Social and auditory experience shapes forebrain responsiveness in zebra finches before the sensitive period of vocal learning.

Early-life experiences with signals used in communication are instrumental in shaping an animal's social interactions. In songbirds, which use vocalizations for guiding social interactions and mate choice, recent studies show that sensory effects on development occur earlier than previously expected, even in embryos and nestlings. Here, we explore the neural dynamics underlying experience-dependent song categorization in young birds prior to the traditionally studied sensitive period of vocal learning that begins around 3 weeks post-hatch. We raised zebra finches either with their biological parents, cross-fostered by Bengalese finches beginning at embryonic day 9, or by only the non-singing mother from 2 days post-hatch. Then, 1-5 days after fledging, we conducted behavioral experiments and extracellular recordings in the auditory forebrain to test responses to zebra finch and Bengalese finch songs. Auditory forebrain neurons in cross-fostered and isolate birds showed increases in firing rate and decreases in responsiveness and selectivity. In cross-fostered birds, decreases in responsiveness and selectivity relative to white noise were specific to conspecific song stimuli, which paralleled behavioral attentiveness to conspecific songs in those same birds. This study shows that auditory and social experience can already impact song 'type' processing in the brains of nestlings, and that brain changes at this age can portend the effects of natal experience in adults.

Estrogens rapidly shape synaptic and intrinsic properties to regulate the temporal precision of songbird auditory neurons.

Sensory neurons parse millisecond-variant sound streams like birdsong and speech with exquisite precision. The auditory pallial cortex of vocal learners like humans and songbirds contains an unconventional neuromodulatory system: neuronal expression of the estrogen synthesis enzyme aromatase. Local forebrain neuroestrogens fluctuate when songbirds hear a song, and subsequently modulate bursting, gain, and temporal coding properties of auditory neurons. However, the way neuroestrogens shape intrinsic and synaptic properties of sensory neurons remains unknown. Here, using a combination of whole-cell patch clamp electrophysiology and calcium imaging, we investigate estrogenic neuromodulation of auditory neurons in a region resembling mammalian auditory association cortex. We found that estradiol rapidly enhances the temporal precision of neuronal firing via a membrane-bound G-protein coupled receptor and that estradiol rapidly suppresses inhibitory synaptic currents while sparing excitation. Notably, the rapid suppression of intrinsic excitability by estradiol was predicted by membrane input resistance and was observed in both males and females. These findings were corroborated by analysis of in vivo electrophysiology recordings, in which local estrogen synthesis blockade caused acute disruption of the temporal correlation of song-evoked firing patterns. Therefore, on a modulatory timescale, neuroestrogens alter intrinsic cellular properties and inhibitory neurotransmitter release to regulate the temporal precision of higher-order sensory neurons.

The form, function, and evolutionary significance of neural aromatization.

Songbirds have emerged as exceptional research subjects for helping us appreciate and understand estrogen synthesis and function in brain. In the context of recognizing the vertebrate-wide importance of brain aromatase expression, in this review we highlight where we believe studies of songbirds have provided clarification and conceptual insight. We follow by focusing on more recent studies of aromatase and neuroestrogen function in the hippocampus and the pallial auditory processing region NCM of songbirds. With perspectives drawn from this body of work, we speculate that the evolution of enhanced neural estrogen signaling, including in the mediation of social behaviors, may have given songbirds the resilience to radiate into one of the most successful vertebrate groups on the planet.

A neural circuit perspective on brain aromatase.

This review explores the role of aromatase in the brain as illuminated by a set of conserved network-level connections identified in several vertebrate taxa. Aromatase-expressing neurons are neurochemically heterogeneous but the brain regions in which they are found are highly-conserved across the vertebrate lineage. During development, aromatase neurons have a prominent role in sexual differentiation of the brain and resultant sex differences in behavior and human brain diseases. Drawing on literature primarily from birds and rodents, we delineate brain regions that express aromatase and that are strongly interconnected, and suggest that, in many species, aromatase expression essentially defines the Social Behavior Network. Moreover, in several cases the inputs to and outputs from this core Social Behavior Network also express aromatase. Recent advances in molecular and genetic tools for neuroscience now enable in-depth and taxonomically diverse studies of the function of aromatase at the neural circuit level.

