# Project 4_Bruchas : Circuit-level Approaches for Dissecting Approach/Avoidance Behaviors Mediated by Nociceptin Systems in Mice

> **NIH NIH P50** · MCLEAN HOSPITAL · 2020 · $501,214

## Abstract

Project Summary
The overall goal of Project 4 is to determine how the nociceptin/receptor system modulates the mesolimbic
dopamine (DA) system and behavioral responses associated with stress, aversion, and motivated behaviors.
We recently identified a population of paranigral ventral tegmental area (pnVTA) nociceptin (PNOC+) neurons
that constrain motivated behavior and regulate the motivation for natural reward seeking. These PNOC+ pnVTA
neurons are engaged during motivation, as well as carry a negative valence when activated. Our extensive body
of preliminary findings strongly implicate these neurons in regulating motivated behaviors, stress responsivity,
and avoidance behavior. Working in close collaboration with the other Projects (in particular, Projects 1 and 3),
Project 4 will use newly developed mouse model for accessing endogenous nociception circuits and focus on
the neurobiological mechanisms of how the prepronociceptin system engages the dopamine system to regulate
motivation – a key component of depressive disorders, including those outlined in this center project. The
research aims of this 5-year project are: (1) to determine the anatomical and functional characteristics of
nociceptin expressing neurons within the ventral midbrain and identify behavioral conditions (acute vs chronic
stress, motivation and Approach-Avoidance) that are modulated by this system; (2) to identify and characterize
pnVTA nociceptin neurons and their afferents involved in motivated behavior that drive negative affective
behavior. The project will use novel and validated mouse cre-driver models that allow unparalleled access to
PNOC+ neurons in the VTA, combined with optogenetic, chemogenetic, calcium imaging, viral tracing, and
behavior to uncover circuit mechanisms that underlie how these neurons are regulated by aversive stimuli. This
project directly synergizes with the other projects outlined in this Conte Center, in two key ways: 1) using novel
cutting-edge mouse models, it will allow to dissect the role of prepronociceptin system in motivation, and 2) it will
comprehensively examine the role of nociceptin circuits in dopamine-dependent behaviors, with direct relevance
to motivational states, avoidance, and stress-induced negative affect. Results from Project 4 will: (1) directly
inform post-mortem analyses probing nociception neurons in the pnVTA of individuals with MDD who died by
suicide (Project 1); (2) synergize with pharmacological challenges used to test the hypothesis that nociceptin
receptor antagonism will normalize neural substrates underlying approach/avoidance behaviors in humans with
MDD and anxiety disorders (Project 1); and (3) integrate with studies using PNOC-IRES-cre mice to determine
how specific populations of nociceptin neurons (striatal vs VTA) regulate motivation, anhedonia, and
approach/avoidance decision making (Project 3). Data emerging from Project 4’s aims, together with the three
other projects and the Computational Modeli...

## Key facts

- **NIH application ID:** 9933625
- **Project number:** 1P50MH119467-01A1
- **Recipient organization:** MCLEAN HOSPITAL
- **Principal Investigator:** Michael R. Bruchas
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $501,214
- **Award type:** 1
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9933625

## Citation

> US National Institutes of Health, RePORTER application 9933625, Project 4_Bruchas : Circuit-level Approaches for Dissecting Approach/Avoidance Behaviors Mediated by Nociceptin Systems in Mice (1P50MH119467-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9933625. Licensed CC0.

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