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Published in final edited form as: Horm Behav. 2012 Mar 5;63(2):208–215. doi: 10.1016/j.yhbeh.2012.02.026

Traumatized and Inflamed - but resilient: glial aromatization and the avian brain

Kelli A Duncan a, Bradley J Walters b, Colin J Saldanha c,d
PMCID: PMC9366899  NIHMSID: NIHMS363169  PMID: 22414444

Abstract

Steroids like estrogens have potent effects on the vertebrate brain, and are provided to neural targets from peripheral and central sources. Estradiol synthesized within the vertebrate CNS modulates neural structure and function, including the pathways involved in neuroprotection, and perhaps, neural repair. Specifically, aromatase; the enzyme responsible for the conversion of testosterone to estradiol, is upregulated in the avian and mammalian brain following disruption of the neuropil by multiple forms of perturbation including mechanical injury, ischemia and excitotoxicity. This injury induced aromatase expression is somewhat unique in that it occurs in astroglia rather than neurons, and is stimulated in response to factors associated with brain damage. In this review, we focus on the induction, expression and consequences of glial aromatization in the songbird brain. We begin with a review of the anatomical consequences of glial estrogen provision followed by a discussion of the cellular mechanisms whereby glial aromatization may affect injury-induced neuroplasticity. We then present the current status of our understanding regarding the inductive role of inflammatory processes in the transcription and translation of astrocytic aromatase. We consider the functional aspects of glial aromatization before concluding with unanswered questions and suggestions for future studies. Birds have long informed us about fundamental questions in endocrinology, immunology, and neuroplasticity; and their unique anatomical and physiological characteristics continue to provide an excellent system in which to learn about brain trauma, inflammation, and neuroprotection.

Keywords: Avian, Aromatase, Neuroprotection, Injury

I. Introduction

Circulating steroids, particularly estrogens, are neuroprotective (Maggi et al., 2004; McEwen et al., 2001; Wise, 2003). The literature is rife with examples of decreases in markers of cell death, and lower susceptibility to actual neural damage in the presence of high circulating estrogens in several species (Belcredito et al., 2001; Bryant et al., 2006; Roselli, 2007; Simpkins and Dykens, 2008; Simpkins et al., 2005). Presumably, these circulating estrogens are a reflection of aromatization at one or more peripheral sites including, but not limited to, the ovaries, testes, adrenals, placenta, and adipose tissue (Simpson et al., 1994; Vanselow et al., 1999). However, the past decade or so has witnessed an impressive surge in our knowledge about the neuroprotective role of estrogens synthesized within the vertebrate brain itself.

The mammalian and avian brain is a site of estrogen synthesis via the discrete and constitutive expression of aromatase, in neurons (Balthazart et al., 1990; Naftolin et al., 1996; Negri-Cesi et al., 2001; Peterson et al., 2005; Saldanha et al., 2000). Songbirds such as the zebra finch (Taeniopygia guttata), distinguish themselves from other homeotherms in that aromatase is particularly abundant and widespread in the brains of this species, detectable via multiple technologies including enzyme activity (Schlinger and Arnold, 1991, 1992), in situ hybridization (Saldanha et al., 1998; Schlinger et al., 1994; Shen et al., 1995; Soma et al., 2003), and immunocytochemistry (Peterson et al., 2005; Saldanha et al., 2000). Aromatization, however, is neither exclusively neuronal nor constitutive in the songbird brain. In this review, we present a burgeoning literature on the induction, regulation, and consequences of aromatase expression in astroglia following various forms of central perturbation in songbird brain. Here, astrocytes and radial glia are defined as vimentin-positive macroglial cells with either stellate or linear morphology, including Bergmann glia in the cerebellum (Sild and Ruthazer, 2011), while microglia are smaller, ramified, macrophages that do not express the intermediate filament protein, vimentin (Saijo and Glass, 2011). The induction of glial aromatase in the zebra finch brain is quite striking (Fig 1) and occurs only in astrocytes and radial glia, but not microglia (Lee et al., 2007). The robust nature of this aromatase induction in songbirds has allowed us to ask and answer fundamental questions regarding the consequences of glial aromatization and the mechanisms responsible for its induction.

