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date: 23 August 2017

Steroids and Plasticity

Summary and Keywords

Given the profound influence of steroids on the organization and activation of the vertebrate central nervous system (CNS), it is perhaps not surprising that these molecules are involved in processes that restructure the cytoarchitecture of the brain. This includes processes such as neurogenesis and the connectivity of neural circuits. In the last 30 years or so, we have learned that the adult vertebrate brain is far from static; it responds to changes in androgens and estrogens, with dramatic alterations in structure and function. Some of these changes have been directly linked to behavior, including sex, social dominance, communication, and memory. Perhaps the most dramatic levels of neuroplasticity are observed in teleosts, where circulating and centrally derived steroids can affect several end points, including cell proliferation, migration, and behavior. Similarly, in passerine songbirds and mammals, testosterone and estradiol are important modulators of adult neuroplasticity, with documented effects on areas of the brain necessary for complex behaviors, including social communication, reproduction, and learning. Given that many of the cellular processes that underlie neuroplasticity are often energetically demanding and temporally protracted, it is somewhat surprising that steroids can affect physiological and behavioral end points quite rapidly. This includes recent demonstrations of extremely rapid effects of estradiol on synaptic neurotransmission and behavior in songbirds and mammals. Indeed, we are only beginning to appreciate the role of temporally and spatially constrained neurosteroidogenesis, like estradiol and testosterone being made in the brain, on the rapid regulation of complex behaviors.

Keywords: estradiol, testosterone, synapse, songbird, teleost, neurogenesis, proliferation, migration

Introduction

Steroid hormones are profound modulators of anatomy and physiology, including (but not limited to) that of neural tissues. Over the last several decades, we have learned a lot about how steroids synthesized in the gonads, adrenal glands, and brain can affect neuroanatomy and neurophysiology. In vertebrates, all steroids derive from cholesterol, which following cleavage and the action of a series of enzymes can be converted into progestins, glucocorticoids, mineralocorticoids, androgens, or estrogens. Of these, perhaps the most dramatic effects on neuroplasticity occur due to the action of androgens and estrogens, and consequently, this article will focus on these molecules.

Androgens and estrogens critically affect the central nervous system (CNS) during development, adolescence, adulthood, and aging (Arnold & Gorski, 1984; Gurney & Konishi, 1980; MacLusky & Naftolin, 1981; McEwen, 1981; Phoenix, Goy, Gerall, & Young, 1959). Collectively, these actions have been referred to as organizational and activational, with the former occurring perinatally and conceptualized as foundational. Later in life, the action of gonadal steroids on a variety of target tissues (including the brain) results in the expression of an impressive gamut of behaviors. These steroids form two categories: androgens, which include dihydrotestosterone (DHT) and testosterone; and estrogens, which include estrone, 17β‎-estradiol (hereafter referred to as estradiol), and estriol. Indeed, the suite of behavioral end points affected by the predominant “sex” steroids testosterone and estradiol now includes memory, mood, balance, learning, and appetite (Garcia-Segura 2008; Maggi, Ciana, Belcredito, & Vegeto, 2004; McEwen, 2002; Wise, 2003).

In the last five decades or so, appreciation for another aspect of the steroidal modulation of the CNS has emerged. Many effects of gonadal steroids appear to be somewhat repetitive or cyclical in character; often involving a neural response to withdrawal of the steroid and a subsequent reemergence of steroid-dependent changes in the brain and behavior when the hormone is more available. For example, canaries exhibit seasonal morphological changes of song control nuclei that have been shown to be testosterone dependent. These song control areas are larger during the breeding season, and decrease in volume, cell number, size and density after the breeding season (Nottebohm, 1981). This seasonal plasticity is due to fluctuating testosterone (Nottebohm, Nottebohm, Crane, & Wingfield, 1987). While the demonstration of cyclical, seasonal patterns of behavior is certainly not new, our understanding of these patterns now involves a more thorough appreciation of the dramatic changes in neuroanatomy and physiology that accompany behavioral transitions. More specifically, particularly during adulthood, we have learned that the vertebrate CNS can lose entire groups of cells, circuits, and connections at times when steroid provision is low. These structures and the behaviors that they control can then reappear later, when steroid provision is restored. This steroid-dependent disappearance and reappearance of neuroanatomy and neurophysiology is what we will refer to as neuroplasticity.

