# Long non-coding enhancer RNA controls stress-induced changes in reward-related behaviors

> **NIH NIH R01** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2024 · $377,500

## Abstract

Project Summary/Abstract
 Chronic stress alters reward-related behavior and this is accompanied by changes in neural
circuit function, especially that involving the medial prefrontal cortex (mPFC). However, the
molecular mechanisms controlling circuit dysfunction and its effect on associated behaviors
remain poorly understood.
 The Npas4 gene encodes the Neuronal PAS domain protein 4 (NPAS4) transcription factor
that functions as a homeostatic regulator of excitatory and inhibitory synaptic connections in
response to changes in synaptic activity. Our preliminary findings in mice show that aversive
stress experience trigger the transient induction of NPAS4 expression in mPFC and that this is
required for chronic social defeat stress (CSDS)-induced reward-related behavior deficit.
Furthermore, these studies show that NPAS4 is required for CSDS-induced reduction of mPFC
pyramidal neuron excitatory transmission and dendritic spine density.
 Interestingly, while protein-coding genes (mRNA) are obviously important for functional
regulation of brain activity, human and rodent genomes encode a much larger number of long
non-coding RNAs (lncRNAs). Emerging evidence demonstrates significant roles for lncRNAs in
gene expression, but the physiological and pathological functions of individual lncRNAs are only
beginning to be explored. To address this knowledge gap, we will study a novel, non-annotated,
lnc-enhancer RNA (lnc-eRNA) transcribed from the enhancer region of Npas4 (Npas4eRNA). We
found that Npas4eRNA is required for Npas4mRNA expression and for CSDS-induced deficits in
sucrose preference. Npas4eRNA forms an DNA:RNA hybrid R-loop structure that is required for
Npas4mRNA expression. We hypothesize that the Npas4eRNA and its R-loop structure directly link
the enhancer-associated transcriptional machinery with the Npas4 transcription start site via 3D
chromatin loop structure.
 In this proposal, we will combine innovative molecular and cellular approaches with
ethologically relevant models of psychosocial and psychological stressors in both male and
female mice and examine the function of Npas4eRNA and R-loop in the PFC for the stress-induced
epigenetic gene regulation, functional and morphological synaptic plasticity, and alterations in
reward-related behaviors.

## Key facts

- **NIH application ID:** 10904868
- **Project number:** 5R01MH129521-02
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Makoto Taniguchi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $377,500
- **Award type:** 5
- **Project period:** 2023-08-10 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10904868

## Citation

> US National Institutes of Health, RePORTER application 10904868, Long non-coding enhancer RNA controls stress-induced changes in reward-related behaviors (5R01MH129521-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10904868. Licensed CC0.

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