GPER-Deficient Rats Exhibit Lower Serum Corticosterone Level and Increased Anxiety-Like Behavior

Zheng, Yi; Wu, Mei‐Mei; Gao, Ting; Meng, Li; Ding, Xiaowei; Meng, Youqiang; Jiao, Yingfu; Luo, Ping; He, Zhenquan; Sun, Tao; Zhang, Guohua; Shi, Xueyin; Rong, Weifang

doi:10.1155/2020/8866187

Cited by 24 publications

(20 citation statements)

References 47 publications

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“…Furthermore, we found that the distribution of GPER immunofluorescence in various tissues using LS-A4272 was consistent with GPER mRNA expression (Zheng, et al, 2020).…”

Section: Acute Mechanical Itch (Alloknesis)supporting

confidence: 71%

“…This pilot data suggests that GPER signaling may be important in itch regulation. To further investigate the role of GPER signaling in acute and chronic itch, we utilized the GPER-knockout (GPER -/-) rats (Luo, et al, 2017;Zheng et al, 2020) and mice. It is worth mentioning here that during daily handling or the acclimatization period before behavior tests, spontaneous scratches were similarly rare in GPER -/rats and mice as in their WT counterparts (Fig.…”

Section: Gper Deficiency Results In Hypersensitivity To Itch In Mice ...mentioning

confidence: 99%

“…Gper-Cre mice (female, 10 weeks old), GPER -/mice (male and female, 8-10 weeks old), GPER -/rats (male and female, 10-12 weeks old) and their age and gender-matched WT controls were used for experiments. Gper-Cre mice were generated in Model Organisms Inc (Shanghai) by knocking the 2A-Cre gene fragment into the Gper gene stop codon based on CRISPR/Cas9 system and has been validated through GPER RNAscope in situ hybridization (Zheng et al, 2020). GPER -/rats and mice were both constructed in BIORAY laboratories Inc (Shanghai).…”

Section: Animalsmentioning

confidence: 99%

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G-Protein-Coupled Estrogen Receptor (GPER) in the Rostral Ventromedial Medulla Is Essential for Mobilizing Descending Inhibition of Itch

et al. 2021

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Chronic itch is a troublesome condition and often difficult to cure. Emerging evidence suggests that the periaqueductal gray-rostral ventromedial medulla (PAG-RVM) pathway may play an important role in regulation of itch, but the cellular organization and molecular mechanisms remain incompletely understood. Here, we report that a group of RVM neurons distinctively express the G protein-coupled estrogen receptor (GPER), which mediates descending inhibition of itch. We found that GPER + neurons in RVM were activated in chronic itch conditions in rats and mice. Selective ablation or chemogenetic suppression of RVM GPER + neurons resulted in mechanical alloknesis and increased scratching in response to pruritogens, whereas chemogenetic activation of GPER + neurons abrogated itch responses, indicating that GPER + neurons are antipruritic. Moreover, GPER-deficient mice and rats of either sex exhibited hypersensitivity to mechanical and chemical itch, a phenotype reversible by μ type opioid receptor (MOR) antagonism. Additionally, significant MOR phosphorylation in the RVM was detected in chronic itch models in wild-type but not in GPER -/rats. Therefore, GPER not only identifies a population of medullary antipruritic neurons but may also determine the descending antipruritic tone through regulating μ-opioid signaling.4 Significance Statement (120 words maximum) Therapeutic options for itch are limited due to as yet incomplete understanding of the mechanisms of itch processing. Our data have provided novel insights into the cellular organization and molecular mechanisms of descending regulation of itch in normal and pathological conditions: GPER + neurons (largely GABAergic) in the RVM are anti-pruritic neurons under tonic opioidergic inhibition; activation of GPER promotes phosphorylation of MOR and dis-inhibition of the anti-pruritic GPER + neurons from inhibitory opioidergic inputs; failure to mobilize GPER + neurons may result in exacerbation of itch. Our data also illuminate on some of the outstanding questions in the field, such as the mechanisms underlying sex bias in itch, pain and opioid analgesia and the paradoxical effects of morphine on pain and itch.

