# Defining a Dystonia Specific Spiking Signature in Cerebellar Nuclei Cells

> **NIH NIH R00** · VIRGINIA POLYTECHNIC INST AND ST UNIV · 2024 · $241,532

## Abstract

Project summary and significance: Dystonia is characterized by involuntary muscle contractions and is
estimated to be the third most common movement disorder in the United States. Dystonia can be the primary
symptom in patients of all ages or present as a secondary symptom in patients with neurodevelopmental and
neurodegenerative disorders and affects function of many nodes in the motor circuit, including the thalamus,
basal ganglia, motor cortex, and cerebellum. This neurological diversity – in addition to the genetic heterogeneity
of hereditary dystonia – has made it difficult to pinpoint therapeutic targets. A better understanding of the
pathophysiology of dystonia is indispensable to the development of more effective treatments. Recent studies
suggest that cerebellar pathophysiology forms a shared mechanism for the inception of etiologically distinct
dystonias; nearly all animal models with overt dystonia-like symptoms have abnormalities in the spiking activity
of cerebellar neurons. Yet, the precise mechanism of cerebellar dysfunction in dystonia is enigmatic, especially
because cerebellar pathophysiology is primarily known to cause other motor disorders, like ataxia and tremor.
This Pathway to Independence Award proposal leverages quantitative, in vivo electrophysiology in genetic,
developmental, and optogenetic mouse models of dystonia to define a dystonia-specific spiking signature in
cerebellar output neurons, and to deduce the developmental divergence of cerebellar function between healthy
and dystonic mice. This knowledge will provide a biomarker and therapeutic target for dystonia, which will be
invaluable for designing new treatments that alleviate or prevent symptoms onset in patients or mutation carriers.
Candidate and career development: Dr. Meike van der Heijden was trained in developmental neuroscience in
the laboratory of Dr. Huda Zoghbi, where she used intersectional genetics to unveil the function and identity of
brainstem respiratory neurons essential for postnatal survival. She then joined the laboratory of Dr. Roy Sillitoe,
a world-leader in cerebellar neuroscience with a strong record of NIH funding, mentorship, and scientific
leadership. Here, she developed an analytical platform and generated a database to assess spiking activity in
cerebellar neurons across mouse models of cerebellar disease (dystonia, ataxia, tremor), and studied how
impaired maturation of cerebellar Purkinje cell function leads to neurological deficits. In this proposal, Dr. Van
der Heijden will build on her skills in in vivo electrophysiology, mouse genetics, and neuroanatomy and expand
her analytical tool-kit, broaden her skills in unbiased quantitative motor function assessment, and acquire
proficiency in acute manipulation of cerebellar circuits using optogenetics. All experiments will be conducted in
the Neurological Research Institute, a collaborative research institute for clinical excellence and world-class
neuroscience research built by Texa...

## Key facts

- **NIH application ID:** 11082166
- **Project number:** 4R00NS130463-02
- **Recipient organization:** VIRGINIA POLYTECHNIC INST AND ST UNIV
- **Principal Investigator:** Meike Esther Van Der Heijden
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $241,532
- **Award type:** 4N
- **Project period:** 2023-01-15 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11082166

## Citation

> US National Institutes of Health, RePORTER application 11082166, Defining a Dystonia Specific Spiking Signature in Cerebellar Nuclei Cells (4R00NS130463-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/11082166. Licensed CC0.

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