Steroid hormones can alter the brain on multiple levels, including changes in biochemical signaling, transcription and translation, intercellular communication, and the connectivity of neural circuits. Many of these changes can involve the restructuring of the CNS and likely involve cellular processes that are temporally protracted. Correspondingly and classically, steroid effects that occur via the regulation of gene transcription and protein synthesis have been conceptualized as relatively slow processes. However, recent work has suggested that steroid hormones can also have rapid, nongenomic actions, in seconds or minutes, but generally within an hour, to exert powerful effects. Rapid provision and response to sex steroid hormones, particularly estradiol, can mediate changes in anatomy, physiology, and behavior. In this review, we will include and highlight our current understanding of how steroid hormones initiate rapid membrane-signaling cascades and can alter both physiology and behavior. We will discuss the cellular mechanisms of steroid-dependent neuroplasticity, including neurogenesis and morphological changes in circuit connectivity. Next, we will describe functional changes due to the steroid-dependent restructuring of the CNS. This includes data on how sex steroids modulate cognition via alteration of neural structure, and this finding has implications for cognitive processing, memory, social behavior, and sensorimotor integration. We focus on work conducted in teleosts, birds, and mammals in an attempt to underscore both the pervasive nature of steroid-dependent neuroplasticity and the strong link between structural change and functional output in several species of these vertebrate classes.

Neurogenesis

Perhaps the most striking and dramatic form of neuroplasticity is reflected in the deterioration and regrowth of entire neural circuits in the adult brain—an important form of brain plasticity regulated by sex steroids. This would necessarily involve the birth of new neurons, but it also includes aspects of neuronal survival, migration, and perhaps most important, the incorporation and/or organization of newly born neurons into functional circuits. Indeed, neurogenesis is generally measured by the amount and/or number of newly divided and proliferating cells, but also by the survival of these cells as they migrate across the adult CNS. Adult neurogenesis has been recognized across vertebrate species for some time (Altman, 1962; Nottebohm, 2002) and has been described in representatives of every vertebrate class, including several species of teleosts, some frogs, and a few species of lizards and turtles. Perhaps the most thorough investigations of the modulation of adult neurogenesis by steroids, however, have been conducted on teleosts, murine rodents, and passerine songbirds.

Steroids and Adult Neurogenesis in Teleosts

The role of aromatizable androgens (the possibility of an androgen like testosterone being converted to an estrogen like estradiol) on plasticity of the adult CNS in teleosts is perhaps limited because the predominant circulating androgen in many of these species is 11-ketotestosterone (11KT), a nonaromatizable androgen. However, relatively recent evidence points to a dramatic association between aromatase (estrogen synthase) and neuroplasticity in the brains of some adult fish. Indeed, the adult teleost brain contains extremely high levels of aromatase in several species, including but not limited to goldfish, rainbow trout, stickleback, plainfin midshipman, zebrafish, and medaka (Pellegrini et al., 2005). Interestingly, in many of these species, aromatase is never expressed in neurons, but it is consistently observed in radial glia (Diotel et al., 2013; Forlano, Deitcher, Myers, & Bass, 2001; Pellegrini et al., 2005). Of particular interest, and best characterized in the zebrafish, is high expression of aromatase B (cyp 19b) in radial glia in proliferative zones of the adult brain.