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“…Furthermore, we found that the distribution of GPER immunofluorescence in various tissues using LS-A4272 was consistent with GPER mRNA expression (Zheng, et al, 2020).…”

Section: Acute Mechanical Itch (Alloknesis)supporting

confidence: 71%

Section: Gper Deficiency Results In Hypersensitivity To Itch In Mice ...mentioning

confidence: 99%

Section: Animalsmentioning

confidence: 99%

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G-Protein-Coupled Estrogen Receptor (GPER) in the Rostral Ventromedial Medulla Is Essential for Mobilizing Descending Inhibition of Itch

et al. 2021

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“…A study reported increased GPER levels in GAD, which further correlated with the anxiety severity in patients irrespective of gender [ 191 ]. In rodents, GPER-deficient rats showed anxiety-like behaviors, as well as low corticosterone [ 192 ]. Interestingly, reports show ERβ signaling has anxiolytic effects [ 193 ], and in mice, ERβ deficiency has been associated with social and mood-related behavioral disturbances via the oxytocin and arginine-vasopressin signaling pathways [ 194 ].…”

Section: Estrogen Receptor and Psychiatric Disordersmentioning

confidence: 99%

The Role of Estrogen Receptors and Their Signaling across Psychiatric Disorders

Hwang

Lee

Kim

et al. 2020

IJMS

109

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Increasing evidence suggests estrogen and estrogen signaling pathway disturbances across psychiatric disorders. Estrogens are not only crucial in sexual maturation and reproduction but are also highly involved in a wide range of brain functions, such as cognition, memory, neurodevelopment, and neuroplasticity. To add more, the recent findings of its neuroprotective and anti-inflammatory effects have grown interested in investigating its potential therapeutic use to psychiatric disorders. In this review, we analyze the emerging literature on estrogen receptors and psychiatric disorders in cellular, preclinical, and clinical studies. Specifically, we discuss the contribution of estrogen receptor and estrogen signaling to cognition and neuroprotection via mediating multiple neural systems, such as dopaminergic, serotonergic, and glutamatergic systems. Then, we assess their disruptions and their potential implications for pathophysiologies in psychiatric disorders. Further, in this review, current treatment strategies involving estrogen and estrogen signaling are evaluated to suggest a future direction in identifying novel treatment strategies in psychiatric disorders.

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“…Our results are in contrast to the study of Trejter et al ( 2015 ) who described that ERα is the highest expressed. It is important to point out that they circumscribed their study to the adrenal cortex, not considering the adrenal medulla, which was demonstrated to be a relevant region of GPER localization (Hazell et al, 2009 ; Zheng et al, 2020 ). The specific role of GPER in adrenal glands is not yet fully understood but it seems that GPER-deficient rats showed a decreased corticosterone basal serum level in both sexes and an increased adrenaline basal serum level in females (Zheng et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Organizational Effects of Estrogens and Androgens on Estrogen and Androgen Receptor Expression in Pituitary and Adrenal Glands in Adult Male and Female Rats

et al. 2022

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Sex steroid hormones, such as androgens and estrogens, are known to exert organizational action at perinatal periods and activational effects during adulthood on the brain and peripheral tissues. These organizational effects are essential for the establishment of biological axes responsible for regulating behaviors, such as reproduction, stress, and emotional responses. Estradiol (E2), testosterone, and their metabolites exert their biological action through genomic and non-genomic mechanisms, bounding to canonical receptors, such as estrogen receptor (ER)α, ERβ, and androgen receptor (AR) or membrane receptors, such as the G protein-coupled estrogen receptor (GPER), respectively. Expression of ERs and AR was found to be different between males and females both in the brain and peripheral tissues, suggesting a sex-dependent regulation of their expression and function. Therefore, studying the ERs and AR distribution and expression levels is key to understand the central and peripheral role of sex steroids in the establishment of sex-specific behaviors in males and females. We investigated the organizational effects of estrogens and androgens in the pituitary and adrenal glands of adult male and female rats. For this, selective blockade of AR with flutamide or 5α-reductase with finasteride or aromatase with letrozole during the first 5 days of life has been performed in male and female pups and then quantification of ERs and AR expression in both glands has been carried out in adulthood. Data show that inhibition of dihydrotestosterone (DHT) and E2 production during the first five postnatal days mainly decreases the ER expression in male to female values and AR expression in female to male levels in the pituitary gland and increases AR expression in female to male levels in the adrenal gland. In contrast, blocking the action of androgens differentially modulates the ERs in males and females and decreases AR in both males and females in both glands. Altogether, the results suggest that neonatal modifications of the androgen and estrogen pathways can potentially lead to permanent modifications of the neuroendocrine functions of the pituitary and adrenal glands in the adulthood of both sexes.

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GPER-Deficient Rats Exhibit Lower Serum Corticosterone Level and Increased Anxiety-Like Behavior

Cited by 24 publications

References 47 publications

G-Protein-Coupled Estrogen Receptor (GPER) in the Rostral Ventromedial Medulla Is Essential for Mobilizing Descending Inhibition of Itch

G-Protein-Coupled Estrogen Receptor (GPER) in the Rostral Ventromedial Medulla Is Essential for Mobilizing Descending Inhibition of Itch

The Role of Estrogen Receptors and Their Signaling across Psychiatric Disorders

Organizational Effects of Estrogens and Androgens on Estrogen and Androgen Receptor Expression in Pituitary and Adrenal Glands in Adult Male and Female Rats

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