# Mu Opioid Receptors in Habenular Networks: Reward and/or Aversion?

> **NIH NIH P50** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $124,999

## Abstract

ABSTRACT
Addiction develops when recreational drug use switches to compulsive drug taking. While the former is
predominantly motivated by reward seeking, the latter is also driven by other factors that include enhanced
stress reactivity, aversive aspects of drug withdrawal and emergence of a negative affect upon protracted
abstinence. In recent years the notion that reward and aversion processing engage overlapping brain
circuits has been established, together with the concept of a reward/aversion network. The habenula (Hb)
encodes both rewarding and aversive aspects of external stimuli, and may therefore represent a central
integrator of reward/aversion circuits. Remarkably, the medial subdivision of habenula (MHb) shows
highest density of mu opioid receptors (MORs) in the brain, but the role of this particular receptor
population is unknown. This project will test the hypothesis that MORs expressed in the MHb regulate
specific aspects of reward and aversion processes related to drug abuse.
 We will capitalize on tools and preliminary findings from the previous funding period. In Aim 1, we
will extensively characterize MOR-expressing neurons in the medial septum-MHb-interpeduncular nucleus
(MS-MHb-IPN) pathway using viral tracers combined with knock-in MOR-mcherry, Cnrb4-Cre or novel
MOR-Cre mice that we currently develop. This Aim will provide circuit-level understanding that will
complement Aims 2 and 3. Aim 2 will identify behaviors, and underlying circuit mechanisms, controlled by
MORs in the MHb. We will examine a range of reward/aversion behaviors potentially mediated at the Hb
level (reward and reward-driven decision-making, morphine and nicotine withdrawal, aversion to morphine
withdrawal and abstinence) using a novel conditional Cnrb4-MOR mouse line. Reduced physical morphine
withdrawal has already been detected and DREADD approaches will be used to recapitulate this behavior,
and possibly other phenotypes. Aim 3 will identify the causal impact of MOR and MOR-positive neuron
activities in MS-MHB-IPN networks, and their broader impact on the brain. We will use pioneering
functional magnetic resonance imaging (fMRI) in live mice, and further fMRI strategies developed in the
Technical Advancement Core, to map brain-wide functional connectivity, seed-based connectional patterns
and inter-node directionality in Cnrb4-MOR mice at rest and after morphine treatment. Consequences of
DREADD-mediated stimulation of MOR+ neurons in the MHb will also be examined by fMRI in live animals.
 In sum, this proposal will reveal the role(s) of the densest and less-well studied MOR population.
The three aims together will determine importance of these receptors in reward/aversion-related behaviors
and elucidate the underlying circuit mechanisms. The project will also provide novel genetic mouse lines for
CSORDA (Cnrb4-MOR, Project III) and the neuroscience community (MOR-Cre), and cutting edge non-
invasive animal imaging that will be applicable within (PTSD...

## Key facts

- **NIH application ID:** 9964746
- **Project number:** 5P50DA005010-34
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** BRIGITTE L. KIEFFER
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $124,999
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9964746

## Citation

> US National Institutes of Health, RePORTER application 9964746, Mu Opioid Receptors in Habenular Networks: Reward and/or Aversion? (5P50DA005010-34). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9964746. Licensed CC0.

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