Estrogen Receptors and the Regulation of Neural Stress Responses

Handa, Robert J.; Mani, Shaila K.; Uht, Rosalie Maire

doi:10.1159/000338397

Cited by 53 publications

(39 citation statements)

References 199 publications

(98 reference statements)

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“…In the rat, PVN neuronal populations are distributed in a spatially specific manner, however, in other species, like mice and humans, this distribution is not as well‐defined. Of importance for this study, the PVN houses an abundant number of neurons that express ERβ, leading us to hypothesize that ERβ may play a key role in the regulation of the HPA axis at this level (Handa, Mani, & Uht, ).…”

Section: Discussionmentioning

confidence: 99%

Distribution and chemical composition of estrogen receptor β neurons in the paraventricular nucleus of the female and male mouse hypothalamus

Oyola

Thompson

Handa

2017

J of Comparative Neurology

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Activation of estrogen receptor beta (ERβ)-expressing neurons regulates the mammalian stress response via the hypothalamic–pituitary–adrenal (HPA) axis. These neurons densely populate the paraventricular nucleus of the hypothalamus (PVN). Recent research has revealed striking differences between rat and mouse PVN cytochemistry, but careful exploration of PVN ERβ neurons in mice has been hindered by a lack of specific ERβ antisera. Therefore, we used male and female transgenic mice expressing EGFP under the control of the mouse ERβ promoter (ERβ-EGFP) to examine the chemical architecture of PVN ERβ cells. Using immunohistochemistry, we found that 90% of ERβ-immunoreactivity (-ir) colocalized with EGFP. Cellular colocalization of EGFP with neuropeptides, transcription modulators, and neuronal tracers was examined throughout the PVN. ERβ-EGFP cells expressed oxytocin more abundantly in the rostral (71 ± 3%) than caudal (33 ± 8%) PVN. Arginine vasopressin colocalized with EGFP more often in females (18 ± 3%) than males (4 ± 1%). Moreover, estrogen receptor α-ir colocalized with ERβ-EGFP at low levels (15 ± 3%). Using a corticotropin releasing hormone-cre driver X tdTomato reporter mouse, we found a moderate colocalization with ERβ-ir (48 ± 16%) in the middle PVN. Peripheral injection of fluorogold revealed that the rostral PVN ERβ-EGFP cells are neuroendocrine neurons whereas non-neuroendocrine (presumably pre-autonomic) ERβ-EGFP neurons predominated in the posterior PVN. These data demonstrate chemoarchitectural differences in ERβ neurons of the mouse PVN that are different from that previously described for the rat, thus, elucidating potential neuronal pathways involved in the regulation of the HPA axis in mice.

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Section: Discussionmentioning

confidence: 99%

Distribution and chemical composition of estrogen receptor β neurons in the paraventricular nucleus of the female and male mouse hypothalamus

Oyola

Thompson

Handa

2017

J of Comparative Neurology

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“…Its anti-inflammatory effect may even attenuate atherogenesis . ERb has also been implicated in brain function and aging (Foster 2012, Handa et al 2012. It was shown to have anxiolytic and antidepressant effects, which may be useful in affective disorders (Hughes et al 2008).…”

Section: Discussionmentioning

confidence: 99%

Targeting estrogen receptor subtypes (ERα and ERβ) with selective ER modulators in ovarian cancer

Chan

Leung

Chan

et al. 2014

Journal of Endocrinology

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Ovarian cancer cells express both estrogen receptor a (ERa) and ERb, and hormonal therapy is an attractive treatment option because of its relatively few side effects. However, estrogen was previously shown to have opposite effects in tumors expressing ERa compared with ERb, indicating that the two receptor subtypes may have opposing effects. This may explain the modest response to nonselective estrogen inhibition in clinical practice. In this study, we aimed to investigate the effect of selectively targeting each ER subtype on ovarian cancer growth. Ovarian cancer cell lines SKOV3 and OV2008, expressing both ER subtypes, were treated with highly selective ER modulators. These results were confirmed on a xenograft model where SKOV3 cells were injected s.c. into ovariectomized mice. We observed that the average size of xenografts in both the DPN-treated group and the MPP-treated group was significantly smaller than that for the vehicle-treated group. In addition, we found that phospho-AKT expressions in SKOV3 cells were reduced by 80% after treatment with MPP and DPN, indicating that the AKT pathway was involved. The combined treatment with MPP and DPN had a synergistic effect in suppressing ovarian cancer cell growth. Our findings indicate that targeting ER subtypes may enhance the response to hormonal treatment in women with ovarian cancer.

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“…Peripherally derived steroid hormones are lipophilic and readily cross the blood brain barrier where they can act at the genomic level via steroid receptors to modify neuronal activity and ultimately animal behavior (Cunningham et al 2012; Graham and Clarke 1997; Handa et al 2012). Whist genomic changes are slow to implement (minutes to hours); progesterone and other peripheral steroids can have rapid effects on neuronal excitability following their metabolism in the brain to neurosteroids (Bitran et al 1993; Mellon and Griffin 2002; Paul and Purdy 1992).…”

Section: Introductionmentioning

confidence: 99%

The role of ovarian hormone-derived neurosteroids on the regulation of GABAA receptors in affective disorders

MacKenzie

Maguire

2014

Psychopharmacology

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Rationale Neuroactive derivatives of steroid hormones, neurosteroids, can act on GABAA receptors (GABAARs) to potentiate the effects of GABA on these receptors. Neurosteroids become elevated to physiologically relevant levels under conditions characterized by increased steroid hormones. There is considerable evidence for plasticity of GABAARs associated with altered levels of neurosteroids which may counteract the fluctuations in the levels of these allosteric modulators. Objectives The objective of this review is to summarize the current literature on GABAAR plasticity under conditions characterized by alterations in neurosteroid levels, such as over the estrous cycle, during puberty, and throughout pregnancy and the postpartum period. Results The expression of specific GABAAR subunits are altered over the estrous cycle, at puberty, and throughout pregnancy and the postpartum period. Inability to regulate δ subunit-containing GABAARs throughout pregnancy and the postpartum period is associated with depression-like behavior restricted to the postpartum period. Conclusions GABAAR plasticity associated with alterations in neurosteroid levels represents a homeostatic compensatory mechanism to maintain an ideal level of inhibition to offset the potentiating effects of neurosteroids on GABAergic inhibition. Failure to properly regulate GABAARs under conditions of altered neurosteroid levels may increase vulnerability to mood disorders, such as premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD), and postpartum depression.

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Estrogen Receptors and the Regulation of Neural Stress Responses

Cited by 53 publications

References 199 publications

Distribution and chemical composition of estrogen receptor β neurons in the paraventricular nucleus of the female and male mouse hypothalamus

Distribution and chemical composition of estrogen receptor β neurons in the paraventricular nucleus of the female and male mouse hypothalamus

Targeting estrogen receptor subtypes (ERα and ERβ) with selective ER modulators in ovarian cancer

The role of ovarian hormone-derived neurosteroids on the regulation of GABAA receptors in affective disorders

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