Dopamine D1 receptor activation drives plasticity in the songbird auditory pallium.

Vocal learning species must form and extensively hone associations between sounds and social contingencies. In songbirds, dopamine signaling guides song motor-production, variability, and motivation, but it is unclear how dopamine regulates fundamental auditory associations for learning new sounds. We hypothesized that dopamine regulates learning in the auditory pallium, in part by interacting with local neuroestradiol signaling. Here, we show that zebra finch auditory neurons frequently coexpress D1 receptor (D1R) protein, neuroestradiol-synthase, GABA, and parvalbumin. Auditory classical conditioning increased neuroplasticity gene induction in D1R-positive neurons. In vitro, D1R pharmacological activation reduced the amplitude of GABAergic and glutamatergic currents and increased the latter's frequency. In vivo, D1R activation reduced the firing of putative interneurons, increased the firing of putative excitatory neurons, and made both neuronal types unable to adapt to novel stimuli. Together, these findings support the hypothesis that dopamine acting via D1Rs modulates auditory association in the songbird sensory pallium.SIGNIFICANCE STATEMENTOur key finding is that auditory forebrain D1 receptors modulate auditory plasticity, in support of the hypothesis that dopamine modulates the formation of associations between sounds and outcomes. Recent work in songbirds has identified roles for dopamine in driving reinforcement learning and motor variability in song production. This leaves open whether dopamine shapes the initial events that are critical for learning vocalizations, e.g., auditory learning. Our study begins to address this question in the songbird caudomedial nidopallium (NCM), an analogue of the mammalian secondary auditory cortex. Our findings indicate that dopamine receptors are important modulators of excitatory/inhibitory balance and sound association learning mechanisms in the NCM, a system that could be a fundamental feature of vertebrate ascending auditory pathways.

Aromatase and nonaromatase neurons in the zebra finch secondary auditory forebrain are indistinct in their song-driven gene induction and intrinsic electrophysiological properties.

Estrogens support major brain functions including cognition, reproduction, neuroprotection and sensory processing. Neuroestrogens are synthesized within some brain areas by the enzyme aromatase and can rapidly modulate local circuit functions, yet the cellular physiology and sensory-response profiles of aromatase neurons are essentially unknown. In songbirds, social and acoustic stimuli drive neuroestrogen elevations in the auditory forebrain caudomedial nidopallium (NCM). In both males and females, neuroestrogens rapidly enhance NCM auditory processing and auditory learning. Estrogen-producing neurons in NCM may therefore exhibit distinguishing profiles for sensory-activation and intrinsic electrophysiology. Here, we explored these questions using both immunocyctochemistry and electrophysiological recordings. Immunoreactivity for aromatase and the immediate early gene EGR1, a marker of activity and plasticity, were quantified in NCM of song-exposed animals versus silence-exposed controls. Using whole-cell patch clamp recordings from NCM slices, we also documented the intrinsic excitability profiles of aromatase-positive and aromatase-negative neurons. We observed that a subset of aromatase neurons were significantly activated during song playback, in both males and females, and in both hemispheres. A comparable population of non-aromatase-expressing neurons were also similarly driven by song stimulation. Membrane properties (i.e., resting membrane potential, rheobase, input resistance and multiple action potential parameters) were similarly indistinguishable between NCM aromatase and non-aromatase neurons. Together, these findings demonstrate that aromatase and non-aromatase neurons in NCM are indistinct in terms of their intrinsic electrophysiology and responses to song. Nevertheless, such similarities in response properties may belie more subtle differences in underlying conductances and/or computational roles that may be crucial to their function.

