# Elucidating the role of the endogenous opioid dynorphin in reward seeking

> **NIH NIH K99** · UNIVERSITY OF WASHINGTON · 2024 · $174,625

## Abstract

Project Summary:
 The primary goal of this training proposal is to understand how dynorphinergic regulation of circuits in the
dorsomedial striatum (DMS) enhances seeking behaviors for natural (sucrose) and drug (fentanyl) rewards.
Enhanced dynorphin-kappa opioid receptor (dyn-KOR) signaling and aberrant striatal activity is associated with
the transition from recreational to persistent opioid-seeking. Yet how dyn neuron activity and subsequent -KOR
modulation of the striatum regulates sucrose or fentanyl-seeking is unknown. During the first phase of my
postdoctoral research, using a combination of pharmacology, genetics, in vivo photometry and optogenetics, I
identified that retrograde dyn transmission at BLA inputs to the DMS enhances BLA-DMS activity, and promotes
natural reward-seeking behaviors. However, when exactly dyn neuron activity and release are engaged in
reward-seeking is unknown. Hence, I will obtain training in, and use in vivo two-photon imaging to understand
how DMS dyn ensembles encode reward-seeking for sucrose, (Aim 1A, K99). I will also extensively characterize
and use a novel dyn biosensor using in vivo photometry to determine if the pattern of ensemble activity is
reflected in subsequent DMS dyn release, (Aim 1B, K99). Furthermore, because aberrant dyn-KOR signaling is
linked to maladaptive opioid-seeking, and my preliminary data suggests a role for dyn-KOR activity to enhance
sucrose-seeking, I will develop and use an oral fentanyl self-administration paradigm in conjunction with in vivo
photometry to dissect when BLA-DMS terminals are engaged during fentanyl-seeking (Aim 2A, K99). I will also
multiplex conditional deletions of dyn in the DMS, or KOR in the BLA, and stimulate dyn release in the DMS,
with in vivo photometry during fentanyl-seeking to determine whether enhanced dyn-KOR signaling negatively
modulates fentanyl-seeking (Aim 2B, K99). For the R00 “independent” phase of my proposal, I propose to extend
the findings from Aims 1 and 2 in my own lab. I will delineate how DMS dyn ensemble activity encodes fentanyl-
seeking, manipulate specific ensembles to control behavior via spatial light modulation, and dissect the necessity
for BLA inputs in the DMS to induce dyn release during fentanyl-seeking (Aim 3, R00). The proposed studies
specifically address how elevated endogenous dynorphin-KOR signaling, via its control of activity in the
DMS, regulates natural and fentanyl reward-seeking. During the proposed K99 training period, I will be trained
in in vivo two-photon calcium imaging approaches, opioid biosensor imaging and oral self-administration.
Additionally, I will actively participate in scientific society conferences, obtain career development training
(budgeting and administrative tasks), and continue to further my scholarly knowledge base (planned interactions
with my mentor and committee members). Altogether, this award will greatly facilitate the development of my
own research program, thereby preparing me ...

## Key facts

- **NIH application ID:** 10874567
- **Project number:** 5K99DA058709-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Raajaram Gowrishankar
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $174,625
- **Award type:** 5
- **Project period:** 2023-07-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10874567

## Citation

> US National Institutes of Health, RePORTER application 10874567, Elucidating the role of the endogenous opioid dynorphin in reward seeking (5K99DA058709-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10874567. Licensed CC0.

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