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 dopamine receptor reversed these abnormalities more effectively than agonism of the D 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.

The human brain contains ~60 billion cerebellar granule cells1, which outnumber all other 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 changes2–6. Although evidence suggests a role for cerebellum in cognition7–10, granule cells are known to encode only sensory11–13 and motor14 context. Using two-photon calcium imaging in behaving mice, here we show that granule cells convey information about the expectation of reward. Mice initiated voluntary forelimb movements for delayed 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 current understanding of these neurons and dramatically enriches contextual information available to postsynaptic Purkinje cells, with important implications for cognitive processing in the cerebellum.

Perceptions, thoughts, and actions unfold over millisecond timescales, while learned behaviors can require many days to mature. While recent experimental advances enable large-scale and long-term neural recordings with high temporal fidelity, it remains a formidable challenge to extract unbiased and interpretable descriptions of how rapid single-trial circuit dynamics change slowly over many trials to mediate learning. We demonstrate a simple tensor component analysis (TCA) can meet this challenge by extracting three interconnected, low-dimensional descriptions of neural data: neuron factors, reflecting cell assemblies; temporal factors, reflecting rapid circuit dynamics mediating perceptions, thoughts, and actions within each trial; and trial factors, describing both long-term learning and trial-to-trial changes in cognitive state. We demonstrate the broad applicability of TCA by revealing insights into diverse datasets derived from artificial neural networks, large-scale calcium imaging of rodent prefrontal cortex during maze navigation, and multielectrode recordings of macaque motor cortex during brain machine interface learning.

SUMMARY A major technological goal in neuroscience is to enable the interrogation of individual cells across the live brain. By creating a curved glass replacement to the dorsal cranium and surgical methods for its installation, we developed a chronic mouse preparation providing optical access to an estimated 800,000–1,100,000 individual neurons across the dorsal surface of neocortex. Post-surgical histological studies revealed comparable glial activation as in control mice. In behaving mice expressing a Ca2+ indicator in cortical pyramidal neurons, we performed Ca2+ imaging across neocortex using an epi-fluorescence macroscope and estimated that 25,000–50,000 individual neurons were accessible per mouse across multiple focal planes. Two-photon microscopy revealed dendritic morphologies throughout neocortex, allowed time-lapse imaging of individual cells, and yielded estimates of >1 million accessible neurons per mouse by serial tiling. This approach supports a variety of optical techniques and enables studies of cells across >30 neocortical areas in behaving mice.

Graphical Abstract Highlights d First simultaneous recordings from neocortex and cerebellum over weeks of learning d Cortical layer 5 and cerebellar granule cells show similar task encoding in experts d Learning increases correlations among initially dissimilar L5 and granule cells d L5 and granule cells converge to similar, low-dimensional, task-encoding activity Correspondence mjwagner@stanford.edu (M.J.W.), mschnitz@stanford.edu (M.J.S.), lluo@stanford.edu (L.L.) In BriefSimultaneous recordings of ensembles of individual neurons in the neocortex and cerebellum provide a view of how these two brain regions learn together. SUMMARYThroughout mammalian neocortex, layer 5 pyramidal (L5) cells project via the pons to a vast number of cerebellar granule cells (GrCs), forming a fundamental pathway. Yet, it is unknown how neuronal dynamics are transformed through the L5/GrC pathway. Here, by directly comparing premotor L5 and GrC activity during a forelimb movement task using dual-site two-photon Ca 2+ imaging, we found that in expert mice, L5 and GrC dynamics were highly similar. L5 cells and GrCs shared a common set of task-encoding activity patterns, possessed similar diversity of responses, and exhibited high correlations comparable to local correlations among L5 cells. Chronic imaging revealed that these dynamics co-emerged in cortex and cerebellum over learning: as behavioral performance improved, initially dissimilar L5 cells and GrCs converged onto a shared, lowdimensional, task-encoding set of neural activity patterns. Thus, a key function of cortico-cerebellar communication is the propagation of shared dynamics that emerge during learning.(A) Experimental schematics. Mice voluntarily moved a manipulandum for sucrose water reward (left). We performed simultaneous Ca 2+ imaging in cerebellar GrCs through a cranial window, and in L5 pyramidal neurons of the premotor cortex using an implanted 1 mm prism (right). GCaMP6f was expressed in L5 cells and GrCs using quadruple transgenic mice Rbp4-Cre/Math1-Cre/Ai93/ztTA. (B) Mean images from representative two-photon Ca 2+ imaging movies in L5 cells (left) and GrCs (right). The spatial filters used to extract fluorescence traces from cells with detected activity are highlighted in grayscale or red/blue (see G below; n = 144 L5 cells/177 GrCs). (C) Forelimb movement task. Water-restricted mice self-initiated trials. The task alternated blocks of 40 trials in which forward movement was followed by a left turn with blocks of 40 trials in which forward movement was followed by a right turn. No cues indicated trial type. (D) Example movements on the virtual right-angle track (left, n = 20 each of pure left and right turns; right, n = 8 error-correction turns in each direction). (E) Average motion over time in forward (black curve) and lateral (colored curves) directions for all pure turn trials in the session in (D), aligned temporally to turn onset (n = 51/63 pure-left/pure-right turns). Dashed vertical line denotes average forward movement onset. (F) Behavioral performanc...

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We present a model as well as experimental results for a surface electrode radiofrequency Paul trap that has a circular electrode geometry well suited for trapping single ions and two-dimensional planar ion crystals. The trap design is compatible with microfabrication and offers a simple method by which the height of the trapped ions above the surface may be changed in situ. We demonstrate trapping of single 88 Sr + ions over an ion height range of 200-1000 µm for several hours under Doppler laser cooling and use these to characterize the trap, finding good agreement with our model.