# Cerebellar Circuitry in the Pathophysiology of Tremor

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $389,954

## Abstract

PROJECT SUMMARY/ ABSTRACT
Tremor is the most common movement disorder and is often highly disabling. How these rhythmic movements
are generated from the abnormal brain circuitry is still poorly understood. Among tremor disorders, essential
tremor (ET) is the most common and a prototypical disorder for tremor. Recent postmortem human pathology
studies have shown that ET might be a disease of cerebellar synaptic pathology. Specifically, there is abnormal
synaptic formation between climbing fibers (CFs) and Purkinje cells (PCs) in the cerebellar cortex of ET patients.
To further investigate the pathophysiology between this PC synaptic pathology and tremor, we established a
mouse model with ET-like PC synaptic pathology and found that this mouse model develops age-related kinetic
tremor that responds to primidone, propranolol, and alcohol, similar to ET patients. However, the detailed
pathophysiology remains obscure. Therefore, we propose a series of experiments to study the relationship
between PC synaptic pathology, PC physiology and tremor in this novel mouse model. In Specific Aim 1, we will
use optogenetic approaches to inhibit PC activities in our novel tremor mouse model and observe whether tremor
could be suppressed. In addition, we will optogenetically enhance PC activities at different frequencies and
observe whether this manipulation will create tremor in wild type mice. In Specific Aim 2, we will determine how
the PC synaptic pathology interacts with PC degenerative changes, which could modulate tremor characteristics
(frequency and amplitude) and the corresponding cerebellar physiology in our tremor mouse model during tremor
onset and tremor progression. In Specific Aim 3, we will manipulate molecules controlling PC synaptic
organization to pinpoint how specific PC synaptic pathology and PC physiology can regulate tremor. We have
developed methods to study anatomical PC synaptic organization and to simultaneously record PC responses
during tremor in freely moving mice, which will allow us to perform detailed examination of how the PC activity
relates to tremor characteristics. Our study will thus provide important insights into the pathophysiology of tremor.

## Key facts

- **NIH application ID:** 10427183
- **Project number:** 5R01NS104423-05
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Sheng-Han Kuo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $389,954
- **Award type:** 5
- **Project period:** 2018-09-05 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10427183

## Citation

> US National Institutes of Health, RePORTER application 10427183, Cerebellar Circuitry in the Pathophysiology of Tremor (5R01NS104423-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10427183. Licensed CC0.

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