# Optogenetic Approaches to Study Post-Stroke Recovery Mechanisms

> **NIH NIH R01** · STANFORD UNIVERSITY · 2024 · $592,625

## Abstract

PROJECT SUMMARY
Stroke is the leading cause of death with very limited treatment options. This devastating neurological disease
is increasingly viewed as a disease of brain connectivity as a damaged stroke area can affect both local and
connected brain regions, causing disruptions in neuronal activity and metabolism network-wide. Recovery of
lost function can occur after stroke and is attributed to brain remodeling in areas adjacent to or connected to
the infarct. In this proposal, we aim to investigate the role of key brain circuits in post-stroke recovery at the
functional, cellular and molecular level, using optogenetics, advanced live imaging and high throughput RNA
sequencing techniques. Previously our lab has demonstrated that selective optogenetic neuronal stimulation in
the ipsilesional motor cortex (iM1) can activate plasticity mechanisms and promote recovery. Recently we have
employed the optogenetic functional MRI technique to systematically map brain-wide changes in neural circuits
after stroke. We have identified key circuits altered by stroke and demonstrated two key circuits restored by
iM1 stimulations. Our map data also revealed two candidate circuits that were not restored by iM1 stimulations,
suggesting that greater recovery could be achieved if we can rescue these circuits by directly stimulating them.
In this proposal we aim to investigate key neural circuits we identified from our activation maps and elucidate
their role in post-stroke recovery. In Aim1 we will use circuit-specific optogenetic tools and functional behavior
tests to interrogate the role of key circuits in post-stroke recovery. This aim will address whether these circuits
have beneficial or maladaptive role during post-stroke recovery. In Aim2 we will examine cellular resolution of
real-time neuronal activity dynamics in key circuits after stroke using a portable live calcium imaging system.
This will elucidate the neural activity dynamics (excitatory and inhibitory) of key circuits at the cellular level,
allowing us to identify the temporal profile and the key neuronal populations altered by stroke, and how iM1
stimulations affect these characteristics to enhance recovery. In Aim3 we will investigate the transcriptome of
key circuit areas using RNAseq, in order to identify key molecular targets and pathways altered by stroke and
by iM1 stimulations. Preliminary RNAseq analysis revealed distinct pathways altered by iM1 stimulations. We
aim to perform RNAseq in multiple regions including iM1 (stimulation site) and ipsilesional thalamus (iM1-
connected region) to elucidate whether similar pathways are involved, and if we can identify a common
molecular signature that drive recovery. We will also perform RNAseq in both sexes in order to ascertain any
sex-specific differences that may be present in post-stroke recovery. Together these results will 1) advance the
understanding of neural circuit dynamics during post-stroke recovery; and 2) identify key neural circui...

## Key facts

- **NIH application ID:** 10740855
- **Project number:** 5R01NS093057-09
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** GARY K STEINBERG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $592,625
- **Award type:** 5
- **Project period:** 2015-08-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10740855

## Citation

> US National Institutes of Health, RePORTER application 10740855, Optogenetic Approaches to Study Post-Stroke Recovery Mechanisms (5R01NS093057-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10740855. Licensed CC0.

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