Brain-derived estrogen and neural function

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Although classically known as an endocrine signal produced by the ovary, 17β-estradiol (E2) is also a neurosteroid produced in neurons and astrocytes in the brain of many different species. In this review, we provide a comprehensive overview of the localization, regulation, sex differences, and physiological/pathological roles of brain-derived E2 (BDE2). Much of what we know regarding the functional roles of BDE2 has come from studies using specific inhibitors of the E2 synthesis enzyme, aromatase, as well as the recent development of conditional forebrain neuron-specific and astrocyte-specific aromatase knockout mouse models. The evidence from these studies supports a critical role for neuron-derived E2 (NDE2) in the regulation of synaptic plasticity, memory, socio-sexual behavior, sexual differentiation, reproduction, injury-induced reactive gliosis, and neuroprotection. Furthermore, we review evidence that astrocyte-derived E2 (ADE2) is induced following brain injury/ischemia, and plays a key role in reactive gliosis, neuroprotection, and cognitive preservation. Finally, we conclude by discussing the key controversies and challenges in this area, as well as potential future directions for the field.

1. Introduction

Aromatase is a cytochrome P450 enzyme that drives the conversion of androgen precursors into estrogens (Fig. 1) (Blakemore and Naftolin, 2016; Simpson et al., 2002). The aromatase-driven catalysis process involves hydroxylation of androgen precursors using three molecules each of NADPH and oxygen to produce one molecule of estrogen (Ryan, 1959). Aromatase is encoded by a single gene, CYP19, which is located on the 21.2 regions of chromosome 15 in humans (Simpson et al., 2002). This gene is 123 kb in length and is expressed in many tissues, including the gonads, bone, breast, adipose, vascular tissue, skin, placenta, and brain (Stocco, 2012). Tissue-specific transcripts of aromatase are produced from the alternative use of several first exons that are promoter-specific (Fig. 2) (Bulun et al., 2004; Simpson et al., 1993). Splicing of the untranslated first exons into the coding exons 2 through 10 produces multiple different aromatase transcripts; however, all of the transcripts code for the same protein. Exon 1.f has classically been considered to be the brain-specific variant. However, ovarian-specific exon PII and adipose-specific exons 1.3 and 1.4 are also expressed in the brain of rodents and humans (Prange-Kiel et al., 2016; Yague et al., 2006). It should be mentioned that teleost fish are unique in that they have two aromatase isoforms, CYP19a which encodes aromatase A, and CYP19b, which encodes aromatase B (Tchoudakova and Callard, 1998). CYP19a is expressed in the gonads, while CYP19b is expressed in both the brain and gonads. Although these two genes are structurally different, they have similar catalytic activities and over 20 different regulatory sites in the promoter, including response elements for sex steroid receptors, and several transcription factors that regulate neurogenesis (Piferrer and Blazquez, 2005).

