Cerebellar encoding of prior knowledge of temporal statistics

We possess the ability to anticipate and preempt occurrences under familiar circumstances, which suggests a reliance on prior experience with regularities in our environment1-6, especially when observations become more uncertain. We know little about the neural mechanisms that can learn the probabilities of events in the environment and use this prior experience to guide actions. To examine this, we studied a rudimentary predictive behavior, eyeblink conditioning, and asked whether a simple effector like the eyelid could adapt its movements to varying probabilities of environmental events that reflect different degrees of uncertainty. We found that predictive eyeblink behavior systematically changed almost all its properties according to the temporal statistics of stimulus probability distributions. We also found that the activity of cerebellar Purkinje cells and putative molecular layer interneurons changed concomitantly with temporal statistics of the stimuli and with behavior. Targeted optogenetic perturbation of Purkinje cells during critical time windows severely attenuated the predictive behavior but left reflexive eyeblinks intact. Furthermore, we discovered a novel Purkinje cell complex spike signal coinciding with the onset of the earliest probable time interval in prior distributions with high uncertainty. This signal could not be explained as a motor or sensory correlate and appears to be anticipatory in nature. Theoretical modeling results pointed to a possible synaptic mechanism for how Purkinje cells could encode prior experience of environmental statistics in their activity through the juxtaposition of long-term depression and potentiation dynamics.