Adverse Effects of Aromatase Inhibition on the Brain and Behavior in a Nonhuman Primate.

Breast cancer patients using aromatase inhibitors (AIs) as an adjuvant therapy often report side effects, including hot flashes, mood changes, and cognitive impairment. Despite long-term use in humans, little is known about the effects of continuous AI administration on the brain and cognition. We used a primate model of human cognitive aging, the common marmoset, to examine the effects of a 4-week daily administration of the AI letrozole (20 µg, p.o.) on cognition, anxiety, thermoregulation, brain estrogen content, and hippocampal pyramidal cell physiology. Letrozole treatment was administered to both male and female marmosets and reduced peripheral levels of estradiol (E2), but unexpectedly increased E2 levels in the hippocampus. Spatial working memory and intrinsic excitability of hippocampal neurons were negatively affected by the treatment possibly due to increased hippocampal E2. While no changes in hypothalamic E2 were observed, thermoregulation was disrupted by letrozole in females only, indicating some impact on hypothalamic activity. These findings suggest adverse effects of AIs on the primate brain and call for new therapies that effectively prevent breast cancer recurrence while minimizing side effects that further compromise quality of life.SIGNIFICANCE STATEMENT Aromatase inhibitors (AIs) are used as an adjuvant therapy for estrogen-receptor-positive breast cancer and are associated with side effects, including hot flashes, depression/anxiety, and memory deficits severe enough for many women to discontinue this life-saving treatment. AIs are also used by men, yet sex differences in the reported side effects have not been systematically studied. We show that AI-treated male and female marmosets exhibit behavioral changes consistent with these CNS symptoms, as well as elevated hippocampal estradiol and compromised hippocampal physiology. These findings illustrate the need for (1) a greater understanding of the precise mechanisms by which AIs impact brain function and (2) the development of new treatment approaches for breast cancer patients that minimize adverse effects on the brain.

Acute neuroestrogen blockade attenuates song-induced immediate early gene expression in auditory regions of male and female zebra finches.

Neuron-derived estrogens are synthesized by aromatase and act through membrane receptors to modulate neuronal physiology. In many systems, long-lasting hormone treatments can alter sensory-evoked neuronal activation. However, the significance of acute neuroestrogen production is less understood. Both sexes of zebra finches can synthesize estrogens rapidly in the auditory cortex, yet it is unclear how this modulates neuronal cell signaling. We examined whether acute estrogen synthesis blockade attenuates auditory-induced expression of early growth response 1 (Egr-1) in the auditory cortex of both sexes. cAMP response element-binding protein phosphorylation (pCREB) induction by song stimuli and acute estrogen synthesis was also examined. We administered the aromatase inhibitor fadrozole prior to song exposure and measured Egr-1 across several auditory regions. Fadrozole attenuated Egr-1 in the auditory cortex greater in males than females. Females had greater expression and clustering of aromatase cells than males in high vocal center (HVC) shelf. Auditory-induced Egr-1 expression exhibited a large sex difference following fadrozole treatment. We did not observe changes in pCREB expression with song presentation or aromatase blockade. These findings are consistent with the hypothesis that acute neuroestrogen synthesis can drive downstream transcriptional responses in several cortical auditory regions, and that this mechanism is more prominent in males.

Auditory learning in an operant task with social reinforcement is dependent on neuroestrogen synthesis in the male songbird auditory cortex.

