# Project 3_Graybiel : Circuit-Specific Disruption, Pharmacological, and Neurophysiological Studies of Approach/Avoidance Behaviors in Mice and Non-Human Primates

> **NIH NIH P50** · MCLEAN HOSPITAL · 2021 · $604,205

## Abstract

PROJECT SUMMARY (PROJECT 3, Project Leader: Graybiel, Massachusetts Institute of Technology)
Our goal is to identify neural circuit mechanisms underlying major depressive disorder (MDD) and anxiety
disorders to advance therapeutic treatments. Project 3’s Aims, coordinated with those of the other Projects, will
capitalize on our findings on the physiology and function of the anterior cingulate cortex (ACC), strongly linked
to MDD and anxiety disorders, and its connections with specialized neurochemical compartments of the striatum
called striosomes. Striosomes are richly interconnected with the neuromodulatory dopamine system, a key site
influencing motivational states and, in dysfunction, neuropsychiatric illness. We developed a non-human primate
(NHP) version of the approach-avoidance (Ap-Av) task used in humans to study anxiety and depression, as well
as rodent models allowing manipulation of the ACC-striatal circuit. We found that manipulation of this circuit can
profoundly bias Ap-Av decisions, increasing avoidance behavior, and such effects can be mimicked by chronic
stress, dose-dependently reversed by anxiolytics in NHPs, and induced by ACC-striosomal circuit manipulations
in rodents. We now propose to determine the influence of nociceptin receptors (NOPR) on this circuit.
Antagonists of NOPR given systemically increase striatal dopamine efflux, and this treatment reduces
depression- and anxiety-related measures in rodent models and has shown initial promising findings in MDD.
Notably, we recently found together with Project 4 that the nociceptin peptide, nociceptin/orphanin FQ (N/OFQ)
is expressed selectively in striosomal neurons, neurons we recently demonstrated project directly to nigral
dopamine neurons. Thus, we hypothesize that NOPR antagonists interrupt striosomal N/OFQ signaling at
dopamine neurons modulating striatal dopamine release and biasing Ap-Av decision-making when individuals
face cost-benefit tradeoffs. Aim 1 tests the hypothesis that NOPR antagonists can normalize a shift in Ap-Av
behavior as well as neural striosomal and dopamine signals induced in mice by prior chronic stress. Aim 2 tests
whether NOPR antagonists shift Ap-Av decision boundaries and neural activity by asking whether NOPR
antagonists remain effective in the absence of striosomal N/OFQ, nigral NOPRs or both. Aim 3, importantly, will
coordinately test NOPR effects in NHPs with recordings and microstimulation in the ACC during Ap-Av decisions.
Contribution to Overall Center Goals and Interactions with Other Center Components. These Aims will
provide a fundamental infrastructure for designing approaches to the treatment of MDD and anxiety disorders, a
goal directly related to the other projects and the NIMH mission to understand, prevent and cure mental illness.
We will establish a crucial behavioral bridge connecting mouse, NHP and human behavioral studies, including
widely used mouse behavioral assays of anhedonia and avolition (Project 4), NHP Ap-Av beha...

## Key facts

- **NIH application ID:** 10142536
- **Project number:** 5P50MH119467-02
- **Recipient organization:** MCLEAN HOSPITAL
- **Principal Investigator:** Ann M Graybiel
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $604,205
- **Award type:** 5
- **Project period:** 2020-04-15 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10142536

## Citation

> US National Institutes of Health, RePORTER application 10142536, Project 3_Graybiel : Circuit-Specific Disruption, Pharmacological, and Neurophysiological Studies of Approach/Avoidance Behaviors in Mice and Non-Human Primates (5P50MH119467-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10142536. Licensed CC0.

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