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Glucocorticoids (CORT) are well-known as important regulators of behaviour and cognition at basal levels and under stress. However, the precise mechanisms governing CORT action and functional outcomes of this action in the brain remain unclear, particularly in model systems other than rodents. In the present study, we investigated the dynamics of CORT regulation in the zebra finch, an important model system for vocal learning, neuroplasticity and cognition. We tested the hypothesis that CORT is locally regulated in the zebra finch brain by quantifying regional and stress-related variation in total CORT across brain regions. In addition, we used an ex vivo slice culture system to test whether CORT regulates target gene expression uniquely in discrete regions of the brain. We documented a robust increase in brain CORT across regions after 30 minutes of restraint stress but, interestingly, baseline and stress-induced CORT levels varied between regions. In addition, CORT treatment of brain slice cultures differentially affected expression of three CORT target genes: it up-regulated expression of FKBP5 in most regions and SGK1 in the hypothalamus only, whereas GILZ was unaffected by CORT treatment across all brain regions investigated. The specific mechanisms producing regional variation in CORT and CORT-dependent downstream gene expression remain unknown, although these data provide additional support for the hypothesis that the songbird brain employs regulatory mechanisms that result in precise control over the influence of CORT on glucocorticoid-sensitive neural circuits., (© 2020 British Society for Neuroendocrinology.)

Oestradiol is abundant in the zebra finch auditory forebrain and has the capacity to modulate neural responses to auditory stimuli with specificity as a result of both hemisphere and sex. Arrhythmic song induces greater ZENK expression than rhythmic song in the caudomedial nidopallium (NCM), caudomedial mesopallium (CMM) and nucleus taeniae (Tn) of adult zebra finches. The increases in the auditory regions (i.e. NCM and CMM) may result from detection of errors in the arrhythmic song relative to the learned template. In the present study, zebra finches were treated with oestradiol, the aromatase inhibitor fadrozole or a control and then exposed to rhythmic or arrhythmic song to assess the effect of oestradiol availability on neural responses to auditory rhythms. ZENK mRNA was significantly greater in the left hemisphere within the NCM, CMM and Tn. Main effects of sex were detected in both auditory regions, with increased ZENK in males in the NCM and in females in the CMM. In the CMM, an effect of hormone treatment also existed. Although no pairwise comparison was statistically significant, the pattern suggested greater ZENK expression in control compared to both fadrozole- and oestradiol-treated birds. In the NCM, an interaction between sex and hormone treatment suggested that the sex effect was restricted to control animals. An additional interaction in the NCM among sex, stimulus rhythmicity and hemisphere indicated that the strongest effect of laterality was present in males exposed to arrhythmic song. The hormone effects suggest that an optimal level of oestradiol may exist for processing rhythmicity of auditory stimuli. The overall pattern for left lateralisation parallels the left lateralisation of language processing in humans and may suggest that this hemisphere is specialised for processing conspecific vocalisations. The reversed sex differences in the NCM and CMM suggest that males and females differentially rely on components of the auditory forebrain for processing conspecific song., (© 2017 British Society for Neuroendocrinology.)

In songbirds and mammals, brain injury results in the up-regulation of aromatase (oestrogen synthase) expression in astroglia. The resulting presumed synthesis of neural oestradiol (E2 ) has neuroprotective effects including a decrease in neurodegeneration, neuroinflammation and apoptosis. The development of therapeutic tools that exploit oestrogenic neuroprotection in the treatment of neurotrauma requires a precise quantification of the endogenous changes in neural aromatase and E2 following brain injury. Surprisingly, the expected increase in neural oestrogens following brain injury has not been demonstrated. Furthermore, we are just beginning to unravel the mechanisms behind the protective effects of centrally synthesised E2 . In the present study, levels of aromatase immunoprotein, neural E2 and steroid receptor mRNA were quantified in adult male and female zebra finches 48 h following a unilateral penetrating brain injury. Both aromatase and E2 were up-regulated in the injured hemisphere of the brain compared to the uninjured hemisphere, demonstrating for the first time a robust increase in neural E2 levels following injury. We did not detect an effect of injury on mRNA expression of the oestrogen receptors (ER)-α, ER-β or GPER-1, but observed a significant decrease in androgen receptor transcription in the injured lobe relative to the contralateral uninjured hemisphere. We conclude that mechanical damage causes a dramatic increase in local aromatisation, and the resultant high levels of central E2 are available to modulate steroid sensitive targets. Studies using alternate methods of receptor detection and/or time points may be necessary to understand the complete suite of mechanisms underlying the neuroprotective effects of induced oestrogen synthesis in this animal model., (© 2015 British Society for Neuroendocrinology.)

