Shogo Ohmae

Climbing fibers encode a temporal-difference prediction error during cerebellar learning in mice

Climbing fiber inputs to Purkinje cells are thought to be involved in generating the instructive signals that drive cerebellar learning. To investigate how these instructive signals are encoded, we recorded the activity of individual climbing fibers during cerebellum-dependent eyeblink conditioning in mice. We found that climbing fibers signaled both the unexpected delivery and the unexpected omission of the periocular airpuff that served as the instructive signal for eyeblink conditioning. In addition, we observed that climbing fibers activated by periocular airpuffs also responded to stimuli from other sensory modalities if those stimuli were novel or if they predicted that the periocular airpuff was about to be presented. This pattern of climbing fiber activity is markedly similar to the responses of dopamine neurons during reinforcement learning, which have been shown to encode a particular type of instructive signal known as a temporal difference prediction error.

Temporally specific sensory signals for the detection of stimulus omission in the primate deep cerebellar nuclei.

The cerebellum is implicated in sensory prediction in the subsecond range. To explore how neurons in the cerebellum encode temporal information for the prediction of sensory events, we trained monkeys to make a saccade in response to either a single omission or deviation of isochronous repetitive stimuli. We found that neurons in the cerebellar dentate nucleus exhibited a gradual elevation of the baseline firing rate as the repetition progressed. Most neurons showed a transient suppression for each stimulus, and this firing modulation also increased gradually, opposed to the sensory adaptation. The magnitude of the enhanced sensory response positively correlated with interstimulus interval. Furthermore, when stimuli appeared unexpectedly earlier than the regular timing, the neuronal modulation became smaller, suggesting that the sensory response depended on the time elapsed since the previous stimulus. The enhancement of neuronal modulation was context dependent and was reduced or even absent when monkeys were unmotivated to detect stimulus omission. A significant negative correlation between neuronal activity at stimulus omission and saccade latency suggested that the timing of each stimulus was predicted by the amount of recovery from the transient response. Because inactivation of the recording sites delayed the detection of stimulus omission but only slightly altered the detection of stimulus deviation, these signals might be necessary for the prediction of stimulus timing but may not be involved only in the generation of saccades. Our results demonstrate a novel mechanism for temporal prediction of upcoming stimuli that accompanies the time-dependent modification of sensory gain in the cerebellum.

Neuronal Activity Related to Reward Size and Rewarded Target Position in Primate Supplementary Eye Field

Several areas of the macaque brain are known to be related to the reward during the performance of saccadic eye-movement tasks. Neurons in the supplementary eye field (SEF) have been reported to be involved in the prediction and detection of a reward. We describe a group of neurons in the SEF that became active during the period of reward delivery after saccades toward a specific direction, but showed weaker activity in other directions, although the same amount of reward was given in each direction. Moreover, this directional reward activity was modulated by the reward size. Our results demonstrate that the SEF cells may reflect both reward amount and target positions toward which a movement was rewarded, and suggest that they may play an important role in providing information about the value of each saccade according to the spatial target location.

Chromatin remodeling inactivates activity genes and regulates neural coding

Epigenetic regulation in the brain The activity of neurons in the brain controls the transcription of genes that influence the pruning of dendritic connections between neurons, and such modifications can influence animal behavior. Yang et al. propose a role for chromatin remodeling by the nucleosome remodeling and deacetylase complex (NuRD) in the inactivation of such activity-dependent transcription in the mouse cerebellum (see the Perspective by Sweatt). Deposition of the histone variant H2A.z at promoters of activity-dependent genes required the NuRD complex. Loss of the NuRD complex function resulted in hypersensitivity of mice to sensory stimuli and excessive neuronal connectivity in animals performing a task on a treadmill. Science, this issue p. 300; see also p. 218 Epigenetic control of transcription influences neuronal connectivity. Activity-dependent transcription influences neuronal connectivity, but the roles and mechanisms of inactivation of activity-dependent genes have remained poorly understood. Genome-wide analyses in the mouse cerebellum revealed that the nucleosome remodeling and deacetylase (NuRD) complex deposits the histone variant H2A.z at promoters of activity-dependent genes, thereby triggering their inactivation. Purification of translating messenger RNAs from synchronously developing granule neurons (Sync-TRAP) showed that conditional knockout of the core NuRD subunit Chd4 impairs inactivation of activity-dependent genes when neurons undergo dendrite pruning. Chd4 knockout or expression of NuRD-regulated activity genes impairs dendrite pruning. Imaging of behaving mice revealed hyperresponsivity of granule neurons to sensorimotor stimuli upon Chd4 knockout. Our findings define an epigenetic mechanism that inactivates activity-dependent transcription and regulates dendrite patterning and sensorimotor encoding in the brain.

Neuronal activity related to anticipated and elapsed time in macaque supplementary eye field

It is essential to sense anticipated and elapsed time in our daily life. Several areas of the brain including parietal cortex, prefrontal cortex, basal ganglia and olivo-cerebellar system are known to be related to this temporal processing. We now describe a number of cells in the supplementary eye field (SEF) with phasic, delay activity and postdelay activity modulation that varied with the length of the delay period. This variation occurred in two manners. First, cells became active with the shorter delay periods (GO signal presented earlier). We call these cells “short-delay cells”. Second, cells became active with the longer delay periods (GO signal presented later). We call these cells “long-delay cells”. However, such changed neuronal activity did not correlate with reaction time. These results suggest that the delay-dependent activity may reflect anticipated and elapsed time during performance of a delayed saccadic eye movement.