Animals continually assess their environment for cues associated with threats, competitors, allies, mates or prey, and experience is crucial for those associations. The auditory cortex is important for these computations to enable valence assignment and associative learning. The caudomedial nidopallium (NCM) is part of the songbird auditory association cortex and it is implicated in juvenile song learning, song memorization, and song perception. Like human auditory cortex, NCM is a site of action of estradiol (E2) and is enriched with the enzyme aromatase (E2-synthase). However, it is unclear how E2 modulates auditory learning and perception in the vertebrate auditory cortex. In this study we employ a novel, auditory-dependent operant task governed by social reinforcement to test the hypothesis that neuro-E2 synthesis supports auditory learning in adult male zebra finches. We show that local suppression of aromatase activity in NCM disrupts auditory association learning. By contrast, post-learning performance is unaffected by either NCM aromatase blockade or NCM pharmacological inactivation, suggesting that NCM E2 production and even NCM itself are not required for post-learning auditory discrimination or memory retrieval. Therefore, neuroestrogen synthesis in auditory cortex supports the association between sounds and behaviorally relevant consequences.

Testosterone synthesis in the female songbird brain.

Decades of work have established the brain as a source of steroid hormones, termed 'neurosteroids'. The neurosteroid neuroestradiol is produced in discrete brain areas and influences cognition, sensory processing, reproduction, neurotransmission, and disease. A prevailing research focus on neuroestradiol has essentially ignored whether its immediate synthesis precursor - the androgen testosterone - is also dynamically regulated within the brain. Testosterone itself can rapidly influence neurophysiology and behavior, and there is indirect evidence that the female brain may synthesize significant quantities of testosterone to regulate cognition, reproduction, and behavior. In songbirds, acoustic communication is regulated by neuroestrogens. Neuroestrogens are rapidly synthetized in the caudomedial nidopallium (NCM) of the auditory cortex of zebra finches in response to song and can influence auditory processing and song discrimination. Here, we examined the in vivo dynamics of NCM levels of the neuroestrogen synthesis precursor, testosterone. Unlike estradiol, testosterone did not appear to fluctuate in the female NCM during song exposure. However, a substantial song-induced elevation of testosterone was revealed in the left hemisphere NCM of females when local aromatization (i.e., conversion to estrogens) was locally blocked. This elevation was eliminated when local androgen synthesis was concomitantly blocked. Further, no parallel elevation was observed in the circulation in response to song playback, consistent with a local, neural origin of testosterone synthesis. To our knowledge, this study provides the first direct demonstration that testosterone fluctuates rapidly in the brain in response to socially-relevant environmental stimuli. Our findings suggest therefore that locally-derived 'neuroandrogens' can dynamically influence brain function and behavior. SIGNIFICANCE STATEMENT: This study demonstrates that androgen synthesis occurs rapidly in vivo in the brain in response to social cues, in a lateralized manner. Specifically, testosterone synthesis occurs within the left secondary auditory cortex when female zebra finches hear male song. Therefore, testosterone could act as a neuromodulator to rapidly shape sensory processing. Androgens have been linked to functions such as the control of female libido, and many steroidal drugs used for contraception, anti-cancer treatments, and sexual dysfunction likely influence the brain synthesis and action of testosterone. The current findings therefore establish a clear role for androgen synthesis in the female brain with implications for understanding neural circuit function and behavior in animals, including humans.

Norepinephrine enhances song responsiveness and encoding in the auditory forebrain of male zebra finches.