The zebrafish brain contains numerous proliferative zones characterized by high numbers of progenitor cells and the strong expression of markers for proliferating and migrating neurons. The proliferative zones include, but are not limited to, the preoptic area, optic tectum, thalamus, and cerebellum (Adolf et al., 2006; Byrd & Brunjes 2001; Chapouton et al., 2006; Grandel, Kaslin, Ganz, Wenzel, & Brand, 2006). Proliferative cells of the adult zebrafish brain are also characterized by high expression of aromatase (Pellegrini et al., 2007). The strong expression of aromatase in progenitor cells in the zebrafish suggests an important role for aromatization in aspects of the maintenance and migration of these cells. Surprisingly, estradiol decreases cell proliferation and migration in several brain areas, including the mediobasal hypothalamus and the junction between the olfactory bulbs and the telencephalon; this pattern is mirrored by aromatase inhibition and the blockade of estrogen receptors (ERs) (Diotel et al., 2013). These data suggest that the high expression of aromatase in the teleost brain may work to inhibit neuroplasticity. While surprising, this pattern of data does leave open the possibility that aromatizable androgens may play a stimulatory role in the proliferation and migration of neurons in the adult teleost brain. Aromatization of these androgens may limit their availability to sensitive cellular targets, thereby keeping proliferative processes in check, including the division and migration of newly born neurons in the adult brain. Many of the studies that have directly examined steroid-dependent effects on neuronal proliferation and migration in the adult brain have been done with passerine and murine animal models.

Steroids and Adult Neurogenesis in Mammals and Songbirds

Newly born cells migrate long distances and are incorporated into functional neural circuits in the adult brain. This can occur in more than one brain area, including the high vocal center (HVC) of songbirds (Alvarez-Buylla, Arturo, & Kirn, 1997; Barnea & Nottebohm, 1994), and in the hippocampus in songbirds and mammals (Altman & Das, 1965), where these new neurons can potentially alter behavior. Although sex steroids have a moderate effect on the generation of neurons in the subventricular zone (Brown, Johnson, & Bottjer, 1993), androgens and estrogens likely influence the survival of neurons (Hidalgo, Barami, Iversen, & Goldman, 1995). Importantly, the modulation of neurogenesis by sex steroids involves chronic effects by androgens and estrogens and relatively recent demonstrations of the rapid effects of estrogens.

Fluctuations of circulating androgens and estrogens can influence neurogenesis via effects on proliferation, migration, and/or survival. Castrated male rats demonstrate decreases in the survival of newly born cells in the hippocampus, an effect reversed by injections of testosterone or the nonaromatizable androgen DHT. In contrast, the administration of estradiol does not appear to rescue castration-dependent decreases in hippocampal cell survival, suggesting a role for androgens, but not estrogens, in this effect (Spritzer & Galea, 2007). Similarly, testosterone implants increase cell survival in the HVC of canaries (Serinus canarius) (Rasika, Nottebohm, & Alvarez-Buylla, 1994) and European starlings (Sturnus vulgaris) (Absil, Pinxten, Balthazart, & Eens, 2003). These effects can involve multiple cell-signaling systems, as demonstrated by the fact that in the canary, testosterone-mediated increases in neuronal survival appear to be brain-derived neurotrophic factor (BDNF) dependent (Rasika, Alvarez-Buylla, & Nottebohm, 1999). The data suggest that in both birds and mammals, androgens may exert potent effects on many aspects of adult neurogenesis.

Estrogens also have been implicated in the regulation of cell proliferation and survival in the adult vertebrate brain. Adult female rats generate more neurons in the hippocampus than do males (Gould, Beylin, Tanapat, Reeves, & Shor, 1999), and females in estrus have higher levels of cell proliferation compared to those in diestrus (Tanapat, Hastings, Reeves, & Gould, 1999). These differences appear to be estradiol dependent, as administration of this steroid to ovariectomized rats increases the number of new cells in the hippocampus compared to ovariectomized females injected with control injection alone (Tanapat et al., 1999). These effects have also been demonstrated in vitro, as treatment of hippocampal cultures with an aromatase inhibitor decreases proliferation relative to controls, an effect reversed by coadministration of estradiol (Fester, Ribeiro-Gouveia, Prange-Kiel, & Rune, 2006). Interestingly, estradiol can also affect neurogenesis in the adult male brain. Castrated males that are administered estradiol have increased cell survival compared to controls in meadow voles (Ormerod, Lee, & Galea, 2004) and prairie voles (Smith, Pencea, Wang, Luskin, & Insel, 2001).

