# Brain-wide mapping of neuronal inhibition by novel inverse activity markers

> **NIH NIH RF1** · SCRIPPS RESEARCH INSTITUTE, THE · 2023 · $3,013,502

## Abstract

Abstract
This project aims to develop the first Inverse Activity Marker (IAM) for detecting neuronal inhibition
(broadly defined as the decrease of neuronal activities). The transcription of immediate early genes
(IEGs) like c-Fos and Arc has been the most widely used for translating neuronal activity into stable,
trackable histological labels to allow structural and functional interrogations. Existing activity targeting
methods, either through direct detection of IEGs or engineered IEG promoters, are optimized for
detecting the sustained increase of neural activity. However, they are generally less effective for
labeling the inhibition of neuronal activity. Therefore, to better understand the bi-directional brain
activities, it is important to have a set of new markers to label the decrease of neuronal activity
opposite to the conventional IEGs, which we propose here as the Inverse Activity Marker.
We aim to develop IAMs based on protein post-translational modifications (PTMs), which are known
to be rapid, bi-directional, and trackable. We hypothesize that if we can identify PTMs inversely
correlated with neuronal activation through unbiased screens, these changes could be developed into
IAMs to report neural inhibition in behaving animals. We established an original optogenetic-
proteomics screening platform, from which we discovered that the phosphorylation of pyruvate
dehydrogenase E1 subunit Alpha 1 or pPDH inversely correlated with neuronal activity. Our central
hypothesis is to test whether pPDH can serve as the first IAM to reflect the inhibition of neural activity
in vitro and in vivo. The method development goal is to integrate IAMs with whole-brain clearing,
lightsheet imaging, and multiplexed labeling to enable a cell-ID compatible tool for unbiased profiling
of brain-wide inhibition. We assembled a team of investigators with well-recognized expertise in
activity-dependent tool development, circuit mapping, electrophysiology, and proteomics and
behaviors. The development and dissemination of these novel tools will bring new perspectives to
understanding the circuit dynamics of the brain.

## Key facts

- **NIH application ID:** 10639977
- **Project number:** 1RF1MH132570-01
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Li Ye
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $3,013,502
- **Award type:** 1
- **Project period:** 2023-05-02 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10639977

## Citation

> US National Institutes of Health, RePORTER application 10639977, Brain-wide mapping of neuronal inhibition by novel inverse activity markers (1RF1MH132570-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10639977. Licensed CC0.

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