Principles Underlying Cerebellothalamocortical Communication

Innumerable functions have been attributed to the cerebellum: they are as fundamental as movement and as far ranging as social motivation. Underlying these functions are its connections with other brain structures. The most prominent of these is the cerebellothalamocortical pathway. Despite its importance, it is not completely understood how this pathway operates. Preliminary data indicates that burst/tonic modes of the thalamus dynamically regulate this communication. In this proposal we use in vitro and in vivo experiments to build realistic conductances of DCN activity for dynamic clamp of the thalamus, and examine exactly how the thalamus controls cerebellar inputs. This approach allows us to rapidly test many features of cerebellothalamic transmission. We will also record the cerebellum in pathophysiological conditions and impose this activity on the thalamus to specifically examine alterations in pathological states. Here we focus on tremor, which has an established cerebellothalamocortical etiology, and an unambiguous behavioral outcome. We will test this using dynamic clamp, in vivo whole-cell, and multisite single-unit recordings. We will also use CRISPR-mediated knockout of controllers of thalamic excitability to understand cerebellothalamic transmission, and pharmacological strategies to normalize pathological activity. This proposal seeks to understand cerebellothalamocortical communication so that it can be controlled to alleviate any cerebellar dysfunction. Project Number: 1R01NS144457-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Christopher Chen | Institution: PENNSYLVANIA STATE UNIV HERSHEY MED CTR, HERSHEY, PA | Award Amount: $585,999 | Activity Code: R01 | Study Section: Sensory-Motor Neuroscience Study Section[SMN] View on NIH RePORTER: https://reporter.nih.gov/project-details/11365642