Although much work focuses on the chronic effect (i.e., greater than 24 hours) of sex steroids on neurogenesis, emerging evidence demonstrates that some aspects of this modulation may occur more rapidly. Short-term exposure (2–4 hours), but not long-term exposure (2–3 days), to estradiol increased survival of neurons in the female vole (Ormerod & Galea, 2001; Ormerod, Lee, & Galea, 2003). Similarly, administration of estradiol for 3 days does not alter either hippocampal proliferation or survival in female voles (Fowler, Freeman, & Wang, 2003). These effects suggest that estradiol’s effects may be more rapid than previously appreciated.

Similar to rodents, the growth of brain nuclei in songbirds is also potently affected by estrogens. Soma, Tramontin, Featherstone, and Brenowitz (2004) treated wild adult male song sparrows (Melospiza melodia) with an aromatase inhibitor either with or without estradiol replacement in breeding and nonbreeding conditions. In breeding males, aromatase inhibition resulted in a decrease in the volume of HVC, an effect partially rescued by concomitant estradiol treatment. In nonbreeding birds, estradiol increased the volume of HVC within two weeks, suggesting that the aromatization of circulating androgens to estrogens may be important modulators of adult neuroplasticity in this species (Soma et al., 2004).

Synaptic Connectivity

In addition to effects on neurogenesis, sex steroids can modulate neural circuitry through the modulation of presynaptic and postsynaptic structure and function. Dendritic spines are small protrusions on the dendrite, and they are the most prominent location for excitatory synaptic connections in the CNS (Harris & Kater, 1994). As such, it is not surprising that dendritic spines are vital for the development and function of neural circuits and may be integral to learning and memory formation (Calverley & Jones, 1990; Eccles, 1979). Spine morphology and spinogenesis have functional implications, where larger spine density has been thought to suggest a stable memory site and storage and newly formed spines are thought to be responsible for memory acquisition (Segal, 2016). Conversely, abnormalities in spine structure are linked to disruptions in synaptic and neuronal synaptic function and are often found in mental illness, the aged brain, or in neurodegenerative diseases (Fiala, Spacek, & Harris, 2002). It has been suggested that increasing the size or number of dendritic spines would enhance the strength and connectivity between neurons (Harris & Kater, 1994). Uncovering how these changes in size, shape, and number occur will provide important insights into memory formation and cognition (Bhatt, Zhang, & Gan, 2009; Bourne & Harris, 2007; Kasai, Fukuda, Watanabe, Hayashi-Takagi, & Noguchi, 2010). Sex steroids, particularly estradiol, have been shown to affect synaptic connectivity via the regulation of dendritic spine density and formation, as well as cellular function via long-term potentiation and neuronal excitability. Here, we limit our discussion to changes in these three categories due to rapid estradiol modulation.

Rapid Regulation of Dendritic Spine Formation and Density by Estradiol

Similar to the early studies conducted on neurogenesis, experiments studying regulation of spine density by estradiol focused on the endocrine status of the animal (Gould, Woolley, Frankfurt, & McEwen, 1990; Woolley, Gould, Frankfurt, & McEwen, 1990). Gonadal steroids, particularly estradiol and progesterone, increases, while ovariectomy decreases dendritic spine density in the rat CA1 hippocampal cells (Gould et al., 1990). Estradiol or progesterone treatment induced relatively rapid changes in spine density, occurring over three days or five hours, respectively. Given the four-day estrus cycle in the rat, these results imply that CA1 hippocampal cells (but interestingly, not CA3) may be constantly undergoing synaptic remodeling, and in turn changes in excitability. Indeed, in an evaluation of natural hormonal state during the estrus cycle, dendritic spine density was the highest during proestrus and dramatically decreases within hours to lower levels late in estrus (Woolley et al., 1990). Dramatic changes in estradiol occur within 24 hours between late afternoon of proestrus and late afternoon of estrus (Smith, Freeman, & Neill, 1975). Remarkably, large changes in dendritic spine density also occur during this time, suggesting that estradiol modulates the spine density in the unmanipulated female rat.