Figure 1.

Figure 1

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Aromatase expression in the zebra finch brain. Constitutive neuronal (left) and induced glial (right) aromatase-positive cells in the zebra finch brain.

II. Injury Induced Glial Aromatase

Disruption of the songbird and rodent neuropil results in a robust and reliable induction of aromatase transcription and translation in non-neuronal cells; a phenomenon first described in vitro (Schlinger et al., 1994) and subsequently confirmed in vivo (Garcia-Segura et al., 1999; Peterson et al., 2001; 2004; Saldanha et al., 2005; Wynne and Saldanha, 2004; Wynne et al., 2008b). This up-regulation occurs in astroglia (astrocytes and radial glia) localized either around the site of mechanical damage (Peterson et al., 2004; Peterson et al., 2001; Wynne and Saldanha, 2004; Wynne et al., 2008b) or in brain areas particularly vulnerable to excitotoxic injury (Azcoitia et al., 2001).

In the songbird, aromatase induction in astroglia can occur at multiple loci, independent of whether these brain areas are capable or incapable of constitutive aromatization (Peterson et al., 2001; Duncan & Saldanha, 2011). More specifically, the cerebellum and entopallium, areas of the zebra finch brain with extremely low or undetectable constitutive aromatase expression, are both capable of expressing glial aromatase following injury (Mirzatoni et al., 2010; Peterson et al., 2001; Wynne and Saldanha, 2004). Glial aromatase is also induced in areas rich in constitutive neuronal aromatase expression such as the hippocampus and caudomedial nidopallium (Peterson et al., 2004; Remage-Healey et al., 2008). Taken together, these data suggest that constitutive aromatase expression is not a prerequisite for, or a deterrent of, the induction of glial aromatase (Duncan and Saldanha, 2011; Mirzatoni et al., 2010; Spence et al., 2009; Wynne and Saldanha, 2004) suggesting the possibility that the regulatory mechanisms involved in glial aromatase expression may be distinct from those associated with constitutive aromatization.

Regardless of inductive mechanism (discussed later in this review), the up-regulation of glial aromatase following perturbation of the songbird brain presumably results in local elevations of estrogens such as 17β-estradiol (E2), as is well established for areas rich in neuronal aromatase in the songbird brain (Charlier et al., 2011; Charlier et al., 2010; Chao et al., 2011). This locally elevated E2 may be available to act upon multiple neuroprotective and/or neuro-reparative pathways. While the precise mechanism by which local estrogen synthesis promotes neuroprotection and neuronal survival has not been fully elucidated, numerous mediators of estrogenic neuroprotection have been characterized using various models of neurodegeneration. In brief, these mechanisms include actions on; second messenger cascades (Mannella and Brinton, 2006; Quesada et al., 2008), mitochondrial function (Simpkins and Dykens, 2008;Simpkins et al., 2005; Green et al., 2000; Prokai and Simpkins, 2007), neurotrophic factors (Buchanan et al., 2000; Fernandez-Galaz et al., 1997; McCarthy et al., 2002;Quesada and Micevych, 2004), apoptotic genes (D'Astous et al., 2006; Lisztwan et al., 2008; Singer et al., 1998), and inflammatory pathways (Arevalo et al., 2012, Cerciat et al., 2010). In this review, we will restrict our discussions to the aromatase-induced neuroprotective mechanisms identified in the songbird brain.

III. Glial aromatase, apoptosis, and secondary degeneration following injury

A key mechanism underlying neuroprotection is the regulation of anti- and pro-apoptotic genes. Upregulated aromatase appears to affect neurodegenerative pathways via an inhibition of apoptotic secondary degeneration. In the songbird brain, as in the mammalian brain (Azcoitia et al., 2001), central administration of the aromatase inhibitor, fadrozole, dramatically increases the volume of damage in the adult male zebra finch brain (Wynne and Saldanha, 2004) and replacement with estradiol prevents the exacerbation of damage by aromatase inhibition (Saldanha et al., 2005). Upregulated aromatase also decreases the number of cells undergoing apoptosis 72 hours post-primary insult (Saldanha et al., 2005; Wynne and Saldanha, 2004). These data suggest that local estradiol provision may limit the amount of delayed cell death, thereby reducing injury. This finding is in excellent agreement with the observed increase in apoptosis in aromatase knockout mice (Hill et al., 2009).

