Estrogen Receptors Modulation of Anxiety-Like Behavior

Borrow, Amanda P.; Handa, Robert J.

doi:10.1016/bs.vh.2016.08.004

Cited by 121 publications

(79 citation statements)

References 112 publications

(153 reference statements)

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“…Studies of estradiol administration to ovariectomized rats and ESR1 null mice have shown consistent evidence that ESR1 is involved in anxiety-like behavior in non-human animals. 40 Our finding of an association between ESR1 and anxiety may have implications for our understanding of sex differences in anxiety disorders, which generally show about a 2:1 female predominance, and greater susceptibility to develop PTSD following traumatic events. 41 Although this increased susceptibility is partially explained by sex-specific exposure to certain kinds of traumatic events, there may also be differential biological context provided in part by the role of the estrogen receptor.…”

Section: Discussionmentioning

confidence: 82%

Reproducible Risk Loci and Psychiatric Comorbidities in Anxiety: Results from ~200,000 Million Veteran Program Participants

Levey

Gelernter

Polimanti

et al. 2019

Preprint

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We used GWAS in the Million Veteran Program sample (nearly 200,000 informative individuals) using a continuous trait for anxiety (GAD-2) to identify 5 genome-wide significant (GWS) signals for European Americans (EA) and 1 for African Americans. The strongest findings were on chromosome 3 (rs4603973, p=7.40×10−11) near the SATB1 locus, a global regulator of gene expression and on chromosome 6 (rs6557168, p=1.04×10−9) near ESR1 which encodes estrogen receptor α. A locus identified on chromosome 7 near MADIL1 (p=1.62×10−8) has been previously identified in GWAS of bipolar disorder and of schizophrenia and may represent a risk factor for psychiatric disorders broadly. SNP-based heritability was estimated to be ~6% for GAD-2. We also GWASed for self-reported anxiety disorder diagnoses (N=224,330) and identified two GWS loci, one (rs35546597, MAF=0.42, p=1.88×10−8) near the AURKB locus, and the other (rsl0534613, MAF=0.41, p=4.92×10−8) near the IQCHE and MADIL1 locus identified in the GAD-2 analysis. We demonstrate reproducibility by replicating our top findings in the summary statistics from the Anxiety NeuroGenetics Study (ANGST) and a UK Biobank neuroticism GWAS. We also replicated top findings from a large UK Biobank preprint, demonstrating stability of GWAS findings in complex traits once sufficient power is attained. Finally, we found evidence of significant genetic overlap between anxiety and major depression using polygenic risk scores, but also found that the main anxiety signals are independent of those for MDD. This work presents novel insights into the neurobiological risk underpinning anxiety and related psychiatric disorders.SignificanceAnxiety disorders are common and often disabling. They are also frequently co-morbid with other mental disorders such as major depressive disorder (MDD); these disorders may share commonalities in their underlying genetic architecture. Using one of the largest homogenously phenotyped cohorts available, the Million Veteran Program sample, we investigated common variants associated with anxiety in genome-wide association studies (GWASes), using survey results from the GAD-2 anxiety scale (as a continuous trait, n=199,611), and self-reported anxiety disorder diagnosis (as a binary trait, n=224,330). This largest GWAS to date for anxiety and related traits identified numerous novel significant associations, several of which are replicated in other datasets, and allows inference of underlying biology.

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Section: Discussionmentioning

confidence: 82%

Reproducible Risk Loci and Psychiatric Comorbidities in Anxiety: Results from ~200,000 Million Veteran Program Participants

Levey

Gelernter

Polimanti

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…Numerous studies indicate that perinatal testosterone exposure induces lasting effects on anxiety behaviors and the HPA axis (Bingham, Wang, Innala, & Viau, ; Seale, Wood, Atkinson, Harbuz, & Lightman, ; Seale, Wood, Atkinson, Lightman, & Harbuz, ; Zuloaga et al, ). Furthermore, adult testosterone and estrogens dynamically regulate anxiety‐ and depressive‐like behaviors as well as glucocorticoid release via actions at their cognate receptors (Borrow & Handa, ; Lund, Hinds, & Handa, ; Lund, Rovis, Chung, & Handa, ; Weiser & Handa, ).…”

Section: Introductionmentioning

confidence: 99%

Characterization and gonadal hormone regulation of a sexually dimorphic corticotropin‐releasing factor receptor 1 cell group

