The organization of cerebello-thalamo-cortical circuit in the motor system - PROJECT SUMMARY/ABSTRACT Precise control of voluntary movement is crucial for almost all behaviors and the quality of life. While many brain regions are involved in the process, the interaction between the cerebral cortex and the cerebellum is particularly essential. When the cerebellum communicates with the cerebral cortex, it sends signals to the thalamus, which relays the information to the cerebral cortex. This cerebello-thalamo-cortical circuit has been studied extensively because of its functional significance. However, the current understanding of the circuit is based mainly on anatomical connection and the assumption that neurons within each brain region behave similarly. Molecular and physiological heterogeneity within the neuronal population is barely considered, posing a challenge in understanding how the circuit allows coordinated movements of the entire body. First, although the cerebellum projects axons to various thalamic subregions, the strength of synaptic transmission substantially varies. Therefore, the anatomical connection does not accurately represent the functional organization of the circuit. Second, many recent studies showed that a neuronal population, traditionally considered a single group, can be divided into several subtypes based on their distinct gene expression profiles. These molecularly defined neuronal subtypes often show different physiological properties and anatomical connectivity, engaged in distinct functional circuits. Recently, we studied the functional properties of the ventrolateral thalamus (VL), one of the thalamic subregions and the primary target of the cerebellum. While the VL is traditionally considered a homogenous neuronal population, our preliminary data showed substantial variation in their excitability and synaptic properties, which might reflect previously unrecognized connectivity between the cerebellum and the VL. Furthermore, a recent study showed that VL neurons consist of several subtypes exhibiting distinct patterns of gene expression. These data suggest that the functional organization of the cerebello-thalamo-cortical circuit is finer and more sophisticated than previously thought. In the proposed research, we will perform whole-cell patch-clamp recordings and circuit tracing with the transgenic mice that label the molecularly defined VL neuron subtypes. We will study their projection patterns to the cerebral cortex and their contribution to the functional heterogeneity in the VL (Aim 1). We will also examine their presynaptic origin in the cerebellar nuclei and the extent to which the cerebellar nuclei contribute to the functional heterogeneity in the VL (Aim 2). Successful completion of this project is expected to provide novel insight into the organization of the motor circuit.
