# An All Optical Platform for Modeling and Monitoring Early Neurodegeneration in Human Neural Circuits

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2022 · $39,162

## Abstract

PROJECT SUMMARY
Treatments for neurodegenerative disorders that slow or delay disease onset, mitigate symptoms, and improve
patient quality of life are desperately needed. A common feature of neurodegenerative diseases such as
Parkinson’s Disease (PD) is synaptic dysfunction and excitatory-inhibitory imbalance. Although traditionally
seen as consequences of cell death, emerging research has shown that these processes may occur before
widespread degeneration, making them promising targets for the development of neuroprotective therapeutics.
Therefore, this project aims to develop new tools to better understand early defects in global neurochemical
dynamics, synaptic physiology, and circuit structure in neurodegeneration. A pre-degeneration model of
sporadic PD will be established in this project by genetic manipulation of endogenous alpha-synuclein, a
central hallmark of the disease (Aim 1). Given the limitations in the translatability of rodent models of PD, this
project utilizes human pluripotent stem cell derived neurons organized in functional circuits using a microfluidic
culture device. This device allows for not only circuit-specific manipulation of alpha-synuclein, but also the
specific maturation and organization of distinct cell types to recapitulate basal ganglia inputs. For high-fidelity
and circuit-specific measurements of changes in circuit structure and function in this model, innovations in
novel optical tools will be pursued. The optical sensors developed in this proposal utilizes a hybrid
chemigenetic strategy that involves a genetically encoded HaloTag based protein scaffold and bright, red-
shifted dyes. A far-red hybrid HaloTag-based chemigenetic glutamate sensor will be utilized alongside a
calcium indicator and optogenetic actuator to allow for all-optical manipulation and read-out of circuit function in
early PD (Aim 2). A split HaloTag-based synaptic sensor will be developed to enable simultaneous
measurement of changes in synaptic density and synaptic glutamate transmission with cell type and input
specificity (Aim 3). These tools will allow us to test the central hypothesis that circuit-specific manipulation of
alpha-synuclein in human cortico-basal ganglia circuitry will result in disparate modulation of glutamate activity,
synapse function, and circuit structure. Successful completion of this project will also result in the
establishment of a general platform from which other neurodegenerative disorders and therapeutic
interventions can be understood.

## Key facts

- **NIH application ID:** 10538043
- **Project number:** 1F31NS129379-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Nikki Tjahjono
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $39,162
- **Award type:** 1
- **Project period:** 2022-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10538043

## Citation

> US National Institutes of Health, RePORTER application 10538043, An All Optical Platform for Modeling and Monitoring Early Neurodegeneration in Human Neural Circuits (1F31NS129379-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10538043. Licensed CC0.

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