Rosinger

Jacobskind

Bulanchuk

et al. 2018

J of Comparative Neurology

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Corticotropin‐releasing factor binds with high affinity to CRF receptor 1 (CRFR1) and is implicated in stress‐related mood disorders such as anxiety and depression. Using a validated CRFR1‐green fluorescent protein (GFP) reporter mouse, our laboratory recently discovered a nucleus of CRFR1 expressing cells that is prominent in the female rostral anteroventral periventricular nucleus (AVPV/PeN), but largely absent in males. This sex difference is present in the early postnatal period and remains dimorphic into adulthood. The present investigation sought to characterize the chemical composition and gonadal hormone regulation of these sexually dimorphic CRFR1 cells using immunohistochemical procedures. We report that CRFR1‐GFP‐ir cells within the female AVPV/PeN are largely distinct from other dimorphic cell populations (kisspeptin, tyrosine hydroxylase). However, CRFR1‐GFP‐ir cells within the AVPV/PeN highly co‐express estrogen receptor alpha as well as glucocorticoid receptor. A single injection of testosterone propionate or estradiol benzoate on the day of birth completely eliminates the AVPV/PeN sex difference, whereas adult gonadectomy has no effect on CRFR1‐GFP cell number. These results indicate that the AVPV/PeN CRFR1 is regulated by perinatal but not adult gonadal hormones. Finally, female AVPV/PeN CRFR1‐GFP‐ir cells are activated following an acute 30‐min restraint stress, as assessed by co‐localization of CRFR1‐GFP cells with phosphorylated (p) CREB. CRFR1‐GFP/pCREB cells were largely absent in the male AVPV/PeN. Together, these data indicate a stress and gonadal hormone responsive nucleus that is unique to females and may contribute to sex‐specific stress responses.

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“…There are two classical ERs found in the brain -ERα and ERβ (Hara et al, 2015). Although both are important for cognitive function (Hara et al, 2015), binding to each receptor subtype has different effects on behavior (Borrow and Handa, 2017). ERα is associated with anxiogenesis, because its knockdown via ShRNA produced a decrease in anxiety (Spiteri et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Adolescent rats show estrous cycle-mediated sex-differences in extinction of conditioned fear

Perry

Ganella

Nguyen

et al. 2020

Preprint

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Anxiety disorders are more prevalent in females than males, and frequently emerge during adolescence. Despite this, preclinical research commonly focuses on adult males. Here we use Pavlovian fear conditioning and extinction in adolescent male and female rats to understand sexand age-dependent processes relevant to anxiety disorders. In experiment 1, 35-day-old male and female rats were exposed to 6 pairings of a conditioned stimulus (CS, a tone) with an aversive unconditioned stimulus (US, a footshock). The next day they were extinguished in a contextually distinct chamber, via 60 presentations of the CS without the US. Extinction recall was tested 24 hours later in the extinction context. Estrous phase was monitored by cytology on vaginal smears taken 1 hour after each behavioral session. In experiment 2, male and female rats were given sham surgery or gonadectomy at 21 days of age. They were then trained and tested as for experiment 1.We observed that females in proestrus or met/diestrus during extinction showed delayed extinction and impaired extinction recall the next day compared to males. Ovariectomy enhanced extinction for female rats, but orchidectomy delayed extinction for males. Plasma analyses showed that met/di/proestrus phases were associated with high estradiol levels. These findings suggest that high plasma estradiol levels impair extinction for adolescent females. While these results contradict what is observed in adult animals, they are consistent with the prevalence of anxiety disorders observed in females. Our findings have important implications for understanding and treating anxiety in adolescents, particularly where treatment involves extinction-based therapies.

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Estrogen Receptors Modulation of Anxiety-Like Behavior

Cited by 121 publications

References 112 publications

Reproducible Risk Loci and Psychiatric Comorbidities in Anxiety: Results from ~200,000 Million Veteran Program Participants

Reproducible Risk Loci and Psychiatric Comorbidities in Anxiety: Results from ~200,000 Million Veteran Program Participants

Characterization and gonadal hormone regulation of a sexually dimorphic corticotropin‐releasing factor receptor 1 cell group

Adolescent rats show estrous cycle-mediated sex-differences in extinction of conditioned fear

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