# Reciprocal interactions between cortical circuit dysfunction and α-synuclein pathology

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $533,127

## Abstract

Project Summary / Abstract
Parkinson disease (PD) is the second most common neurodegenerative disease, leading to disability and death
for individuals, and significant costs for caregivers and society. Cognitive impairment is a common cause of
functional impairment in PD and a central feature of the related disorder Dementia with Lewy Bodies (DLB). To
date, there are no disease-modifying therapies to prevent the development or progression of these symptoms.
In both PD and DLB, intraneuronal inclusions of the protein alpha-synuclein (α-syn) in limbic and cortical regions
correlates with cortical hypometabolism, hallucinations, and progression to dementia, suggesting a central role
for α-syn in cognitive impairment. However, the specific effects and mechanisms by which α-syn pathology
impacts the function of cortical neurons and circuits remain unknown. In addition, the cortex exhibits regional
vulnerability, both to the deposition of α-syn and to the degree of functional impairment, for unknown reasons.
Thus, major gaps remain in our understanding of how cortical circuits become dysfunctional in PD and DLB and
how specific features of cortical circuits impact the spread and accumulation of α-syn. Here, Dr. Zeiger will lead
a research group to test the hypothesis that a reciprocal relationship exists between α-syn pathology and
neuronal activity, such that cortical α-syn accumulation directly disrupts neuronal activity, and conversely, that
changes in neuronal activity influence the progression of α-syn pathology. In Aim 1, Dr. Zeiger’s group will use
a novel model system in a mouse model of PD to directly define how α-syn impacts the function of different
disease-relevant cortical circuits. Innovative longitudinal two-photon imaging methods will be used to
simultaneously monitor neuronal activity and the accumulation of α-syn inclusions with single-cell resolution.
This will then be correlated with behavioral studies to better understand how α-syn-mediated circuit dysfunction
leads to cognitive and motor symptoms. The impact of co-existing Alzheimer’s disease amyloid-beta pathology
on α-syn-mediated circuit dysfunction will also be tested. In Aim 2, Dr. Zeiger’s group will test the hypothesis that
changes in activity can increase or decrease the accumulation of α-syn in the cortex. Advanced transgenic
mouse lines and viral tools will be used to specifically manipulate the activity of different components of
corticostriatal circuits to define how the activity of specific sub-populations of neurons contribute to the
progression of PD pathology. Together, these studies will uncover basic mechanisms about how cortical circuits
are affected in PD and DLB. This information is also of great importance for future translational studies aiming
to use therapeutic neuromodulation to treat symptoms arising from cortical circuit dysfunction or potentially even
slow disease progression in PD and DLB.

## Key facts

- **NIH application ID:** 10765725
- **Project number:** 5R01NS129517-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** William Abel Zeiger
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $533,127
- **Award type:** 5
- **Project period:** 2023-02-01 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10765725

## Citation

> US National Institutes of Health, RePORTER application 10765725, Reciprocal interactions between cortical circuit dysfunction and α-synuclein pathology (5R01NS129517-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10765725. Licensed CC0.

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