# Cerebellar modulation of seizures through the cerebello-thalamo-cortical pathway

> **NIH NIH F31** · BAYLOR COLLEGE OF MEDICINE · 2022 · $46,236

## Abstract

PROJECT SUMMARY/ABSTRACT
Seizures are a devastating and often fatal neurological condition that manifests as a standalone disease or as
a comorbidity in other debilitating conditions. Unfortunately, treatments are often ineffective, in part because
the neural origins of seizures are unclear. As a first step towards identifying seizure loci in the brain, I designed
an optogenetic approach in mice that provides a versatile method for generating severe seizures. This
approach allows me to test whether specific brain regions have the capacity to initiate seizures and interrogate
the circuit mechanisms underlying seizure propagation and maintenance. The seizure model I generated is
based on controlling the function of neural circuits in a brain region called the cerebellum, now considered the
hub for all motor functions and a central target in a growing list of brain diseases. There is an extensive
literature implicating cerebellar dysfunction in epilepsy: in particular, its output may drive the uncontrollable
movements during seizures. Using optogenetics, I have identified a cerebellar receiving region of the thalamus,
the ventral posteromedial nucleus (VPM), as a powerful region of seizure initiation. The VPM is a major point of
convergence of cerebellar and basal ganglia circuitry and could therefore mediate involuntary movements in
several diseases. Delivery of light pulses to the VPM in channelrhodopsin-expressing mice elicits immediate,
reproducible seizures that begin with myoclonic forelimb movements that progress to severe full body
convulsions. I tested the specificity of the VPM as the main locus driving the behavior by stimulating
surrounding thalamic nuclei and did not observe obvious behavioral abnormalities. Furthermore, the duration
and severity of these optogenetic induced seizures worsens upon repeated stimulation over days. Interestingly,
these behaviors are reminiscent of clinical reports that human seizures worsen and become more frequent
following the first outbreak. My data raise the intriguing hypothesis that a discrete pool of neurons in the VPM
may be a fulcrum site for seizures, into which the cerebellum provides a powerful stimulatory role that controls
seizure severity. To test this hypothesis, I will use mice to determine the features of seizure pathophysiology
(Aim1), test how cerebellar circuits interact with the thalamus and other regions to generate seizures (Aim2),
and uncover the cellular firing mechanisms that produce seizures (Aim3). The experiments in each aim will
include state-of-the-art anatomical and in vivo physiological techniques. The completion of these aims will call
for a reevaluation of subcortical structures in seizure genesis, especially since the cerebellum was one of the
first targets for deep brain stimulation in the treatment of epilepsy. The availability of new therapeutic brain
targets for drug-resistant epilepsy will provide alternate healthcare considerations for reducing the impact of
severe...

## Key facts

- **NIH application ID:** 10295773
- **Project number:** 5F31NS115432-03
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Jaclyn Beckinghausen
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,236
- **Award type:** 5
- **Project period:** 2019-12-01 → 2022-02-06

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10295773

## Citation

> US National Institutes of Health, RePORTER application 10295773, Cerebellar modulation of seizures through the cerebello-thalamo-cortical pathway (5F31NS115432-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10295773. Licensed CC0.

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