Evidence map›Paper›PMID 40452046›Full record

ArticleBiology of sex differences2025

High ovarian hormones present during fear extinction reduce fear relapse through a nigrostriatal dopamine pathway.

Alyssa A Hohorst, Margaret K Tanner, Rebecca Han, Kamryn M Korth, Jessica D Westerman, Carolina Sanchez Mendoza, Miles Q Dryden, Lareina A Alvarez, Remla A Abdul, Esteban C Loetz and 2 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Biology of sex differences, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

12 authors.

Alyssa A HohorstDepartment of Psychology, University of Colorado Denver, Denver, CO, USA.
Margaret K TannerDepartment of Psychology, University of Colorado Denver, Denver, CO, USA.
Rebecca HanDepartment of Psychology, University of Colorado Denver, Denver, CO, USA.
Kamryn M KorthDepartment of Psychology, University of Colorado Denver, Denver, CO, USA.
Jessica D WestermanDepartment of Psychology, University of Colorado Denver, Denver, CO, USA.
Carolina Sanchez MendozaDepartment of Psychology, University of Colorado Denver, Denver, CO, USA.
Miles Q DrydenDepartment of Psychology, University of Colorado Denver, Denver, CO, USA.
Lareina A AlvarezDepartment of Integrative Biology, University of Colorado Denver, Denver, CO, USA.
Remla A AbdulDepartment of Integrative Biology, University of Colorado Denver, Denver, CO, USA.
Esteban C LoetzDepartment of Psychology, University of Colorado Denver, Denver, CO, USA.
Erik B OlesonDepartment of Psychology, University of Colorado Denver, Denver, CO, USA.
Benjamin N GreenwoodDepartment of Psychology, University of Colorado Denver, Denver, CO, USA. benjamin.greenwood@ucdenver.edu.

Funding

PILOT STUDY--SUBSTRATE METABOLISM IN EXTREMELY LOW BIRTH WEIGHT INFANTSP30DK048520 · NIDDK · UNIVERSITY OF COLORADO DENVER · PI JANINE A HIGGINS · 1995 to 2026
$32.6M
Sex and circuit-specific determinants of exercise-induced stress resilienceR01MH125898 · NIMH · UNIVERSITY OF COLORADO DENVER · PI BEN N GREENWOOD · 2022 to 2026
$3.0M
Nigrostriatal Dopaminergic Modulation of Fear ExtinctionR15MH114026 · NIMH · UNIVERSITY OF COLORADO DENVER · PI GREENWOOD, BEN N · 2017 to 2020
$933k
NIDDK NIH HHS P30 DK048520NIMH NIH HHS 125898NIMH NIH HHS R01 MH125898NIMH NIH HHS R15 MH114026
6 · The paper itself

Abstract

backgroundElevated ovarian hormones during fear extinction can enhance fear extinction memory retention and reduce fear renewal, but the mechanisms remain unknown. High levels of ovarian hormones are associated with heightened dopamine (DA) transmission, a key player in fear extinction. In males, stimulation of substantia nigra (SN) DA neurons during fear extinction reduces renewal; an effect mimicked by DA D1 receptor agonist administration into the dorsolateral striatum (DLS), a primary target of the SN. The current studies tested the role of the SN-DLS pathway in estrous cycle-modulation of fear extinction and relapse.

methodsMale and female Long-Evans rats were used to investigate the effects of sex and ovarian hormone levels during fear extinction on later fear relapse and underlying mechanisms. Fear extinction-induced cFos in SN DA neurons was quantified with double-label immunohistochemistry. An intersectional chemogenetic approach was used to determine whether SN-DLS pathway activity during fear extinction is necessary and sufficient for observed effects of ovarian hormones on fear relapse. Finally, fast scan cyclic voltammetry revealed the effects of sex and ovarian hormones on electrically-evoked DA release in the DLS and verified the effectiveness of chemogenetic approaches.

resultsFemale rats exposed to fear extinction during proestrus or estrus (Pro/Est; high hormones) had less relapse (renewal and spontaneous recovery) compared to males or females exposed to fear extinction during metestrus or diestrus (Met/Di; low hormones). Fear extinction-induced cFos within SN DA neurons and electrically-evoked DA release in the DLS was highest in female rats during Pro/Est. The behavioral and neurochemical effects of Pro/Est were mimicked by estradiol administration to ovariectomized female rats. Inhibition of the SN-DLS pathway suppressed electrically-evoked DA release in the DLS and restored fear renewal in females exposed to simultaneous fear extinction and SN-DLS inhibition during Pro/Est. Conversely, stimulation of the SN-DLS pathway during extinction reduced fear renewal in males.

conclusionsResults indicate that ovarian hormones present during fear extinction reduce later fear relapse through a SN-DLS dopamine pathway. Data suggest the SN-DLS DA pathway is a novel target for the reduction of fear relapse in both sexes.

Indexed as

Corpus StriatumDopamineExtinction, PsychologicalFearSubstantia NigraAnimalsDopaminergic NeuronsEstrous CycleFemaleMaleRatsRats, Long-EvansSex CharacteristicsDopamineDopamineDorsolateral striatumEstrogenEstrous cycleFear extinctionFear renewalSpontaneous recoverySubstantia nigra

Identifiers

PMID40452046
PMCPMC12128558

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.