# Bridging the gap from genes to circuits to behavior in understanding cognitive dysfunction

> **NIH NIH DP2** · ROCKEFELLER UNIVERSITY · 2022 · $508,500

## Abstract

Project Summary
Title: Bridging the gap from genes to circuits to behavior in understanding cognitive dysfunction
Abstract: Neuropsychiatric disorders are a leading cause of disability, afflicting more than 20% of individuals
worldwide with, in most cases, no existing cure. A significant portion of the disability stems from cognitive
dysfunction, including disturbances in the regulation of attention, learning, memory and executive function,
which manifest in heterogeneous ways in disorders such as ADHD, schizophrenia, Alzheimer's, Parkinson's,
PTSD, drug additions, etc. While often thought of as affecting primarily the elderly, cognitive disturbances are
becoming increasingly seen as affecting young people as well. Despite decades of intense study, many of the
basic mechanisms underlying these cognitive disturbances appear elusive, preventing us from successfully
understanding or treating them. Here, I propose a new approach to study cognitive dysfunction using a state-
of-the-art diverse outbred (DO) mouse resource, where there is a unique opportunity to form cross-disciplinary
insights. We will begin by phenotyping large numbers of genetically diverse mice through cognitive behavioral
assays, and use advanced statistical genetics approaches to identify genetic loci linked to specific cognitive
traits. Given the high likelihood of mapping many of these genetic loci to a single gene and even to a few single
nucleotide polymorphisms (SNPs), we will knock-in these SNPs (or haplotypic blocks of SNPs) through
genome engineering technology to make highly specific genetic models that re-create the behavior, and related
phenotypes. These mouse models will then be used to systematically explore circuit-level mechanisms for
cognitive dysfunction using advanced technologies for monitoring and manipulating brain-wide neural activity.
Such an approach will provide a framework to bridge the long-standing gap in mechanistic insight, between
genes and neural circuits, that underlie cognitive dysfunction. Ideally, it will provide both molecular and circuit
level handles with which to improve human cognitive symptoms underlying complex neuropsychiatric disease.
The convergence of significant advances in sequencing technology, statistical genetic methods, gene-editing
technology, and brain-wide imaging capabilities create a fertile environment now for using the DO mouse
resource to enable transformative advances in understanding and treating mental illness.

## Key facts

- **NIH application ID:** 9976669
- **Project number:** 4DP2AG058487-02
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** Priya Rajasethupathy
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $508,500
- **Award type:** 4N
- **Project period:** 2017-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9976669

## Citation

> US National Institutes of Health, RePORTER application 9976669, Bridging the gap from genes to circuits to behavior in understanding cognitive dysfunction (4DP2AG058487-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9976669. Licensed CC0.

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