosynaptic projection from the cerebellum to a structure known primarily for its nonmotor functions. Our data support a role for the cerebellum in reward processing and in control of social behavior. We propose that this Cb-VTA pathway may explain, at least in part, the association between the cerebellum and addictive behaviors, and provides a basis for a role for the cerebellum in other motivated and social behaviors. In addition to contributing to reward processing, the VTA also targets a number of other brain regions, such as the prefrontal cortex, that in turn sustain a large repertoire of motor and nonmotor behaviors. Direct cerebellar innervation of the VTA provides a pathway by which the cerebellum may modulate these diverse behaviors. The Cb-VTA pathway delineated here provides a mechanism by which cerebellar dysfunction, by adversely affecting the VTA and its targets, might contribute to mental disorders such as ASD and schizophrenia.

Also:
Also: http://www.einstein.yu.edu/news/releases/1323/brains-cerebellum-found-to-influence-addictive-and-social-behavior