Norepinephrine (NE) can dynamically modulate excitability and functional connectivity of neural circuits in response to changes in external and internal states. Regulation by NE has been demonstrated extensively in mammalian sensory cortices, but whether NE-dependent modulation in sensory cortex alters response properties in downstream sensorimotor regions is less clear. Here we examine this question in male zebra finches, a songbird species with complex vocalizations and a well-defined neural network for auditory processing of those vocalizations. We test the hypothesis that NE modulates auditory processing and encoding, using paired extracellular electrophysiology recordings and pattern classifier analyses. We report that a NE infusion into the auditory cortical region NCM (caudomedial nidopallium; analogous to mammalian secondary auditory cortex) enhances the auditory responses, burst firing, and coding properties of single NCM neurons. Furthermore, we report that NE-dependent changes in NCM coding properties, but not auditory response strength, are transmitted downstream to the sensorimotor nucleus HVC. Finally, NE modulation in the NCM of males is qualitatively similar to that observed in females: in both sexes, NE increases auditory response strengths. However, we observed a sex difference in the mechanism of enhancement: whereas NE increases response strength in females by decreasing baseline firing rates, NE increases response strength in males by increasing auditory-evoked activity. Therefore, NE signaling exhibits a compensatory sex difference to achieve a similar, state-dependent enhancement in signal-to-noise ratio and coding accuracy in males and females. In summary, our results provide further evidence for adrenergic regulation of sensory processing and modulation of auditory/sensorimotor functional connectivity. NEW & NOTEWORTHY This study documents that the catecholamine norepinephrine (also known as noradrenaline) acts in the auditory cortex to shape local processing of complex sound stimuli. Moreover, it also enhances the coding accuracy of neurons in the auditory cortex as well as in the downstream sensorimotor cortex. Finally, this study shows that while the sensory-enhancing effects of norepinephrine are similar in males and females, there are sex differences in the mode of action.

Neuroestrogens rapidly shape auditory circuits to support communication learning and perception: Evidence from songbirds.

Contribution to Special Issue on Fast effects of steroids. Steroid hormones, such as estrogens, were once thought to be exclusively synthesized in the ovaries and enact transcriptional changes over the course of hours to days. However, estrogens are also locally synthesized within neural circuits, wherein they rapidly (within minutes) modulate a range of behaviors, including spatial cognition and communication. Here, we review the role of brain-derived estrogens (neuroestrogens) as modulators within sensory circuits in songbirds. We first present songbirds as an attractive model to explore how neuroestrogens in auditory cortex modulate vocal communication processing and learning. Further, we examine how estrogens may enhance vocal learning and auditory memory consolidation in sensory cortex via mechanisms similar to those found in the hippocampus of rodents and birds. Finally, we propose future directions for investigation, including: 1) the extent of developmental and hemispheric shifts in aromatase and membrane estrogen receptor expression in auditory circuits; 2) how neuroestrogens may impact inhibitory interneurons to regulate audition and critical period plasticity; and, 3) dendritic spine plasticity as a candidate mechanism mediating estrogen-dependent effects on vocal learning. Together, this perspective of estrogens as neuromodulators in the vertebrate brain has opened new avenues in understanding sensory plasticity, including how hormones can act on communication circuits to influence behaviors in other vocal learning species, such as in language acquisition and speech processing in humans.

Steroids and the brain: 50years of research, conceptual shifts and the ascent of non-classical and membrane-initiated actions.

This brief commentary reviews key steps in the history of steroid endocrinology that have resulted in important conceptual shifts. Our understanding of the "Fast Effects of Steroids" now reflect substantial progress, including the major concept that steroids act rapidly on a variety of physiological and behavioral responses, via mechanisms that are too fast to be fully accounted for by classical receptor-dependent regulation of gene transcription. Several so-called 'non-classical' mechanisms have been identified and include binding to membrane receptors and regulating non genomic signaling cascades. We survey the discovery of steroids, the initial characterization of their intracellular receptors, key progress in the understanding of the genomic effects of steroids and then the progressive discovery of the rapid non-classical and membrane-initiated actions of steroids. Foundational discoveries about brain steroid synthesis in neural processes and terminals has converged with emerging evidence for the rapid actions of steroids on brain and behavior. Had the rapid effects of steroids in the central nervous system been discovered first, these molecules would likely now be considered as a class of neurotransmitter.

Actions of Steroids: New Neurotransmitters.