The foundational work correlating changes in estradiol levels to dendritic spine density has led to other attempts to evaluate the rapid changes in spine formation and density caused by estradiol, some which occur within 30 minutes (Sanchez et al., 2009; Srivastava, Woolfrey, & Penzes, 2013; Srivastava et al., 2008, 2010). In cell culture studies, application of estradiol increases density within 20 minutes (Sanchez et al., 2009; Srivastava et al., 2008), but decreases to baseline 60 minutes following application (Sanchez et al., 2009). These effects have been shown to be estradiol dependent through removal and replacement studies where application of an aromatase inhibitor decreases spine density, and estradiol treatment increases spine density, respectively (Srivastava et al., 2008; Zhou et al., 2010).

Implications of estradiol increasing dendritic spine density have been intensely studied in relation to memory, reproductive behavior, and recovery from brain trauma. Testosterone or estradiol injections increased spine density in CA1 two hours following treatment, but also enhanced memory in the male rat (Jacome et al., 2016). Similar work has shown estradiol ability to regulate spine density in the apical and basal medial prefrontal cortex, as well as CA1, within 30 minutes of application (Luine, 2016). Rapid and dramatic increases in spine density in the prefrontal cortex and hippocampus following estradiol may serve to enhance memory consolidation. Interestingly, estradiol modulates spine density in brain areas not likely involved in memory, like the arcuate nucleus (Christensen, Dewing, & Micevych, 2011), although the stimulation of dendritic sprouting in this region occurs more slowly than that observed in the hippocampus. Finally, following cerebral ischemia, estradiol or selective estrogen receptor modulators (SERMs) reduce the loss of dendritic spine density in female rats (Khan, Wakade, de Sevilla, & Brann, 2014), suggesting that estrogenic signaling may play a neuroprotective role. Thus, the relatively rapid modulation of dendritic spines by estradiol may have important implications in the modulation and preservation of complex behaviors, perhaps via effects on synaptic connectivity and synaptic neurophysiology.

Rapid Regulation of Synaptic Function by Estradiol

Estradiol may affect memory encoding by facilitating long-term potentiation (LTP) in male rats (Kramár et al., 2009), ovariectomized female rats (Smith & McMahon, 2006), and mice (Sung et al., 2007). This enhancement can occur as quickly as 30 minutes following treatment with estradiol, an effect apparently mediated by ER-β‎, but not ER-α‎ (Kramár et al., 2009). Two mechanisms have been proposed for the enhanced LTP following rapid estradiol synthesis. Estradiol may cause a reduced threshold for the induction of LTP, thereby increasing the probability of neuronal firing. Alternatively, estradiol may increase the ceiling of potentiation (Kramár et al., 2009), thereby increasing the temporal range of enhanced neurotransmission. Indeed, treatment with estradiol has been shown to regulate excitatory synaptic transmission by increasing the slope and frequency of excitatory postsynaptic potential within minutes in hippocampal cells (Kim et al., 2006; Rudick & Woolley, 2003), suggesting that potentiation may occur via both presynaptic and postsynaptic mechanisms. In agreement, estradiol increases presynaptic glutamate release and is mediated by postsynaptic ER-β‎, but not ER-α‎ (Smejkalova & Woolley, 2010).

Correspondingly, and interestingly, estradiol infusions decrease inhibitory postsynaptic potentials in hippocampal slices from females, but not males (Huang & Woolley, 2012), suggesting the possibility that estradiol-dependent mechanisms may be sexually dimorphic in rats. These changes in neuronal excitability appear to greatly affect behavior, given that they translate into seizures at the behavioral level. Taken together, these data provide evidence that rapid estradiol signaling modulates synaptic function in vivo to affect behavioral end points, and it may do so in a sex-specific manner. As discussed next, the estrogenic modulation of behavior extends to multiple species and includes other complex behaviors such as memory function.