Indeed, the role of glial aromatization in decreasing the spread of apoptosis from the site of primary damage is strikingly robust in the songbird brain. Wynne et al., (2008b) treated adult male zebra finches with injections of either fadrozole or saline in contralateral telencephalic lobes and assessed the extent of degeneration as measured by the marker Fluoro-Jade B at various times post-injury from 2 hr to 6 weeks. While the halo of degeneration was restricted and statistically invariant across the time points in the lobe injected with saline, the hemisphere treated with fadrozole demonstrated a marked degeneration peaks between 24 and 72hr post surgery. Both the incidence and temporal pattern of this wave of secondary degeneration is in agreement with the patterns of cell death reported following various forms of neural insult to the mammalian brain (Carswell et al., 2005; Chen and Swanson, 2003; Garcia-Ovejero et al., 2005; Pekny and Nilsson, 2005; Sato et al., 2001; Wise et al., 2005). Although it is difficult to directly compare across experimental protocols, treatments, and dependent measures, the data suggest that the up-regulation of aromatase in the songbird brain is robust enough to completely dampen the wave of secondary degeneration that is diagnostic of severe brain trauma in humans and other mammals. However, the striking lack of a wave of secondary degeneration in the zebra finch brain suggests a profound influence of glial aromatization in this species as opposed to mammals and may be a reflection of the dramatic neuroplasticity within the songbird brain. This influence may involve additional mechanisms of neuroplasticity including neurogenesis and cell migration.

IV. Glial aromatase, neurogenesis, and migration following injury

Neurogenesis

In recent years, the literature on the neurogenic effects of estrogens has exploded (reviewed in Barha and Galea, 2010; Mazzucco et al., 2006). It is well established that there are two primary neurogenic niches in the mammalian brain, the subgranular zone (SGZ) of the hippocampal (HP) dentate gyrus (DG) and the subventricular zone (SVZ) of the lateral ventricles (Alvarez-Buylla and Lim, 2004; Goldman and Chen, 2011; Ming and Song, 2011; Taupin, 2006). In non-mammals, which ostensibly lack a DG, the bulk of neurogenesis takes place at the ventricular zone (VZ) from whence newly formed neurons migrate dorsally and radially to populate various regions throughout the cerebrum (Barker et al., 2011). It is only recently that investigators have begun to test the ability of estrogens to promote subventricular (or ventricular) neurogenesis (Brock et al., 2010; Li et al., 2011; Mirzatoni et al., 2010; Suzuki et al., 2007; Veyrac and Bakker, 2011; Walters et al., 2011).

Despite the pronounced ability of estrogens to promote neurogenesis in the DG, several studies have suggested that neither physiological nor supra-physiological doses of E2 increase baseline adult neurogenesis in the VZ/SVZ of birds or mammals (Brock et al., 2010; Mirzatoni et al., 2010; Veyrac and Bakker, 2011). However, recent evidence suggests that estrogens can influence VZ/SVZ neurogenesis in birds and mammals, but only in the context of injury (Li et al., 2011; Suzuki et al., 2007; Walters et al., 2011). These findings suggest that while estrogen signaling does not appear to play a role in baseline SVZ neurogenesis, it may be necessary for SVZ neurogenesis typical of cerebral insult, and may even further enhance neurogenesis in an injured brain.

In the zebra finch brain, injury-induced cytogenesis in the dorsal VZ is significantly decreased after ovariectomy or systemic aromatase inhibition (Peterson et al 2007; Lee et al 2007), while exogenous E2 administration enhances VZ neurogenesis when it is paired with a penetrating brain injury (Walters et al. 2011). These findings confirm that estrogen signaling can contribute to VZ neurogenesis, particularly after injury. The precise mechanism underlying this influence is unclear, but it is possible that brain trauma may increase the susceptibility of VZ cells to estrogenic signaling. While this hypothesis awaits testing, the data demonstrate a dynamic interplay among damage, estrogenic signaling, and neurogenesis; and suggest that local E2 synthesis and signaling could perhaps be manipulated to promote therapeutic regeneration.

