# Nigrostriatal Dopaminergic Modulation of Fear Extinction

> **NIH NIH R15** · UNIVERSITY OF COLORADO DENVER · 2020 · $466,500

## Abstract

Project Summary
Fear extinction, the process of learning that cues associated with past trauma no longer pose a threat, is a
common target of therapeutic strategies for common anxiety and trauma-related disorders. However, fear
extinction memories are labile, and fear and anxiety tend to relapse even following successful extinction.
Unfortunately, manipulations of known extinction circuits have had limited success reducing relapse. We have
observed that activation of the nigrostriatal dopamine (DA) pathway, consisting of DA neurons in the substantia
nigra (SN) that project to the dorsal striatum (DS), during fear extinction can enhance extinction and reduce
relapse. Since the nigrostriatal DA pathway has not previously been considered in the context of fear extinction,
understanding how nigrostriatal DA reduces relapse could lead to novel strategies for the prevention of relapse
after extinction. Our published & preliminary data indicate that sub-circuits within the nigrostriatal DA pathway
that target distinct medial (DMS) & lateral (DLS) networks of neurons in the DS have unique roles in fear
extinction & relapse. SN DA neurons projecting to the DMS (DASN-DMS circuit), but not SN DA neurons projecting
to the DLS (DASN-DLS circuit), seem to contribute to normal fear extinction that remains susceptible to relapse.
However, in order for activation of the nigrostriatal DA pathway to reduce relapse, the DASN-DLS circuit needs to
be recruited during fear extinction training & retrieval. Consistent with this possibility are exciting emerging data
in females challenging existing dogma that deficits in fear inhibition contribute to the higher prevalence of trauma-
related disorders in females than males. We have observed that female rats can be protected from relapse if
exposed to fear extinction training during phases of the estrous cycle when estrogen is high. Recruitment of the
DASN-DLS circuit could contribute to this sex difference, as preliminary data indicate that females exposed to fear
extinction when estrogen is high recruit both the DMS & DLS, whereas extinction normally recruits the DMS, but
not the DLS. Together, these data support the hypothesis that the DASN-DMS circuit supports fear extinction & can
strengthen fear extinction retrieval in males & females with minimal impact on relapse. In contrast, the DASN-DLS
circuit is not normally involved in fear extinction, but can render fear extinction memory resistant to relapse if
recruited during fear extinction training, such as occurs in females during estrous phases with high estrogen. In
Aim 1, we will determine the DASN-DS sub-circuits involved in fear extinction in males and cycling females by 1)
measuring their activity during fear extinction using dual-viral neural tract tracing and 2) inhibiting their activity
using retrograde chemogenetics. In Aim 2, we will use retrograde optogenetics to determine if augmentation of
fear extinction & protection from relapse can be separately produce...

## Key facts

- **NIH application ID:** 9964220
- **Project number:** 2R15MH114026-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** BEN N GREENWOOD
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $466,500
- **Award type:** 2
- **Project period:** 2017-06-16 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9964220

## Citation

> US National Institutes of Health, RePORTER application 9964220, Nigrostriatal Dopaminergic Modulation of Fear Extinction (2R15MH114026-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9964220. Licensed CC0.

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