# Neurocircuitry of motivated reward-seeking after stress

> **NIH NIH R56** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2024 · $606,029

## Abstract

Project Summary/Abstract
Stress is a risk factor for the development of neuropsychiatric disorders. Over recent years, it is becoming
increasingly clear that dopaminergic circuitry originating in the ventral tegmental area, which is the most well
studied in the context of motivation, is also critical for the behavioral response to stress suggesting an interaction
between stress, motivation, and stress-coping behaviors. Recent studies have determined that the medial
habenulo-interpeduncular nucleus (MHb-IPN) axis, and particularly the IPN responds to aversive stimuli,
contributes to avoidance behavior, and modulates anxiety-like behavior as a component of the extrahypothalamic
stress network. However, the MHb-IPN axis also controls nicotine intake in rodent models, receives dopamine
input from the VTA, and contributes to novelty preference suggesting a role for this pathway in reward seeking
and motivation. Interestingly, we have determined that the IPN GABAergic neurons are activated by acute
stressors; whereas, rewarding stimuli including sucrose reduces activity, which, when mimicked using
optogenetics, reduces stress-induced anxiety-like behavior in mice. These data suggest that one critical function
of the IPN and associated circuitry may be in motivating reward seeking as a stress-coping strategy. However,
neuronal sub-populations underlying this effect are unknown as are the IPN efferents and afferents that mediate
effects of stress on motivated reward seeking. Thus, the goal of this application is to build off these data and test
the hypothesis that IPN neuronal sub-populations, IPN efferents, and IPN afferents drive reward seeking as a
coping mechanism for stress reduction. In Aim 1, we will combine GCaMP expression with fiber photometry and
optogenetics to test if an IPN GABAergic neuron sub-population activated by acute stressors exhibits reduced
activity during reward behaviors and contributes to stress-induced increased motivation for sucrose seeking.
Aim 2 will test if a sub-population of IPN neurons that project to the laterodorsal tegmental area contributes to
reward seeking during stress through modulation of dopaminergic reward circuits. Aim 3 will test the hypothesis
that acute stress engages IPN afferents that are critical for the effects of stressors on reward behavior and
seeking. It is anticipated that elucidating circuitry and mechanisms underlying coping behaviors and effects of
stressors on reward seeking and consumption in an understudied brain region will yield great insights into
behaviors that may be dysregulated in neuropsychiatric disorders and set the foundation for therapeutic
strategies for new treatment.

## Key facts

- **NIH application ID:** 11122586
- **Project number:** 1R56MH137986-01
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** ANDREW R TAPPER
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $606,029
- **Award type:** 1
- **Project period:** 2024-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11122586

## Citation

> US National Institutes of Health, RePORTER application 11122586, Neurocircuitry of motivated reward-seeking after stress (1R56MH137986-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11122586. Licensed CC0.

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