Cell Migration

The migration and incorporation of new neurons into pre-existing, damaged, and/or new circuits is a critical aspect brain trauma and repair. This is particularly important in the context of brain injury where it is hoped that neurogenesis can contribute to the recovery of motor and/or cognitive functions after damage. Radial glia have long been studied as important scaffolds of neuronal migration during development (Hatten and Heintz, 1995;Rosen et al., 1994); and their potential role in restorative processes following neural injury has been intensely studied in animals as diverse as lizards (Romero-Aleman et al., 2004) and rodents (Yang et al., 1997). Additionally, E2 signaling has been implicated in neuronal migration during development (Wang et al., 2003) and in adult neurogenesis (Williams et al., 1999). Thus, aromatase expression in radial glia may be key in processes of neuronal migration towards the restoration of brain structure and function following brain damage. While several studies have demonstrated the constitutive expression of aromatase in radial glia in teleost fish (Diotel et al., 2011; Forlano et al., 2001; Pellegrini et al., 2007; Tong et al., 2009), such a pattern of expression is not seen in mammals, but is revealed by injury in the songbird brain.

In the zebra finch brain, radial glia upregulate aromatase in response to injuries near the VZ (Peterson et al., 2004) and the numbers of aromatase positive glia and BrdU positive cells are highly correlated, with numbers of both decreasing as a function of distance from the injury site (Peterson et al., 2007). Additionally, mitotic cells aggregate around, possibly contact, and appear to migrate along injury-induced aromatase expressing radial glia (Peterson et al. 2004; Peterson et al. 2007). These findings suggest that injury induced aromatization may play a role in the migration of new neurons to sites of damage, however much more work is needed to determine what proportion of newly generated cells become neurons, how many of these cells, if any, migrate or incorporate into sites of damage, and whether or not any causal relationship underlies the correlations of these cells with aromatase positive radial glia.

V. What can a naturally plastic brain teach us about brain damage and repair?

The aforementioned effects of local, induced aromatization on neurogenesis and cell migration are rapid, dramatic, and sustained in the songbird brain. It is likely that the reliable nature of this induction may be a superimposition of two distinct, yet related phenomena. The songbird has long been an excellent model for the study of natural neuroplasticity (Nottebohm, 2004; Saldanha and Schlinger, 2008; Schlinger and Saldanha, 2005). Although the specific mechanisms may differ, natural mechanisms of neuroplasticity and plasticity revealed by artificial insult may be related via the underlying cellular mechanisms of neural reorganization regarding E2 provisions.

We propose that the ability to upregulate glial aromatase following injury is related to natural mechanisms of neuroplasticity. Following injury, we posit that the brain reactivates E2-mediated developmental pathways as mechanisms for use during neural recovery and repair. Schlinger & Saldanha (2005), among others (Goodson et al., 2005) have suggested that the songbird brain is capable of maintaining physiological processes characteristic of a developing and young CNS long into adulthood. In support of this hypothesis, we have found that brain injury results in the upregulation of gene products with an established role in neural development and in cellular proliferation and survival. Specifically, mechanical damage results in a robust increase in bone morphogenetic proteins (BMPs) in the songbird brain (Walters & Saldanha, 2008).

BMP2 as a potential mediator of the actions of local aromatase in the injured brain

