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Roles and Functions of Brain-Derived Estrogen
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Roles and Functions of Brain-Derived Estrogen

A special issue of Biology (ISSN 2079-7737). This special issue belongs to the section "Neuroscience".

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 15572

Special Issue Editor

Dr. Yujiao Lu

E-Mail Website
Guest Editor
Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
Interests: brain-derived estrogen; dementia; neuron-glia interaction; neuroprotection

Special Issue Information

Dear Colleagues, 

Estrogen is an essential steroid hormone that targets the central nervous system. The neuromodulatory actions of estrogen in the brain have been widely documented, including reproduction, parental behaviors, neuroplasticity and cognition, as well as neuroprotection. Estrogen can be released by many endocrine organs, while ovary was traditionally believed to be the main source.

However, in past decades the key enzyme for estrogen synthesis, aromatase, was further observed in brain across species, making the belief that brain is another important organ that can locally produce estrogen (neuroestrogen). It was shown that aromatase activity is almost exclusively detected in neurons of various brain regions of both sexes in physiological state, producing an estrogen concentration even higher than that in circulation. Moreover, the neuronal aromatase is specifically localized at synapses and presynaptic terminals, leading to the hypothesis that de novo-synthesized neuroestrogen may act as a neurotransmitter or neuromodulator—a completely distinct functioning manner from ovarian estrogen. Aromatase expression is also strongly induced in activated astrocytes in aging and injured brains, making reactive astrocytes another critical source of brain estrogen production.

Understanding the unique functions of neuron- and astrocyte-derived estrogen across different brain regions in both sexes will be of high clinical value in future neurological disease therapy.

This Special Issue will focus on studies investigating the distribution of estrogen synthesis enzymes, aromatase in the brain, the distribution and functions of estrogen receptors, the roles of neuron- and astrocyte-derived estrogen, and neuron–glia interaction following brain-derived estrogen alterations in aging, acute brain injury and neurodegenerative diseases from both clinical and pre-clinical animal research. We cordially invite you to submit your work to this Special Issue. Both original research articles and reviews are welcomed.

I look forward to receiving your contributions.

Dr. Yujiao Lu
Guest Editor

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Keywords

  • neuron-derived estrogen
  • astrocyte-derived estrogen
  • 17β-estradiol
  • aromatase
  • neuroprotection
  • neuroinflammation
  • synaptic plasticity
  • memory

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Published Papers (5 papers)

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Research

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18 pages, 13166 KiB  
Article
Brain-Derived Estrogen Regulates Neurogenesis, Learning and Memory with Aging in Female Rats
by Yuanyuan Huang, Wuxiang Sun, Fujia Gao, Haoran Ma, Tao Yuan, Zixuan Liu, Huiyu Liu, Jiewei Hu, Jing Bai, Xin Zhang and Ruimin Wang
Biology 2023, 12(6), 760; https://doi.org/10.3390/biology12060760 - 23 May 2023
Cited by 5 | Viewed by 2620
Abstract
Although 17β-estradiol (E2) can be locally synthesized in the brain, whether and how brain-derived E2 (BDE2) impacts neurogenesis with aging is largely unclear. In this study, we examined the hippocampal neural stem cells, neurogenesis, and gliogenesis of 1, 3, 6, 14, and 18-month [...] Read more.
Although 17β-estradiol (E2) can be locally synthesized in the brain, whether and how brain-derived E2 (BDE2) impacts neurogenesis with aging is largely unclear. In this study, we examined the hippocampal neural stem cells, neurogenesis, and gliogenesis of 1, 3, 6, 14, and 18-month (Mon) female rats. Female forebrain neuronal aromatase knockout (FBN-ARO-KO) rats and letrozole-treated rats were also employed. We demonstraed that (1) the number of neural stem cells declined over 14-Mon age, and the differentiation of astrocytes and microglia markedly elevated and exhibited excessive activation. KO rats showed declines in astrocyte A2 subtype and elevation in A1 subtype at 18 Mon; (2) neurogenesis sharply dropped from 1-Mon age; (3) KO suppressed dentate gyrus (DG) neurogenesis at 1, 6 and 18 Mon. Additionally, KO and letrozole treatment led to declined neurogenesis at 1-Mon age, compared to age-matched WT controls; (4) FBN-ARO-KO inhibited CREB-BDNF activation, and decreased protein levels of neurofilament, spinophilin and PSD95. Notably, hippocampal-dependent spatial learning and memory was impaired in juvenile (1 Mon) and adulthood (6 Mon) KO rats. Taken together, we demonstrated that BDE2 plays a pivotal role for hippocampal neurogenesis, as well as learning and memory during female aging, especially in juvenile and middle age. Full article
(This article belongs to the Special Issue Roles and Functions of Brain-Derived Estrogen)
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17 pages, 4659 KiB  
Article
Both Nuclear and Membrane Estrogen Receptor Alpha Impact the Expression of Estrogen Receptors and Plasticity Markers in the Mouse Hypothalamus and Hippocampus
by Sanoara Mazid, Elizabeth M. Waters, Chloe Lopez-Lee, Renata Poultan Kamakura, Batsheva R. Rubin, Ellis R. Levin, Bruce S. McEwen and Teresa A. Milner
Biology 2023, 12(4), 632; https://doi.org/10.3390/biology12040632 - 21 Apr 2023
Cited by 5 | Viewed by 2494
Abstract
Estrogens via estrogen receptor alpha (ERα) genomic and nongenomic signaling can influence plasticity processes in numerous brain regions. Using mice that express nuclear only ERα (NOER) or membrane only ERα (MOER), this study examined the effect of receptor compartmentalization on the paraventricular nucleus [...] Read more.
Estrogens via estrogen receptor alpha (ERα) genomic and nongenomic signaling can influence plasticity processes in numerous brain regions. Using mice that express nuclear only ERα (NOER) or membrane only ERα (MOER), this study examined the effect of receptor compartmentalization on the paraventricular nucleus of the hypothalamus (PVN) and the hippocampus. The absence of nuclear and membrane ERα expression impacted females but not males in these two brain areas. In the PVN, quantitative immunohistochemistry showed that the absence of nuclear ERα increased nuclear ERβ. Moreover, in the hippocampus CA1, immuno-electron microscopy revealed that the absence of either nuclear or membrane ERα decreased extranuclear ERα and pTrkB in synapses. In contrast, in the dentate gyrus, the absence of nuclear ERα increased pTrkB in synapses, whereas the absence of membrane ERα decreased pTrkB in axons. However, the absence of membrane only ERα decreased the sprouting of mossy fibers in CA3 as reflected by changes in zinc transporter immunolabeling. Altogether these findings support the idea that both membrane and nuclear ERα contribute overlapping and unique actions of estrogen that are tissue- and cellular-specific. Full article
(This article belongs to the Special Issue Roles and Functions of Brain-Derived Estrogen)
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Graphical abstract