Estrogens, the product of aromatase activation, are steroid hormones that can act upon estrogen receptors in tissues throughout the body and brain. The most potent and most studied estrogen is 17β-estradiol (E2), while the other estrogens, estrone (E1) and estriol (E3), are considered weak estrogens. E2 has been implicated in the regulation of many diverse physiological and pathological processes, including reproduction, sexual differentiation, and behavior, cancer biology, bone physiology, synaptic plasticity, cognitive function, anti-inflammatory actions, and neuroprotection (Azcoitia et al., 2018; Boon et al., 2010; Brann et al., 2007; Brocca and Garcia-Segura, 2019; Cortez et al., 2010; Dhandapani and Brann, 2003; Emmanuelle et al., 2021; Khan et al., 2013; Kramar et al., 2013; Saldanha, 2020; Vegeto et al., 2008). While the role of gonadal-derived E2 has been studied extensively, the roles and functions of brain-derived E2 (BDE2) have received less attention and have only recently begun to be fully appreciated. Hence, this review will focus on the localization, regulation, and functions of BDE2 in the brain. Much of the work in this area has been conducted in rodents and the songbird. However, where available, we will present and discuss findings in other species including humans and non-human primates. Much of what we know about the roles and functions of BDE2 in the brain has come from studies using pharmacological aromatase inhibitors (see Fig. 3). However, since both neurons and astrocytes can produce E2, using such a cell non-specific pharmacological approach provides challenges in determining the specific role of neuron-derived E2 (NDE2) versus astrocyte-derived E2 (ADE2) in the brain. Whole-body global aromatase knockout mice support a role for E2 in anti-inflammation, synaptic plasticity and cognition, and neuroprotection from neurodegenerative disorders (Simpson et al., 2002). However, these studies are poorly suited to distinguish the role and specific contributions of brain-derived versus gonadal-derived aromatase/E2 to these effects. Recent work by our group (Lu et al., 2019, 2020; Wang et al., 2020) using brain cell-specific aromatase knockout animal models has helped address this issue and give important insights into the respective roles and functions of NDE2 versus ADE2 in the brain in both physiological and pathological states. We will review this emerging work, as well as discuss existing controversies, and potential future directions for the advancement of knowledge in this important area.

2. Aromatase localization in the brain
2.1. Human
2.2. Non-human primate
2.3. Rat
2.4. Mouse
2.5. Bird
2.6. Fish, amphibians, and reptiles

3. Aromatase regulation in the brain
Aromatase and BDE2 levels in the brain can be regulated by both transcriptional and post-transcriptional mechanisms, as well as a diverse array of intrinsic and extrinsic factors (Fig. 4). In this section, we will review these key mechanisms and factors that control aromatase expression/activity and E2 production in the brain

3.1. Phosphorylation
3.2. Glutamate
3.3. Transcriptional regulation
3.4. Gonadectomy and sex differences
3.5. Hormones
3.6. Aging, diet, metabolism, and obesity
3.7. Environmental pollutants
3.8. Drugs
3.9. Brain injury and inflammation

4. Role of brain aromatase and BDE2 in sexual differentiation, reproduction, and socio-sexual behavior
The above studies demonstrated aromatase localization and BDE2 production in many brain regions in multiple species, and showed regulation occurs by multiple processes and factors, often in a tissue- or cell-specific manner. In the following sections, we will review and discuss the evidence supporting multiple important functional roles implicated for BDE2 in the brain.

4.1. Regulation of sexual differentiation
4.2. Regulation of reproduction
4.3. Regulation of socio-sexual behavior

5. Role of brain aromatase and BDE2 in synaptic plasticity and cognitive function
5.1. Synaptic plasticity
5.2. Cognitive function

6. Role of brain aromatase and BDE2 in neuroprotection
6.1. Aromatase inhibitor and knockdown studies
6.2. Conditional knockout studies - role of NDE2 in neuroprotection
6.3. Conditional knockout studies - role of ADE2 in neuroprotection

7. Future directions and conclusions
Despite the remarkable progress described above in elucidating BDE2 functions in the brain, there remain many unanswered questions that require further studies. Below, we have summarized key questions and future directions that could help advance this important research area and provide clarity to areas where controversy currently exists.

7.1. Development of new animal models
7.2. Sex differences
7.3. Additional clinical studies
7.4. Microglial regulation

In conclusion, the findings described in this review provide substantial evidence of aromatase expression and local E2 production in many different brain areas of almost all species studied to date. E2 is produced in neurons basally, while production in astrocytes is induced by stress, brain injury, or ischemia. A strength of this body of work is that many different techniques were used in studying the localization of aromatase and E2 production in the brain, and many different approaches were used to confirm the roles of BDE2 in the brain, including aromatase inhibitor and knockdown studies, as well as global aromatase and brain cell-specific aromatase knockout animal models. A role for NDE2 is implicated in a diverse spectrum of functions in the brain, including regulation of sexual differentiation, reproduction, sociosexual behavior, synaptic plasticity, LTP, memory and cognition, auditory processing, injury-induced reactive gliosis and astrocyte phenotype, neuroprotection, and anti-inflammatory effects. Following its induction after brain injury or ischemia, ADE2 has been implicated in the regulation of reactive gliosis, astrocyte phenotype, neuroprotection, cognitive preservation, and anti-inflammatory effects. Collectively, these findings demonstrate a critical role for BDE2 in many different brain functions in both physiological and pathological conditions.