Several neuropeptides with the C-terminal Arg-Phe-NH(2) (RFa) sequence have been identified in the hypothalamus of a variety of vertebrates. The present study was conducted to isolate novel RFa peptides from the zebra finch brain. Peptides were isolated by immunoaffinity purification using an antibody that recognises avian RFa peptides. The isolated peptide consisted of 25 amino acids with RFa at its C-terminus. The sequence was SGTLGNLAEEINGYNRRKGGFTFRFa. Alignment of the peptide with vertebrate 26RFa has revealed that the identified peptide is the zebra finch 26RFa. We also cloned the precursor cDNA encoding this peptide. Synteny analysis of the gene showed a high conservation of this gene among vertebrates. In addition, we cloned the cDNA encoding a putative 26RFa receptor, G protein-coupled receptor 103 (GPR103) in the zebra finch brain. GPR103 cDNA encoded a 432 amino acid protein that has seven transmembrane domains. In situ hybridisation analysis in the brain showed that the expression of 26RFa mRNA is confined to the anterior-medial hypothalamic area, ventromedial nucleus of the hypothalamus and the lateral hypothalamic area, the brain regions that are involved in the regulation of feeding behaviour, whereas GPR103 mRNA is distributed throughout the brain in addition to the hypothalamic nuclei. When administered centrally in free-feeding male zebra finches, 26RFa increased food intake 24 h after injection without body mass change. Diencephalic GPR103 mRNA expression was up-regulated by fasting for 10 h. Our data suggest that the hypothalamic 26RFa-its receptor system plays an important role in the central control of food intake and energy homeostasis in the zebra finch., (© 2011 The Authors. Journal of Neuroendocrinology © 2011 Blackwell Publishing Ltd.)

The song system of zebra finches differs dramatically between the sexes in terms of both structure and function. Only males sing and the brain regions regulating the learning and production of this behaviour are far more developed in males than females. Mechanisms regulating sexual differentiation likely include both direct genetic and hormonal processes. Expression of both mRNA and the protein product for secretory carrier membrane protein 1 (SCAMP1), a sex chromosome gene, are increased in the brains of juvenile males compared to females. Here we investigated developmental changes in SCAMP1 containing cells in song nuclei and co-localisation with androgen receptor (AR) protein from post-hatching day 25 through adulthood. Almost all SCAMP1 cells co-expressed AR and approximately half of the AR cells expressed SCAMP1 in the HVC and robust nucleus in the arcopallium (RA) of both sexes and in the Area X of males (which could not be clearly defined in females). In HVC and RA, more single and double-labelled cells were detected in males than females overall, and the sex differences increased as animals matured. The results suggest the potential for interaction of these two proteins in regulating development of brain and/or behaviour., (© 2011 The Authors. Journal of Neuroendocrinology © 2011 Blackwell Publishing Ltd.)

The enzyme aromatase, which converts androgens into oestrogens, is expressed throughout the brain in zebra finches. Aromatase is enzymatically active in both cell bodies and synaptic terminals of neurones of the songbird brain, particularly within the forebrain motor and auditory networks. Aromatisation within synaptic terminals could thus provide localised and acute modulatory oestrogens within the forebrain during singing and/or audition. In male zebra finches, we tested the hypothesis that forebrain aromatase activity is elevated during singing behaviour and/or hearing male song. The present study reports that aromatase activity is elevated in males that were singing for 30 min compared to nonsinging males, and that this elevation occurs only within the cellular compartment that contains synaptic terminals. In a separate experiment, males that heard acoustic playback of song for 30 min exhibited no differences in aromatase activity or in aromatase mRNA levels, as revealed by quantitative polymerase chain reaction analysis. Therefore, these results indicate that activation of the motor pathway for song production is linked to local elevations in synaptic aromatase activity within the forebrain of male zebra finches. Future experiments could assess whether elevated synaptic aromatase activity during song is dependent on acute regulation of the aromatase protein.