# Lateral habenula circuit dysregulation in mild traumatic brain injury

> **NIH NIH R21** · HENRY M. JACKSON FDN FOR THE ADV MIL/MED · 2021 · $228,744

## Abstract

Summary
Traumatic brain injury (TBI) contributes to almost 30% of all injury-related deaths in the United States,
but the majority of TBI injuries are mild (mTBI). Anxiety, depression and social impairments are
frequently reported as long-term consequences of mTBI that are likely mediated by dysfunction of brain
dopamine (DA) and serotonin (SERT) signaling in reward circuits induced by mTBI. The lateral
habenula, LHb, is a highly conserved diencephalic structure that is unequivocally important in encoding
negative reward information and conveying aversive motivational signals through its prominent inhibitory
influence on midbrain DA neurons and raphe SERT neurons. Compared to the growing literature of LHb
studies aimed at understanding the contribution of the LHb to development of depression, anxiety and
drug withdrawal, the role of LHb in long-term effects of experimental brain injuries on dysregulation of
the brain reward circuits is unclear. In this proposal, we aim to demonstrate that dysfunction of LHb
neural circuits (specifically focusing on the entopeduncular nucleus (EP)-LHb circuitry) following mTBI
contributes to dysregulation of brain reward pathways underlying social anhedonia using state‐of‐the‐art
physiological, optogenetic and chemogenetic approaches. We also explore alterations in dynorphin-kappa
opioid receptor (DYN/KOR) system induced by mTBI that can contribute to dysregulation of LHb neural
circuits and mediate part of the negative affective and anhedonic states of social withdrawal following
mTBI. The results of this research will advance our understanding of dysregulation of DYN/KOR
signaling in LHb neural systems critical to mood and reward regulation in a cell- and circuit-specific
manner following mTBI and help to develop more effective therapeutic intervention to reverse the long-
term changes in the function of reward pathways after mTBI.

## Key facts

- **NIH application ID:** 10151285
- **Project number:** 1R21NS120628-01
- **Recipient organization:** HENRY M. JACKSON FDN FOR THE ADV MIL/MED
- **Principal Investigator:** Fereshteh S Nugent
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $228,744
- **Award type:** 1
- **Project period:** 2021-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10151285

## Citation

> US National Institutes of Health, RePORTER application 10151285, Lateral habenula circuit dysregulation in mild traumatic brain injury (1R21NS120628-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10151285. Licensed CC0.

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