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Fig. 1. Simplified Biosynthetic Pathway for Estrogens. Estrogen synthesis begins with the conversion of cholesterol to pregnenolone in mitochondria. Through a series of steps, pregnenolone is converted into androstenedione, which is converted into testosterone and estrone (E1). Testosterone is then converted into 17β-estradiol (E2) through the action of aromatase (CYP19A). As also shown, CYP19A can be inhibited by various aromatase inhibitors for research purposes and for therapies. Chemical structures were generated from the ChemSpider webpage (http://www.chems
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Fig. 2. Partial Aromatase Gene Structure. Tissue-specific promoters in untranslated first exons are responsible for tissue-specific transcripts of aromatase. Promoter 1.f is typically considered the brain-specific promoter; however, promoters 1.3 and 1.4 have also been reported to be expressed in the brain
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Fig. 3. Primary aromatase inhibitors are used to inhibit aromatase activity in the brain in animals and humans. Chemical structures were generated from the ChemSpider webpage (ChemSpider | Search and share chemistry).
Screenshot (9368).png


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Fig. 4. Summary diagram illustrating multiple processes and factors that have been implicated to regulate brain aromatase. See text for full description and discussion. BDE2 = brain-derived 17β-estradiol. Created with
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Fig. 5. Schematic illustration of the potential mechanisms underlying neuron-derived E2 (NDE2) regulation of synaptic plasticity. It is proposed that neuron-derived E2 (NDE2) regulates synaptic plasticity via both rapid and genomic signaling mechanisms. 1) Membrane localized estrogen receptors (estrogen receptorα and β, ERα and ERβ, and G-protein coupled estrogen receptor-1, GPER1) can bind NDE2 and 2) the receptor-bound NDE2 then induces rapid PI3K/AKT and MEK/ERK kinase signaling, which is capable of quickly shaping synaptic plasticity. In addition, the activated intracellular kinase signaling also phosphorylates the important transcriptional factor, CREB which further translocates into the nucleus to facilitate the expressions of neurotrophic factor BDNF and synaptic protein PSD95. BDNF can also regulate synaptic plasticity by coupling to the rapid intracellular kinases. Moreover, BDNF signaling activates cofilin which is required for F-actin assembly and dendritic spine formation. Intracellular ERα and ERβ act in the genomic signaling pathway by transactivating estrogen response elements (ERE) in regulated genes and promoting genes transcription. CRE = cAMP response element.
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Fig. 6. Cognitive functions regulated by neuron-derived E2 (NDE2) and the commonly used behavioral tests for rodent studies. Neuron-derived E2 (NDE2) is critical for hippocampus-dependent spatial reference memory, which is often tested using the Barnes Maze test. Hippocampus-dependent recognition memory is another important cognitive function that is regulated by NDE2 and which can be assessed using the Novel Object Recognition Test (NORT). In addition, NDE2 was also demonstrated to regulate contextual, but not cued fear memory, which can be evaluated using Fearing Conditioning Test. Finally, NDE2 is essential to prevent depressive-like behavior in female mice, which can be tested with the Forced Swimming Test.
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Fig. 7. Proposed mechanisms underlying neuron-derived E2 (NDE2) neuroprotection in the ischemic brain. See text for full description. FBN-ARO-KO: forebrain neuron-specific aromatase knockout.
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Fig. 8. Proposed mechanisms underlying astrocyte-derived E2 (ADE2) neuroprotection in the ischemic brain. See text for full description. GFAP-ARO-KO: astrocyte-specific aromatase knockout
Screenshot (9374).png
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