Journal Article

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

Han, Rebecca, Dryden, Miles Q., Abdul, Remla A., Korth, Kamryn M., Greenwood, Benjamin N., Oleson, Erik B., Tanner, Margaret K., Alvarez, Lareina A., Hohorst, Alyssa A., Westerman, Jessica D., Mendoza, Carolina Sanchez, Loetz, Esteban C.

2025

Overview

Background Elevated 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. Methods Male 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. Results Female 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. Conclusions Results 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. Plain Language summary Women are at higher risk than men for common psychiatric disorders such as post-traumatic stress disorder. Exposure therapy is used to treat these disorders whereby subjects learn that cues previously paired with trauma no longer predict danger. However, the efficacy of exposure therapy is limited by the return of fear (relapse), even after successful fear extinction. Research is needed to better understand sex differences in the processes governing fear extinction learning and relapse. Levels of ovarian hormones present during fear extinction can influence the strength of fear extinction memory and relapse, but the mechanisms underlying the effect of ovarian hormones remain unknown. Due to an emerging role for dopamine (DA) and the substantia nigra-to-dorsolateral striatum (SN-DLS) DA pathway in relapse-resistant fear extinction, we investigated the involvement of the SN-DLS DA pathway in ovarian hormone-modulation of fear extinction and relapse. We observe that females with elevated ovarian hormones during fear extinction have less fear relapse compared to males and females with low ovarian hormones, an effect attributable to estradiol. Elevated ovarian hormones potentiated DA neural activity during fear extinction in the SN and DA release in the DLS, while inhibition of the SN-DLS pathway during fear extinction restores fear relapse in females exposed to fear extinction in the presence of high ovarian hormones. Additionally, stimulation of the SN-DLS pathway during fear extinction reduces relapse in males. The results of this study implicate the SN-DLS pathway as a novel target for the reduction of relapse in both sexes. Highlights High levels of ovarian hormones during fear extinction is associated with low levels of fear relapse in adult, female rats. Electrically-evoked dopamine release in the dorsolateral striatum is potentiated by estradiol and is highest in phases of the estrous cycle characterized by high levels of ovarian hormones. Activity of substantia nigra dopamine neurons during fear extinction is greatest in females exposed to fear extinction during estrous cycle phases associated with high levels of ovarian hormones. Inhibition of the substantia nigra-to-dorsolateral striatum pathway during fear extinction restores fear relapse in females exposed to extinction during conditions of high ovarian hormones. Stimulation of the substantia nigra-to-dorsolateral striatum pathway during fear extinction reduces fear relapse in males.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: 17β-Estradiol / Animals / Biological diversity conservation / Biomedical and Life Sciences / Biomedicine / Corpus Striatum - physiology / Dopamine / Dopamine - metabolism / Dopamine D1 receptors / Dopaminergic Neurons - physiology / Endocrinology / Estrogen / Estrogens / Estrous cycle / Estrous Cycle - physiology / Estrus cycle / Extinction (Learning) / Extinction behavior / Extinction, Psychological - physiology / Fear - physiology / Fear conditioning / Fear extinction / Fear renewal / Female / Females / Gender differences / Hormones / Human Physiology / Immunohistochemistry / Laboratory animals / Male / Males / Neostriatum / Neurons / Ovariectomy / Ovaries / Penicillin G / Phenols / Rats / Rats, Long-Evans / Sex Characteristics / Sexes / Spontaneous recovery / Substantia nigra / Substantia Nigra - metabolism / Substantia Nigra - physiology