Bone morphogenetic protein 2 (BMP2) has been implicated in many processes that overlap with estrogenic effects in the injured brain, namely synaptic plasticity, neurite growth and branching, neuronal survival, neuroinflammation, neurogenesis, and astrogliogenesis (Colak et al., 2008; Espejo et al., 1999; Fukui et al., 2003; Gratacos et al., 2001a; Gratacos et al., 2001b; Hattori et al., 1999; Hori et al., 2006; Reiriz et al., 1999; Rifas, 2006; Rosendahl et al., 2002; Shou et al., 2000; Sun et al., 2007; Uemura et al., 2002; Xin et al., 2006; Yanagisawa et al., 2001a; Yanagisawa et al., 2001b). Using penetrating brain injuries in zebra finches, we have shown previously that BMP2 expression is increased in response to insult and can be decreased, at least in part by the inhibition of local aromatase at the site of injury (Walters and Saldanha, 2008). Much like the response of aromatase to brain injury, immunostaining suggests that upregulation of BMP2 is predominant immediately around sites of damage at both 3 and 7 days following injury, (Fig 2) which is consistent with similar patterns of staining seen with an antibody against BMP2/4 following brain injury in mice (Hampton et al., 2007). Interestingly, while constitutive BMP2 expression appears to be almost exclusively neuronal (Sato et al., 2010), injury induced BMP2 expression appears to be glial, again mirroring the patterns of injury-induced aromatase. One exception, however, is that aromatase is produced in astroglia in response to injury (Garcia-Segura et al., 1999;Peterson et al., 2001) while BMP2 appears to be produced by macrosialin-positive microglia (Fig 2).

Figure 2.

Figure 2

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BMP2 expression following injury in the zebra finch brain. Injury induced (INJ) BMP2 expression in the adult zebra finch brain is non-neuronal. A) Western blots of telencephalic tissue homogenate from adult zebra finches reveal a ~50 kDa band that is consistent with the predicted molecular weight of zebra finch BMP2, when stained using an anti-BMP2 antibody (Abnova clone 1A11). B) INJ BMP2 positive cells (green) around the site of injury (dashed line) do not co-localize with the neuron specific proteins HuC/HuD (red) when examined at either 3 or 7 days after injury. However, INJ BMP2 is expressed in microglial-like cells in the adult zebra finch brain. C) BMP2 positive cells co-express the microglia/macrophage specific protein macrosialin (CD68). BMP2 positive cells (green) in other parts of the zebra finch brain, including the diencephalon (Dienc) are not co-labeled by the CD68 antibody (red). Constitutive BMP2 expression is primarily neuronal, as typified by immunostaining in the Entopallium (Ento) where BMP2 co-express the neuronal proteins HuC/HuD (stained using the mouse anti HuC/HuD antibody, clone 16A11, from Invitrogen). Macrosialin was immunostained using the rat anti-CD68 antibody (clone FA- 11) from AbD Serotec.

These correlations with injury induced aromatase expression, the demonstrated effect of local aromatase inhibition on BMP2 expression after brain injury (Walters & Saldanha, 2008), and the previously demonstrated effects of BMP2 on mammalian neuronal survival (Espejo et al., 1999; Hattori et al., 1999; Shou et al., 2000; Xin et al., 2006) led us to wonder whether (or not) BMP2 might affect neuroprotective effects of glial aromatization. To test this, we injected agarose beads coated with the BMP-inhibitor noggin directly into cerebral injury sites in adult zebra finches, while injecting contralateral injury sites with beads coated in BSA only. Noggin treated injuries had a significantly higher lesion volume than vehicle treated injuries suggesting that BMPs are neuroprotective following brain injury (Fig. 3). Together, these findings suggest that BMP2 is responsive to local injury-induced aromatization and is likely neuroprotective, though more work is needed to determine how much the differences in lesion volume are due to neuronal survival and whether or not this effect is due to BMP2 specifically, as noggin can also inhibit BMP4 and to a lesser extent BMP7, both of which are expressed in the adult finch brain (Walters and Saldanha, 2008).

Figure 3.

Figure 3

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Antagonism of BMP signaling around cerebral injury in the adult zebra finch brain results in increased lesion volume. (A) Affi-Gel Blue agarose beads (Bio-rad) were soaked in the BMP antagonist noggin (0.5 mg/mL of 10% BSA) and injected into the cerebrum of adult zebra finches. (B) Contralateral hemispheres were injected with Afii-Gel Blue beads that were soaked in 10% bovine serum albumin (BSA) only. Rabbit anti-phospho Smad 1/5/8 staining (Millipore AB3848) demonstrates an area devoid of BMP signaling activity around the primary insult (A) while no such absence of pSmad 1/5/8 staining was seen in BSA treated controls (B). Treatment of injured hemispheres with noggin resulted in greater lesion volume than in hemispheres treated with BSA only when examined 72 hrs. after injury (C). *p = 0.035, Mann-Whitney test.