Rapid Modulation of Behavior by Estradiol

Teleosts

Many species of teleost fish demonstrate rapid and dramatic changes in anatomy and physiology during transitions in social hierarchies, reproductive societies, and even individual sex. Since all of these entities involve social behaviors including stress, affiliation, aggression, and reproduction, it is perhaps not surprising that these changes in physical appearance and behavior occur during equally dramatic changes in the levels of circulating steroids. Males of the cichlid species Astatotilapia burtoni demonstrate a fluid social structure wherein low-ranking males often challenge those of a higher rank for greater access to mates and territories (Hofmann & Fernald, 2001; Maruska & Fernald, 2011). These challenges, when successful, result in morphological and behavioral changes, including transitions from drab to bright coloration and an increase in aggressive and reproductive behaviors within 30 minutes (Maruska, 2015). Correlated with these changes in behavior is a steep and significant rise in circulating levels of the steroids testosterone, 11-Ketotestosterone, estradiol, and progesterone within 30 minutes (Maruska, 2015). A finer analysis reveals that while steroid levels are negatively and positively correlated with submissive and reproductive behaviors, respectively, no such correlation is detectable with aggressive behaviors (Maruska, 2015). These data suggest the possibility that peripheral or central levels of steroid synthesis may rapidly modulate neural targets and affect behavior in this species.

The idea that peripheral levels of steroids can rapidly affect neural targets and alter behavior is supported by studies in the midshipman fish (Porichthys notatus) and goldfish (Cariassius auratus). In the former, peripheral estradiol administration increases the duration of firing in a hindbrain nucleus within 5 minutes (Remage-Healey & Bass, 2007; Remage-Healey & Bass, 2004). Similarly, though not as rapidly, testosterone or estradiol administration increases the frequency of social approach to visual cues in goldfish (Lord, Bond, & Thompson, 2009). Importantly, while estradiol can alter this behavior within 10 minutes, it takes about 30 minutes for testosterone to achieve the same result, strongly suggesting the involvement of aromatization as key in this rapid modulation of behavior (Lord, Bond, & Thompson, 2009). Indeed, the abundant expression of aromatase in the teleost brain, including that of the goldfish, suggests the possibility of neural aromatization as a candidate for the rapid effects of E2 on behavior (Diotel et al., 2013; Gelinas & Callard, 1997).

Rapid Modulation of Behavior in Mammals and Birds: Reproductive Behavior

Peripheral or central levels of steroid synthesis may rapidly modulate neural targets and affect behavior such as sexual behavior, social behavior, and aggression in both rodents and songbirds. Estradiol is capable of having rapid effects on reproductive behaviors in both rat and quail models (Abdelgadir, 1994; Cornil, Taziaux, Baillien, Ball, & Balthazart, 2006). In a castrated male rat, a single injection of estradiol rapidly increases mounting and reduces latency to mount within 15–30 minutes (Abdelgadir, 1994). Interestingly and similar to teleost studies, testosterone did not influence male sex behavior in this study, suggesting that aromatization and the rapid effects of estradiol synthesis is responsible for the patterns of behavior. In a similar study in the Japanese quail, inhibition of aromatase affected male reproductive behaviors, an effect apparent 30–40 minutes following treatment (Cornil et al., 2006). In turn, estradiol administration enhances (and estrogen receptor antagonists inhibit) male sexual motivation, but not performance, within minutes (Seredynski, Balthazart, Ball, & Cornil, 2015). Rapid estradiol signaling may regulate female sexual behavior in the rat. A pulse of estradiol given over 15 minutes directly to the ventromedial nucleus of the hypothalamus potentiates the behavioral effect (lordosis) of the second pulse of estradiol given over one hour, five hours after the first pulse (Kow & Pfaff, 2004). One single, long pulse of estradiol was unable to produce normal sexual behavior, suggesting that the synergy of nongenomic and genomic estradiol signaling may be necessary for lordosis. Further work on how membrane-initiated signaling of estradiol affects reproductive behavior is currently being investigated (Micevych, Wong, & Mittelman-Smith, 2015).

