Investigation of an Excitatory Nucleo-pontine-cortical Feedback Pathway in Cerebellum-mediated Associative Motor Learning 

The cerebellum is a critical part of the brain responsible mainly for motor coordination and sensorimotor learning. It enables accurate and precise movement which requires precision at scale of millisecond despite delay in sensory feedback through various forms of learning. An important research question for cerebellum has been to elucidate the relationship between its anatomical structure and its computational function. Cerebellum forms various feedforward and feedback projections both internally and with many pre-and post-cerebellar regions. Although it is known that closed-loop circuitries between cortical and subcortical regions can modulate the neural function to facilitate control, little is known about the role of these feedbacks (especially positive feedback) in the cerebellar system. Our preliminary studies show that by inhibiting the projection from interpositus nucleus (Int), a subnucleus of deep cerebellum nucleus (DCN), to pontine nucleus (PN), acquisition of delay eyeblink conditioning (dEBC), a classical form of cerebellum-dependent associative learning, was significantly slowed down in rats. We speculate that efference copy signal from Int is fed back to the cerebellar cortex via PN to modulate motor learning. However, the mechanism of this novel nucleo-pontine-cortical feedback pathway in mediating motor learning remains to be elucidated in detail. In this proposed study, we will first test the hypothesis that manipulating the Int-to-PN projection during the conditioned motor response (CR) time windows will have the most significant effect on dEBC acquisition and expression. This will provide evidence to support that motor-related signal plays the most significant role in modulating behavior via this pathway. Next, we will use Cre-dependent viral-based and chemical neural tracing to characterize the properties of this nucleo-pontine-cortical pathway. These neural tracing experiments will provide evidence to test the following hypotheses: (1) the Int-to-PN projection conveys excitatory efference copy signal (hence a positive feedback); (2) a subpopulation of PN neurons integrates feedforward auditory sensory signal and feedback efference copy signal and conveys them to the cerebellar cortex to modulate dEBC motor learning. Finally, we will perform whole cell patch clamp recording on brain slice to characterize the electrophysiological properties of this feedback pathway by examining the response properties of the neurons in the PN and cerebellar cortex. The success of this proposed study will advance our understanding about how feedback circuitries contribute to motor learning and control in the brain. These knowledge will potentially inspire new clinical application of eyeblink reflex and development of more robust brain-machine interface.