It is of critical importance to consider the mechanisms responsible for the induction of BMP2 and aromatase around sites of injury in the songbird brain. In the songbird, we have made some progress in answering the latter interaction. Specifically, we have begun asking what mechanisms associated with mechanical injury may be responsible for the transcription and translation of aromatase in reactive glia.

VI. Neuroinflammation regulates injury induced glial aromatase

Initially, it was thought that the upregulation of aromatase in glial cells was due to alterations in splicing or promoter activity between the neuronal and glial populations. However, qPCR analysis of multiple exons of the known aromatase transcripts and sequencing of the injury induced and constitutive CNS transcripts confirmed that neural aromatase does differ from the aromatase expressed in the ovary (Ramachandran et al., 1999), but revealed no difference between the injury-induced aromatase transcript and the constitutively expressed neuronal transcript in the adult zebra finch brain (Wynne et al., 2008a). These data suggest that expression of glial aromatase is due to either the activation of an alternative promoter or enhancer, or the release of inhibition by other regulatory elements in the non-coding sequence or by RNA interference, thus giving rise to a transcript that is identical in sequence to the form that is constitutively expressed in neurons (Le Page et al., 2008; Saldanha et al., 2009; Wynne et al., 2008a).

The hypothesis that an alternate promoter may be responsible for the induction of glial aromatase led us to identify factors associated with neurotrauma that are also known to activate aromatase promoters. Cytokines, a major class of signals up-regulated by traumatic brain injury regulate aromatase gene expression via alternate promoters in normal and malignant breast tissue (Purohit et al., 1995; Purohit et al., 2005; Reed et al., 1993; Singh et al., 1997) and microinjections of cytokines into a rat stab wound significantly increase gliosis (Ghirnikar et al., 1998). We therefore reasoned, that cytokine expression may be associated with the up-regulation of glial aromatase in the songbird brain. Using a model that induces cytokine expression without inducing cell death, we were able to ascertain a potential role for cytokines in mediating glial aromatase expression. Briefly, we unilaterally exposed the neuropil to either phytohemagglutinin, a plant lectin, or saline without creating any damage to the tissue (Duncan and Saldanha, 2011). Phytohemagglutinin stimulates T lymphocytes to release cytokines, and many avian researchers have used phytohemagglutinin to study immunocompetence (Vinkler et al., 2010). Exposure of the brain to the phytohemagglutinin increased expression of astrocytic glial aromatase 24 hours following surgery as detected by both qPCR and immunohistochemistry (Fig 4). The lack of evident damage was confirmed by the lack of detectable apoptosis in either brain hemisphere 24hr post treatment. The induction of glial aromatase, however, was treatment specific, as vehicle treated contralateral hemispheres did not show an increase in aromatase expression. These data suggest that glial aromatase is more strongly associated with immune factors and less with cell death. As cell death is a naturally occurring phenomenon in the songbird brain, large numbers of cells die in the song circuit of seasonal breeders during the fall and winter (Nottebohm, 2004; Goodson et al., 2005; Schlinger & Saldanha, 2005). Nonetheless, glial aromatase has never been observed in the uninjured songbird brain, suggesting that cell death is not sufficient to elicit glial aromatase expression in the same manner as neuroinflammation. It is important to acknowledge that while inflammation is sufficient to induce aromatase in glia, we have yet to test the necessity of either inflammation or cell death in this process.

Figure 4.

Figure 4

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Neuroinflammation induces glial aromatase in the uninjured brain. A) Photomicrographs illustrating the induction of aromatase positive glial cells following with PHA induced neuroinflammatory treatment or saline. B) Photomicrograph of PHA-induced cells at a higher magnification. C) Aromatase mRNA expression following PHA treatment, analyzed using qPCR. D) Similar to aromatase positive cells following injury, PHA induced glial cells (red) also co-localize with Vimentin (green); arrow heads denote areas of co-localization. Images modified from Duncan & Saldanha, 2011. * denotes a significant difference between treatment.