17 pages, 4782 KiB  
Article
Effects of Ventromedial Hypothalamic Nucleus (VMN) Aromatase Gene Knockdown on VMN Glycogen Metabolism and Glucoregulatory Neurotransmission
by Karen P. Briski, A. S. M. Hasan Mahmood, Md. Main Uddin, Mostafa M. H. Ibrahim and Khaggeswar Bheemanapally
Biology 2023, 12(2), 242; https://doi.org/10.3390/biology12020242 - 3 Feb 2023
Cited by 2 | Viewed by 2570
Abstract
The enzyme aromatase is expressed at high levels in the ventromedial hypothalamic nucleus (VMN), a principal component of the brain gluco-regulatory network. Current research utilized selective gene knockdown tools to investigate the premise that VMN neuroestradiol controls glucostasis. Intra-VMN aromatase siRNA administration decreased [...] Read more.
The enzyme aromatase is expressed at high levels in the ventromedial hypothalamic nucleus (VMN), a principal component of the brain gluco-regulatory network. Current research utilized selective gene knockdown tools to investigate the premise that VMN neuroestradiol controls glucostasis. Intra-VMN aromatase siRNA administration decreased baseline aromatase protein expression and tissue estradiol concentrations and either reversed or attenuated the hypoglycemic regulation of these profiles in a VMN segment-specific manner. Aromatase gene repression down-regulated protein biomarkers for gluco-stimulatory (nitric oxide; NO) and -inhibitory (gamma-aminobutyric acid; GABA) neurochemical transmitters. Insulin-induced hypoglycemia (IIH) up- or down-regulated neuronal nitric oxide synthase (nNOS) and glutamate decarboxylase65/67 (GAD), respectively, throughout the VMN. Interestingly, IIH caused divergent changes in tissue aromatase and estradiol levels in rostral (diminished) versus middle and caudal (elevated) VMN. Aromatase knockdown prevented hypoglycemic nNOS augmentation in VMN middle and caudal segments, but abolished the GAD inhibitory response to IIH throughout this nucleus. VMN nitrergic and GABAergic neurons monitor stimulus-specific glycogen breakdown. Here, glycogen synthase (GS) and phosphorylase brain- (GPbb; AMP-sensitive) and muscle- (GPmm; noradrenergic –responsive) type isoform responses to aromatase siRNA were evaluated. Aromatase repression reduced GPbb and GPmm content in euglycemic controls and prevented hypoglycemic regulation of GPmm but not GPbb expression while reversing glycogen accumulation. Aromatase siRNA elevated baseline glucagon and corticosterone secretion and abolished hypoglycemic hyperglucagonemia and hypercorticosteronemia. Outcomes document the involvement of VMN neuroestradiol signaling in brain control of glucose homeostasis. Aromatase regulation of VMN gluco-regulatory signaling of hypoglycemia-associated energy imbalance may entail, in part, control of GP variant-mediated glycogen disassembly. Full article
(This article belongs to the Special Issue Roles and Functions of Brain-Derived Estrogen)
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16 pages, 3764 KiB  
Article
Anti-Inflammatory Actions of G-Protein-Coupled Estrogen Receptor 1 (GPER) and Brain-Derived Estrogen Following Cerebral Ischemia in Ovariectomized Rats
by Jing Xu, Jing Bai, Fujia Gao, Chao Xu, Yuanyuan Huang, Danyang Li, Lu Wang and Ruimin Wang
Biology 2023, 12(1), 99; https://doi.org/10.3390/biology12010099 - 9 Jan 2023
Cited by 2 | Viewed by 2265
Abstract
Global cerebral ischemia can elicit rapid innate neuroprotective mechanisms that protect against delayed neuronal death. Brain-derived 17β-estradiol (BDE2), an endogenous neuroprotectant, is synthesized from testosterone by the enzyme aromatase (Aro) and is upregulated by brain ischemia and inflammation. Our recent study revealed that [...] Read more.
Global cerebral ischemia can elicit rapid innate neuroprotective mechanisms that protect against delayed neuronal death. Brain-derived 17β-estradiol (BDE2), an endogenous neuroprotectant, is synthesized from testosterone by the enzyme aromatase (Aro) and is upregulated by brain ischemia and inflammation. Our recent study revealed that G1, a specific G-protein-coupled estrogen receptor 1 (GPER) agonist, exerts anti-inflammatory and anti-apoptotic roles after global cerebral ischemia (GCI). Herein, we aimed to elucidate whether G1 modulates the early inflammatory process and the potential underlying mechanisms in the ovariectomized rat hippocampal CA1 region. G1 was found to markedly reduce pro-inflammatory (iNOS, MHCII, and CD68) and to enhance anti-inflammatory (CD206, Arginase 1, IL1RA, PPARγ, and BDNF) markers after 1 and 3 days of reperfusion after GCI. Intriguingly, the neuroprotection of G1 was blocked by the Aro inhibitor, letrozole. Conversely, the GPER antagonist, G36, inhibited Aro-BDE2 signaling and exacerbated neuronal damage. As a whole, this work demonstrates a novel anti-inflammatory role of GPER, involving a synergistic mediation with BDE2 during the early stage of GCI. Full article
(This article belongs to the Special Issue Roles and Functions of Brain-Derived Estrogen)
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Review