Over the past two decades, the classical understanding of steroid action has been updated to include rapid, membrane-initiated, neurotransmitter-like functions. While steroids were known to function on very short time spans to induce physiological and behavioral changes, the mechanisms by which these changes occur are now becoming more clear. In avian systems, rapid estradiol effects can be mediated via local alterations in aromatase activity, which precisely regulates the temporal and spatial availability of estrogens. Acute regulation of brain-derived estrogens has been shown to rapidly affect sensorimotor function and sexual motivation in birds. In rodents, estrogens and progesterone are critical for reproduction, including preovulatory events and female sexual receptivity. Membrane progesterone receptor as well as classical progesterone receptor trafficked to the membrane mediate reproductive-related hypothalamic physiology, via second messenger systems with dopamine-induced cell signals. In addition to these relatively rapid actions, estrogen membrane-initiated signaling elicits changes in morphology. In the arcuate nucleus of the hypothalamus, these changes are needed for lordosis behavior. Recent evidence also demonstrates that membrane glucocorticoid receptor is present in numerous cell types and species, including mammals. Further, membrane glucocorticoid receptor influences glucocorticoid receptor translocation to the nucleus effecting transcriptional activity. The studies presented here underscore the evidence that steroids behave like neurotransmitters to regulate CNS functions. In the future, we hope to fully characterize steroid receptor-specific functions in the brain.

Norepinephrine Modulates Coding of Complex Vocalizations in the Songbird Auditory Cortex Independent of Local Neuroestrogen Synthesis.

The catecholamine norepinephrine plays a significant role in auditory processing. Most studies to date have examined the effects of norepinephrine on the neuronal response to relatively simple stimuli, such as tones and calls. It is less clear how norepinephrine shapes the detection of complex syntactical sounds, as well as the coding properties of sensory neurons. Songbirds provide an opportunity to understand how auditory neurons encode complex, learned vocalizations, and the potential role of norepinephrine in modulating the neuronal computations for acoustic communication. Here, we infused norepinephrine into the zebra finch auditory cortex and performed extracellular recordings to study the modulation of song representations in single neurons. Consistent with its proposed role in enhancing signal detection, norepinephrine decreased spontaneous activity and firing during stimuli, yet it significantly enhanced the auditory signal-to-noise ratio. These effects were all mimicked by clonidine, an α-2 receptor agonist. Moreover, a pattern classifier analysis indicated that norepinephrine enhanced the ability of single neurons to accurately encode complex auditory stimuli. Because neuroestrogens are also known to enhance auditory processing in the songbird brain, we tested the hypothesis that norepinephrine actions depend on local estrogen synthesis. Neither norepinephrine nor adrenergic receptor antagonist infusion into the auditory cortex had detectable effects on local estradiol levels. Moreover, pretreatment with fadrozole, a specific aromatase inhibitor, did not block norepinephrine's neuromodulatory effects. Together, these findings indicate that norepinephrine enhances signal detection and information encoding for complex auditory stimuli by suppressing spontaneous "noise" activity and that these actions are independent of local neuroestrogen synthesis.

Sex differences and rapid estrogen signaling: A look at songbird audition.

The actions of estrogens have been associated with brain differentiation and sexual dimorphism in a wide range of vertebrates. Here we consider the actions of brain-derived 'neuroestrogens' in the forebrain and the accompanying differences and similarities observed between males and females in a variety of species. We summarize recent evidence showing that baseline and fluctuating levels of neuroestrogens within the auditory forebrain of male and female zebra finches are largely similar, and that neuroestrogens enhance auditory representations in both sexes. With a comparative perspective we review evidence that non-genomic mechanisms of neuroestrogen actions are sexually differentiated, and we propose a working model for nonclassical estrogen signaling via the MAPK intracellular signaling cascade in the songbird auditory forebrain that is informed by the way sex differences may be compensated. This view may lead to a more comprehensive understanding of how sex influences estradiol-dependent modulation of sensorimotor representations.

Inhibition of local estrogen synthesis in the hippocampus impairs hippocampal memory consolidation in ovariectomized female mice.

