# CEREBELLAR FUNCTION IN TREMOR

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2021 · $160,000

## Abstract

PROJECT SUMMARY/ABSTRACT
Tremor is the most common movement disorder. It impairs voluntary actions by causing intense
shaking during walking, eating, and speaking. The shaking is repetitive and highly rhythmic as the
affected body parts “oscillate” back and forth. Oscillation frequency is a defining feature of tremor;
distinct tremors are found in Parkinson’s disease, dystonia, and essential tremor (ET). Because
tremor disorders have a neurological basis, it implies that specific brain oscillations drive the body to
oscillate at the same frequency. However, it is still not clear where in the central nervous system the
oscillations begin, and the processes that lead to oscillations in the connected brain regions remain
unknown. In ET, which is the most prevalent form of pathological tremor, a hindbrain motor region
called the cerebellum has been heavily implicated as the major source of abnormal activity. But, how
abnormal cerebellar activity leads to oscillating motions has been challenging to test. This is largely
because of the lack of an appropriate animal model. To address this problem, we identified a mouse
genetic model that exhibits the core features of ET. We have generated compelling preliminary data
showing that the loss of a Purkinje cell gene, Car8, causes an ET-like tremor that mimics the human
condition in its frequency, progression with age, and responsiveness to alcohol. Here, we will expand
on this work by testing the hypothesis that loss of Car8 function causes cerebellar oscillations that
drive tremorgenic activity in the thalamocortical circuit. In our first aim, we will trace the path of the 4-
12Hz tremor oscillations from the cerebellum to the inferior olive, thalamus, and motor cortex in active
mice. We will therefore identify the major brain oscillators that contribute to ET pathophysiology. In
our second aim, we define the cellular origin of the tremor by testing if genetically and optogenetically
altering Purkinje cell firing modulates tremor in Car8 mice. Because cerebellar inhibitory interneurons
are also implicated in ET, we will also test if modulating their activity onto Purkinje cells influences
tremor. This experiment will address how local circuit wiring impacts network-wide oscillations. Next
we will take advantage of the robust connectivity of the cerebellar nuclei with the rest of the motor
system, plus the efficacy of deep brain stimulation (DBS). In our third aim, we will use the Car8 mice
to test whether the cerebellar nuclei are an effective target for DBS. We hypothesize that directing the
DBS to the cerebellar nuclei will prevent the spread of pathological oscillations away from the source.
The utility of Car8 as a preclinical model shows promise towards uncovering the mechanisms for how
DBS works. Our research has importance to human health because we introduce a multi-disciplinary
approach to study a broad spectrum of tremors that are all challenging to define, diagnose, and treat.

## Key facts

- **NIH application ID:** 10459139
- **Project number:** 3R01NS100874-05S1
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Roy Vincent Sillitoe
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $160,000
- **Award type:** 3
- **Project period:** 2021-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10459139

## Citation

> US National Institutes of Health, RePORTER application 10459139, CEREBELLAR FUNCTION IN TREMOR (3R01NS100874-05S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10459139. Licensed CC0.

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