# Role of prefrontal dopamine circuits in threat avoidance learning

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $722,526

## Abstract

PROJECT SUMMARY
Ongoing evaluation of environmental cues that predict aversive outcomes enable animals to avoid threats.
However, learned avoidance can easily become maladaptive. Excessive or inappropriate avoidance is a core
feature of numerous psychiatric disorders (e.g., depression, anxiety, PTSD and OCD). Although pathological
behavior in these conditions is linked to dysfunction in the prefrontal cortex, we lack the detailed neurobiological
understanding necessary to design precisely targeted therapeutic interventions. The medial prefrontal cortex
(mPFC) is required for learning associations that drive approach or avoidance behaviors, but the circuit
mechanisms that underlie this process are poorly understood. Prefrontal dopamine (DA), in contrast with
subcortical DA, most strongly encodes aversive stimuli. DA has a well-established role in plasticity and shapes
activity in projection-specific mPFC neuronal populations expressing either D1 or D2 receptors (D1R or D2R).
However, the role of prefrontal DA, and D1R+ vs. D2R+ populations, in avoidance learning remains largely
mysterious. We will address these deficits using innovative tools that allow us to measure and/or manipulate DA
and mPFC neuron populations while mice learn to avoid threats. We will test the specific hypothesis that DA
generates an mPFC activity state required for flexibly learning to associate cues with actions that preempt
aversive outcomes. In Aim 1, we will use temporally precise measurement and manipulation of prefrontal DA to
thoroughly interrogate the timing and causality of DA dynamics during threat avoidance learning. In Aim 2, we
will use miniaturized head-mounted microscopes and simultaneous optogenetic silencing of mPFC-projecting
DA neurons to determine the causal role of DA in modifying emergent neural activity patterns required for
avoidance learning. Finally, in Aim 3, we will focus on D1R+ and D2R+ cell-type specific circuits by recording
their activity and electrically silencing them during threat avoidance learning. This proposal directly addresses a
pressing need to understand the cell-type and circuit-specific mechanisms that mediate avoidance learning. Our
research can inform pharmacological, psychotherapeutic and brain stimulation interventions for a variety of
psychiatric conditions characterized by maladaptive avoidance.

## Key facts

- **NIH application ID:** 10946529
- **Project number:** 1R01MH137461-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Laura Anne DeNardo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $722,526
- **Award type:** 1
- **Project period:** 2024-07-11 → 2029-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10946529

## Citation

> US National Institutes of Health, RePORTER application 10946529, Role of prefrontal dopamine circuits in threat avoidance learning (1R01MH137461-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10946529. Licensed CC0.

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