Communication and Social Behavior

In a foundational set of experiments, Remage-Healey, Oyama, and Schlinger found that aromatase (estrogen synthase) is elevated in males that were singing compared to nonsinging males (Remage-Healey, Oyama, & Schlinger, 2009). Interestingly, the elevation in aromatase activity was found only in synaptic terminals in the forebrain of the male zebra finch. Previous studies have localized aromatase to the synapse (Peterson, Yarram, Schlinger, & Saldanha, 2005; Rohmann, Schlinger, & Saldanha, 2007), suggesting that estradiol may be rapidly synthesized at the synapse and contribute to song production in the male songbird. Interestingly, males have higher synaptic aromatase compared to females, which suggests the localization of aromatase may reflect the sex-specific production of song in males but not females (Rohmann, Schlinger, & Saldanha, 2007). In follow-up studies using in vivo retro dialysis, estradiol was found to acutely regulate social interaction (Remage-Healey, Maidment, & Schlinger, 2008). Local, but not peripheral, levels of estradiol increased following a male’s interaction with a female. The local increase in estradiol only occurred in the caudal medial nidopallium (NCM) in male zebra finches, an auditory processing region similar to the mammalian auditory cortex that is responsible for the processing of song. Inhibition of estradiol production in the NCM rapidly affected behavioral responses to song, suggesting that estradiol synthesis in the NCM enhances song preference and behavior in the zebra finch (Remage-Healey, 2012).

Learning and Memory

The synaptic synthesis of estrogens has also been implicated in the modulation of spatial memory in songbirds. In zebra finches, the hippocampus is a brain region with abundant synaptic aromatase but little to no somal aromatase expression. This characteristic permits the manipulation of aromatase in a brain region where aromatization is predominantly synaptic, thereby allowing for the evaluation of the function of synaptic aromatization. Bailey, Ma, Soma, and Saldanha (2013) placed unmanipulated silastic implants or silastic implants infiltrated with an aromatase inhibitor on the surface of the hippocampus. A separate group of birds served as shams or received bilateral lesions of the hippocampus. Birds subsequently learned a novel spatial memory task, and the acquisition and performance of spatial memory were measured. Birds treated with the aromatase inhibitor and those that received hippocampal lesions took longer to acquire the spatial memory task and made more mistakes during the probe trial than did birds who received just silastic implants or sham controls. These data strongly suggest that hippocampal aromatization may support complex spatial memory function in this species.

The past few decades have dramatically changed our understanding of the vertebrate CNS, especially the brain. Perhaps most notable is the realization that the vertebrate brain is subject to extensive reorganization far into adulthood. This includes significant changes in the adult mammalian CNS, considerable restructuring of brain nuclei and circuits in the songbird CNS, and a dramatic level of neurogenesis in the teleost brain. The birth of new neurons, their migration from proliferative zones to distal locations in the brain, and their incorporation into circuits all suggest a level of neuroplasticity unappreciated until only about three decades ago. Among the many modulators of vertebrate neuroplasticity, testosterone and estradiol have emerged as potent activators of many plastic end points, including neurogenesis, migration, connectivity, and behavioral output of the CNS. While early work underscored the chronic and sustained action of gonadal steroids, we have come to learn that they can work much faster and modulate physiological end points within seconds to minutes. This finding provides a framework for further studies on the function of peripheral and central steroidogenesis since in the majority of vertebrates, circulating levels of testosterone and estradiol do not change rapidly. Teleosts appear to be an exception since they do show changes in plasma steroid concentration within 30 minutes, particularly in keeping with reproductive and social behavioral change. In addition to hormone provision, these rapid changes may also be a reflection of alterations in sensitivity. The discovery of membrane-bound receptors for several steroid molecules has provided a mechanism whereby neurons and other cells of the CNS may be able to respond rapidly to extremely specific sites of neurosteroidogenesis, such as the presynaptic bouton. This evolution in our understanding of the steroidal modulation of neuroplasticity continues to expand the considerable gamut of structural and functional end points regulated by steroids.

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