What factor of neuroinflammation induces glial cells is unknown in the zebra finch brain, yet the pro-inflammatory cytokine, Interleukin -6, induces astrogliosis (Woiciechowsky et al., 2004) and has been shown to increase expression of aromatase in breast cancer cells, making it a strong candidate (Bulun et al., 2007; Bulun and Simpson, 2008). Future studies will aim to identify a cytokine specific promoter of aromatase in the avian brain. Finally, it is possible that inflammatory processes may be critical not only as inducers of glial aromatase, but also as cellular targets of glial estrogen provision. While this area of study is relatively novel, the field has seen considerable progress in understanding the role of glial aromatization on other neuroanatomical and physiological consequences of glial estrogen provision.

VI. Behavioral effects of glial aromatase following injury in the songbird brain

To the best of our knowledge, a single study has attempted to test the role of injury induced aromatase and estrogen provision on behavior in any vertebrate. Spence et al., (2009) created small lesions within the cerebellum of adult female zebra finches while blocking synthesis of estrogens with or without estrogen replacement around the lesion site (Spence et al., 2009). Birds were tested on a spatial memory task as well as a motor task. Although no effects on motor function were detected, estrogen provision via injury induced astrocytes and Bergmann glia appeared to lessen the errors made on a spatial memory task testing (Spence et al., 2009). As previously stated, aromatase is only detectable in the songbird cerebellum following damage (Mirzatoni et al., 2010) strongly supporting the hypothesis that the behavioral effects observed above were due to glial aromatase and not constitutive estrogen provision. Depending on the area examined there are sex differences in response to glial aromatase. When examining expression in the cerebellum, females upregulate more aromatase than males (Mirzatoni et al., 2010) however when examined in the entopallium it appears that females produce less glial aromatase (unpublished data). This discrepancy in the results is enticing and suggests an exciting line of future research.

IV. Conclusions and Future Directions

The past decade has shown a widening of our knowledge of the roles that hormones play in mediating injury in the songbird brain. Earlier studies suggest that variations in aromatase expression may influence natural cycles of cytogenesis and cell death (Metzdorf et al., 1999; Soma et al., 2004). Indeed, several research groups have proposed that the dramatic seasonal plasticity of the songbird brain may be, in part, a reflection of variations in constitutive central aromatization (Saldanha et al., 2009;Saldanha & Schlinger, 2008; Saldanha et al., 1998). Superimposed upon these characteristics, we are now beginning to understand a pluripotent role for glial aromatization following brain injury in the songbird; one that involves a mitigating effect on secondary, apoptotic cell death, and an acceleration of potentially restorative effect on neurogenesis (Lee et al., 2007; Peterson et al., 2004; Walters et al., 2011; Walters and Saldanha, 2008; Wynne and Saldanha, 2004). While much has been identified, the need remains for further exploration. 1) The response of glial aromatase following injury in other songbirds has yet to be determined, leaving us bereft of any information on what role, if any, seasonality has on the glial aromatase response to injury or inflammation in the songbird brain. 2) While the expression of aromatase is clear, the concentrations of locally produced estrogens that act upon cells immediately around the injury site is unknown. Finally, selective estrogen receptor modulators and other estrogenic products significantly decrease expression of proinflammatory cytokines (Arevalo et al., 2012,Cerciat et al., 2010. Thus, 3) the role of injury induced estrogen production on neuroinflammation in the avian brain, remains unknown, and a possible site for a novel neuroimmune/neuroendocrine regulation of neuroprotection.

Highlights.

  • Following injury aromatase is upregulated in astroglia in the brain.

  • This review examines how the avian brain responds to injury.

  • The avian brain provides a model for the study of estrogen mediated neuroprotection.

Acknowledgements

This work was supported by National Institutes of Health RO1NS042767 (CJS), a Supplement to NS042767 (KAD) and the American Heart Association (09PRE2010168 BJW).

Footnotes

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Contributor Information

Kelli A. Duncan, Email: keduncan@vassar.edu.

Bradley J. Walters, Email: Bradley.Walters@stjude.org.

Colin J. Saldanha, Email: saldanha@american.edu.

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