Brain and behavior differ between males and females across vertebrate species. The zebra finch song system is a particularly useful model for understanding mechanisms that regulate development of sex differences in neural structure and function for many reasons, including extremely large morphological differences between males and females in a relatively simple neural circuit in which brain regions have clearly identified functions. Recent sequencing of the zebra finch genome provides new access to molecular tools and resources. As in mammalian species, estradiol (E2) can induce some masculinization, but a variety of pieces of evidence indicate that additional molecules are critical to normal male development. I propose to test a new, unique hypothesis, that the steroid hormone E2 acts in concert with masculine levels of expression of one or more sex chromosome genes to regulate appropriate male development. This work will provide critical novel information, as data on interactions between E2 and other molecules regulating sexual differentiation are very limited across species. The experiments involve three genes that we determined exhibit increased expression in specific song control nuclei in developing males compared to females. Collectively, the studies will provide a cohesive body of information integrating hormonal and genetic factors regulating development of brain structure and a learned social behavior - vocal communication, the primary modality used by humans. Specifically, we will use combinations of molecular, cellular, anatomical and behavioral approaches to test hypotheses about the relationships among E2 and specific molecules in development of forebrain structure and function. The ideas, which are not mutually exclusive, include that: (1) E2 increases expression of secretory carrier membrane protein 1 (SCAMP1), tubulin specific chaperone A (TBCA) and/or tyrosine kinase B (TrkB, the high affinity receptor for brain derived neurotrophic factor - BDNF);(2) These genes and the BDNF ligand modulate masculinization, in part by increasing responsiveness of the developing brain to E2;and (3) E2 and the genes/proteins can have complementary effects, including that E2 increases availability of BDNF, SCAMP1 and TBCA are positioned to facilitate BDNF's release, and TBCA and TrkB are localized such that they can increase BDNF's ability to act.

Public Health Relevance

The experiments in this proposal will provide data directly applicable to the priorities of the National Institute of Mental Health. They will identify the rols of specific genes/proteins and how they may interact with each other and a steroid hormone to regulate development of components of a neural circuit that controls the development and production of learned vocalizations. This work will elucidate the roles of molecular processes critical to normal maturation of brain structure and social communication, and will increase knowledge about factors contributing to related mental health disorders, such as schizophrenia, autism and depression.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
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Panchision, David M
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Michigan State University
Schools of Arts and Sciences
East Lansing
United States
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Lampen, J; McAuley, J D; Chang, S-E et al. (2017) ZENK induction in the zebra finch brain by song: Relationship to hemisphere, rhythm, oestradiol and sex. J Neuroendocrinol 29:
Lampen, Jennifer; McAuley, J Devin; Chang, Soo-Eun et al. (2017) Neural activity associated with rhythmicity of song in juvenile male and female zebra finches. Behav Processes :
Beach, Linda Qi; Tang, Yu Ping; Kerver, Halie et al. (2016) Inhibition of TrkB limits development of the zebra finch song system. Brain Res 1642:467-477
Wade, Juli (2016) Genetic regulation of sex differences in songbirds and lizards. Philos Trans R Soc Lond B Biol Sci 371:20150112
Tang, Yu Ping; Wade, Juli (2016) Sex and age differences in brain-derived neurotrophic factor and vimentin in the zebra finch song system: Relationships to newly generated cells. J Comp Neurol 524:1081-96
Beach, L Q; Wade, J (2015) Masculinisation of the zebra finch song system: roles of oestradiol and the Z-chromosome gene tubulin-specific chaperone protein A. J Neuroendocrinol 27:324-34
Lampen, Jennifer; Jones, Katherine; McAuley, J Devin et al. (2014) Arrhythmic song exposure increases ZENK expression in auditory cortical areas and nucleus taeniae of the adult zebra Finch. PLoS One 9:e108841
Tang, Yu Ping; Wade, Juli (2014) Tracheosyringeal nerve transection in juvenile male zebra finches decreases BDNF in HVC and RA and the projection between them. Neurosci Lett 583:26-31
Tang, Y P; Wade, J (2013) Developmental changes in BDNF protein in the song control nuclei of zebra finches. Neuroscience 250:578-87
Qi, L M; Wade, J (2013) Sexually dimorphic and developmentally regulated expression of tubulin-specific chaperone protein A in the LMAN of zebra finches. Neuroscience 247:182-90

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