# Epigenetic regulation of Cdk5 in cognition and emotion

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $525,038

## Abstract

PROJECT SUMMARY
Negative valence states can be modeled in mice using fear conditioning and reward seeking (an example of
frustrative nonreward). Such states lead to transcriptional aberrations at the level of both individual genes and
genome-wide; these changes are also sexually dimorphic. One gene of considerable interest is cyclin-dependent
kinase 5 (Cdk5). While most prior studies have focused on the mechanisms of Cdk5 protein activation and
signaling in stress-evoked behavior, we recently reported that cocaine exposure and fear conditioning lead to
transcriptional regulation of Cdk5 in male mouse brain. This proposal will directly examine the connection
between Cdk5 gene activation and Cdk5 protein activity.
Furthermore, there is emerging evidence that Cdk5-associated histone modifications correlate with drug-, and
fear-induced Cdk5 expression. The current proposal explores the functional relevance of stress-induced histone
modifications at the murine Cdk5 locus across multiple behavioral paradigms using the innovative approach of
locus-specific epigenetic editing. This approach allows us to recapitulate endogenous mechanisms of gene
expression, avoiding non-physiologically relevant changes in protein expression resulting from traditional
knockout or overexpression. Furthermore, we apply cell-type specific analyses to elucidate Cdk5 function in
brain regions across the corticostriatal-limbic circuitry in the regulation of negative valence states. This proposal
will examine the direct functional relevance of sex-specific, epigenetic regulation of Cdk5 by fear conditioning
(Aim 1) and cocaine seeking during abstinence (Aim 2) using targeted epigenetic editing. Sex- and region-
specific phosphoproteomic profiling will be applied to define relevant Cdk5 targets. Identification of the precise
transcriptional and epigenetic mechanisms by which stress regulates specific gene expression is critical for the
development of targeted antidepressant treatments.

## Key facts

- **NIH application ID:** 10757947
- **Project number:** 5R01MH126027-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Elizabeth A Heller
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $525,038
- **Award type:** 5
- **Project period:** 2023-01-01 → 2027-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10757947

## Citation

> US National Institutes of Health, RePORTER application 10757947, Epigenetic regulation of Cdk5 in cognition and emotion (5R01MH126027-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10757947. Licensed CC0.

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