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10 pages, 1023 KiB  
Review
Brain-Derived Estrogen and Neurological Disorders
by Darrell W. Brann, Yujiao Lu, Jing Wang, Gangadhara R. Sareddy, Uday P. Pratap, Quanguang Zhang, Rajeshwar R. Tekmal and Ratna K. Vadlamudi
Biology 2022, 11(12), 1698; https://doi.org/10.3390/biology11121698 - 24 Nov 2022
Cited by 7 | Viewed by 4815
Abstract
Astrocytes and neurons in the male and female brains produce the neurosteroid brain-derived 17β-estradiol (BDE2) from androgen precursors. In this review, we discuss evidence that suggest BDE2 has a role in a number of neurological conditions, such as focal and [...] Read more.
Astrocytes and neurons in the male and female brains produce the neurosteroid brain-derived 17β-estradiol (BDE2) from androgen precursors. In this review, we discuss evidence that suggest BDE2 has a role in a number of neurological conditions, such as focal and global cerebral ischemia, traumatic brain injury, excitotoxicity, epilepsy, Alzheimer’s disease, and Parkinson’s disease. Much of what we have learned about BDE2 in neurological disorders has come from use of aromatase inhibitors and global aromatase knockout mice. Recently, our group developed astrocyte- and neuron-specific aromatase knockout mice, which have helped to clarify the precise functions of astrocyte-derived 17β-estradiol (ADE2) and neuron-derived 17β-estradiol (NDE2) in the brain. The available evidence to date suggests a primarily beneficial role of BDE2 in facilitating neuroprotection, synaptic and cognitive preservation, regulation of reactive astrocyte and microglia activation, and anti-inflammatory effects. Most of these beneficial effects appear to be due to ADE2, which is induced in most neurological disorders, but there is also recent evidence that NDE2 exerts similar beneficial effects. Furthermore, in certain situations, BDE2 may also have deleterious effects, as recent evidence suggests its overproduction in epilepsy contributes to seizure induction. In this review, we examine the current state of this quickly developing topic, as well as possible future studies that may be required to provide continuing growth in the field. Full article
(This article belongs to the Special Issue Roles and Functions of Brain-Derived Estrogen)
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