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A sizable fraction of granule cells convey information about the expectation of reward, with different populations responding to reward delivery, anticipation and omission, with some responses evolving over time with learning. Reward response in granule cells Classical theories suggest that granule cells in the cerebellum carry sensory and motor signals, enabling downstream Purkinje cells to sense fine contextual changes relating to movement. Using two-photon calcium imaging in behaving mice, Liqun Luo and colleagues also show that a sizable fraction of granule cells convey information about the expectation of reward. Different populations responded to reward delivery, anticipation and omission and some responses evolved over time with learning. The discovery of reward-related signals in granule cells has implications for both models of sensorimotor learning and of cognitive processing in the cerebellum. The human brain contains approximately 60 billion cerebellar granule cells.sup.1, which outnumber all other brain neurons combined. Classical theories posit that a large, diverse population of granule cells allows for highly detailed representations of sensorimotor context, enabling downstream Purkinje cells to sense fine contextual changes.sup.2,3,4,5,6. Although evidence suggests a role for the cerebellum in cognition.sup.7,8,9,10, granule cells are known to encode only sensory.sup.11,12,13 and motor.sup.14 context. Here, using two-photon calcium imaging in behaving mice, we show that granule cells convey information about the expectation of reward. Mice initiated voluntary forelimb movements for delayed sugar-water reward. Some granule cells responded preferentially to reward or reward omission, whereas others selectively encoded reward anticipation. Reward responses were not restricted to forelimb movement, as a Pavlovian task evoked similar responses. Compared to predictable rewards, unexpected rewards elicited markedly different granule cell activity despite identical stimuli and licking responses. In both tasks, reward signals were widespread throughout multiple cerebellar lobules. Tracking the same granule cells over several days of learning revealed that cells with reward-anticipating responses emerged from those that responded at the start of learning to reward delivery, whereas reward-omission responses grew stronger as learning progressed. The discovery of predictive, non-sensorimotor encoding in granule cells is a major departure from the current understanding of these neurons and markedly enriches the contextual information available to postsynaptic Purkinje cells, with important implications for cognitive processing in the cerebellum., Author(s): Mark J. Wagner [sup.1] , Tony Hyun Kim [sup.1] [sup.2] , Joan Savall [sup.1] , Mark J. Schnitzer [sup.1] [sup.3] , Liqun Luo [sup.1] Author Affiliations: (1) Department of [...]

Loss of dopamine in Parkinson's disease is hypothesized to impede movement by inducing hypo- and hyperactivity in striatal spiny projection neurons (SPNs) of the direct (dSPNs) and indirect (iSPNs) pathways in the basal ganglia, respectively. The opposite imbalance might underlie hyperkinetic abnormalities, such as dyskinesia caused by treatment of Parkinson's disease with the dopamine precursor l-DOPA. Here we monitored thousands of SPNs in behaving mice, before and after dopamine depletion and during l-DOPA-induced dyskinesia. Normally, intermingled clusters of dSPNs and iSPNs coactivated before movement. Dopamine depletion unbalanced SPN activity rates and disrupted the movement-encoding iSPN clusters. Matching their clinical efficacy, l-DOPA or agonism of the D.sub.2 dopamine receptor reversed these abnormalities more effectively than agonism of the D.sub.1 dopamine receptor. The opposite pathophysiology arose in l-DOPA-induced dyskinesia, during which iSPNs showed hypoactivity and dSPNs showed unclustered hyperactivity. Therefore, both the spatiotemporal profiles and rates of SPN activity appear crucial to striatal function, and next-generation treatments for basal ganglia disorders should target both facets of striatal activity.In mouse models of Parkinson's disease and dyskinesia, striatal spiny projection neurons of the direct and indirect pathways have abnormal, imbalanced levels of spontaneous and locomotor-related activity, with the two different disease states characterized by opposite abnormalities., Author(s): Jones G. Parker [sup.1] [sup.2] , Jesse D. Marshall [sup.1] [sup.3] [sup.5] , Biafra Ahanonu [sup.1] [sup.3] , Yu-Wei Wu [sup.4] , Tony Hyun Kim [sup.1] , Benjamin F. [...]