The potent estrogen 17ß-Estradiol (E2) plays a critical role in mediating hippocampal function, yet the precise mechanisms through which E2 enhances hippocampal memory remain unclear. In young adult female rodents, the beneficial effects of E2 on memory are generally attributed to ovarian-synthesized E2. However, E2 is also synthesized in the adult brain in numerous species, where it regulates synaptic plasticity and is synthesized in response to experiences such as exposure to females or conspecific song. Although de novo E2 synthesis has been demonstrated in rodent hippocampal cultures, little is known about the functional role of local E2 synthesis in mediating hippocampal memory function. Therefore, the present study examined the role of hippocampal E2 synthesis in hippocampal memory consolidation. Using bilateral dorsal hippocampal infusions of the aromatase inhibitor letrozole, we first found that blockade of dorsal hippocampal E2 synthesis impaired hippocampal memory consolidation. We next found that elevated levels of E2 in the dorsal hippocampus observed 30min after object training were blocked by dorsal hippocampal infusion of letrozole, suggesting that behavioral experience increases acute and local E2 synthesis. Finally, aromatase inhibition did not prevent exogenous E2 from enhancing hippocampal memory consolidation, indicating that hippocampal E2 synthesis is not necessary for exogenous E2 to enhance hippocampal memory. Combined, these data are consistent with the hypothesis that hippocampally-synthesized E2 is necessary for hippocampus-dependent memory consolidation in rodents.

Frank Beach Award Winner: Steroids as neuromodulators of brain circuits and behavior.

Neurons communicate primarily via action potentials that transmit information on the timescale of milliseconds. Neurons also integrate information via alterations in gene transcription and protein translation that are sustained for hours to days after initiation. Positioned between these two signaling timescales are the minute-by-minute actions of neuromodulators. Over the course of minutes, the classical neuromodulators (such as serotonin, dopamine, octopamine, and norepinephrine) can alter and/or stabilize neural circuit patterning as well as behavioral states. Neuromodulators allow many flexible outputs from neural circuits and can encode information content into the firing state of neural networks. The idea that steroid molecules can operate as genuine behavioral neuromodulators - synthesized by and acting within brain circuits on a minute-by-minute timescale - has gained traction in recent years. Evidence for brain steroid synthesis at synaptic terminals has converged with evidence for the rapid actions of brain-derived steroids on neural circuits and behavior. The general principle emerging from this work is that the production of steroid hormones within brain circuits can alter their functional connectivity and shift sensory representations by enhancing their information coding. Steroids produced in the brain can therefore change the information content of neuronal networks to rapidly modulate sensory experience and sensorimotor functions.

Establishing regional specificity of neuroestrogen action.

The specificity of estrogen signaling in brain is defined at one level by the types and distributions of receptor molecules that are activated by estrogens. At another level, as our understanding of the neurobiology of the estrogen synthetic enzyme aromatase has grown, questions have emerged as to how neuroactive estrogens reach specific target receptors in functionally relevant concentrations. Here we explore the spatial specificity of neuroestrogen signaling with a focus on studies of songbirds to provide perspective on some as-yet unresolved questions. Studies conducted in both male and female songbirds have helped to clarify these interesting facets of neuroestrogen physiology.

Brain estrogen signaling effects acute modulation of acoustic communication behaviors: A working hypothesis.

Although estrogens are widely considered circulating "sex steroid hormones" typically associated with female reproduction, recent evidence suggests that estrogens can act as local modulators of brain circuits in both males and females. The functional implications of this newly characterized estrogen signaling system have begun to emerge. This essay summarizes evidence in support of the hypothesis that the rapid production of estrogens in brain circuits can drive acute changes in both the production and perception of acoustic communication behaviors. These studies have revealed two fundamental neurobiological concepts: (1) estrogens can be locally produced in brain circuits, independent of levels in nearby circuits and in the circulation and (2) estrogens can have very rapid effects within these brain circuits to modulate social vocalizations, acoustic processing, and sensorimotor integration. This vertebrate-wide span of research, including vocalizing fishes, amphibians, and birds, emphasizes the importance of comparative model systems in understanding principles of neurobiology.