Cerebellar roles in self-timing for sub- and supra-second intervals

Previous studies suggest that the cerebellum and basal ganglia are involved in sub-second and supra-second timing, respectively. To test this hypothesis at the cellular level, we examined the activity of single neurons in the cerebellar dentate nucleus in monkeys performing the oculomotor version of the self-timing task. Animals were trained to report the passage of time of 400, 600, 1200, or 2400 ms following a visual cue by making self-initiated memory-guided saccades. We found a sizeable preparatory neuronal activity before self-timed saccades across delay intervals, while the time course of activity correlated with the trial-by-trial variation of saccade latency in different ways depending on the length of the delay intervals. For the shorter delay intervals, the ramping up of neuronal firing rate started just after the visual cue and the rate of rise of neuronal activity correlated with saccade timing. In contrast, for the longest delay (2400 ms), the preparatory activity started late during the delay period, and its onset time correlated with self-timed saccade latency. Because electrical microstimulation applied to the recording sites during saccade preparation advanced self-timed but not reactive saccades, regardless of their directions, the signals in the cerebellum may have a causal role in self-timing. We suggest that the cerebellum may regulate timing in both sub-second and supra-second ranges, although its relative contribution might be greater for sub-second than for supra-second time intervals. SIGNIFICANCE STATEMENT How we decide the timing of self-initiated movement is a fundamental question. According to the prevailing hypothesis, the cerebellum plays a role in monitoring sub-second timing, whereas the basal ganglia are important for supra-second timing. To verify this, we explored neuronal signals in the monkey cerebellum while animals reported the passage of time in the range 400–2400 ms by making eye movements. Contrary to our expectations, we found that neurons in the cerebellar dentate nucleus exhibited a similar preparatory activity for both sub-second and supra-second intervals, and that electrical simulation advanced self-timed saccades in both conditions. We suggest that the cerebellum plays a causal role in the fine adjustment of self-timing in a larger time range than previously thought.

Different contributions of preparatory activity in the basal ganglia and cerebellum for self-timing

The ability to flexibly adjust movement timing is important for everyday life. Although the basal ganglia and cerebellum have been implicated in monitoring of supra- and sub-second intervals, respectively, the underlying neuronal mechanism remains unclear. Here, we show that in monkeys trained to generate a self-initiated saccade at instructed timing following a visual cue, neurons in the caudate nucleus kept track of passage of time throughout the delay period, while those in the cerebellar dentate nucleus were recruited only during the last part of the delay period. Conversely, neuronal correlates of trial-by-trial variation of self-timing emerged earlier in the cerebellum than the striatum. Local inactivation of respective recording sites confirmed the difference in their relative contributions to supra- and sub-second intervals. These results suggest that the basal ganglia may measure elapsed time relative to the intended interval, while the cerebellum might be responsible for the fine adjustment of self-timing.

Two different mechanisms for the detection of stimulus omission

Although we can detect slight changes in musical rhythm, the underlying neural mechanism remains elusive. Here we show that two distinct mechanisms are automatically selected depending on the speed of the rhythm. When human subjects detected a single omission of isochronous repetitive auditory stimuli, reaction time strongly depended on the stimulus onset asynchrony (SOA) for shorter SOAs (<250 ms), but was almost constant for longer SOAs. For shorter SOAs, subjects were unable to detect stimulus omission when either monaural stimuli or those in different frequencies were randomly presented. In contrast, for longer SOAs, reaction time increased when different tempos were presented simultaneously to different ears. These results suggest that depending on the speed of rhythms, the brain may use either temporal grouping of discrete sounds or temporal prediction of upcoming stimuli to detect the absence of a regular stimulus. Because we also found a similar relationship between reaction time and SOA for both visual and tactile stimuli, dual detection strategies could be generalized to other sensory modalities.

Single-Unit Extracellular Recording from the Cerebellum During Eyeblink Conditioning in Head-Fixed Mice

This chapter presents a method for performing in vivo single-unit extracellular recordings and optogenetics during an associative, cerebellum-dependent learning task in head-fixed mice. The method uses a cylindrical treadmill system that reduces stress in the mice by allowing them to walk freely, yet it provides enough stability to maintain single-unit isolation of neurons for tens of minutes to hours. Using this system, we have investigated sensorimotor coding in the cerebellum while mice perform learned skilled movements.

Facilitation of temporal prediction by electrical stimulation to the primate cerebellar nuclei

The cerebellum is known to be involved in temporal information processing. However, the underlying neuronal mechanisms remain unclear. In our previous study, monkeys were trained to make a saccade in response to a single omission of periodically presented visual stimuli. To detect stimulus omission, animals had to predict the timing of each next stimulus. During this task, neurons in the cerebellar dentate nucleus exhibited a transient decrement of activity followed by a gradual increase in firing rate that peaked around the time of the next stimulus (Ohmae et al., 2013). In the present study, to address how these two components of neuronal activity contributed to omission detection, we applied electrical microstimulation to the recording site at different timing during the task. We found that electrical stimulation just before the stimulus omission shortened the latencies of both contraversive and ipsiversive saccades. Because the changes in saccade latency non-linearly depended on the timing of stimulation in each inter-stimulus interval, and electrical stimulation just before the early stimulus in the sequence failed to evoke saccades, the neuronal activity in the dentate nucleus might regulate temporal prediction rather than facilitating saccade execution. Our results support the hypothesis that the firing modulation in each inter-stimulus interval in the dentate nucleus represents neuronal code for the temporal prediction of next stimulus.