Formation and Function of Circuitry for Vocal Learning

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DESCRIPTION (provided by applicant): The long-term goal of this grant is to understand the neural mechanisms for auditory-guided vocal learning. The objective addressed in this application is to identify molecular signatures of functional circuits for vocal motor learning. The learned song of songbirds is the best characterized exemplar of vocal learning, however few of the molecules that define and operate within the functional circuitry are known. Traditional laboratory species do not modify their innate vocalizations, so it has been improbable, until now, to test a molecule identified in the vocal learning of another animal group for its function birdsong. This improbability has changed with the identification of FOXP2 as the first monogenetic locus for a human language disorder. The core deficit of humans bearing a FOXP2 mutation is in the accuracy and consistency and human speech and in generating sequential movements of the orpfacial musculature. This behavioral phenotype is accompanied by abnormal structure and function of a cortical-striatal circuit that participates in speech. Together, these findings indicate that FOXP2 lies along one neural path linked to speech. We propose to use molecular, behavioral, and genetic intervention techniques in songbirds to discover the role of FoxP molecules in the vocal learning circuit of the zebra finch. Songbirds are ideal for these studies as a corticalstriatal circuit underlies song production and development. Further, each of the three phases of song learning can be extended or exaggerated by manipulating auditory input. Therefore, any developmental correlations observed for candidate neural mechanisms of vocal learning can be secondarily screened to determine whether the correlation persists beyond chronological age to behavioral state. The songbird thereby offers an unrivalled opportunity for screening candidate molecules prior to selecting them for functional tests. Specific Aim 1 will determine whether FoxP neural expression patterns are regulated during song learning. Specific Aim 2 tests the hypothesis that changes in FoxP expression correlate specifically with the sensorimotor phase of song learning and song maintenance. Specific Aim 3 uses altered genetic expression of FoxP molecules to test whether they are necessary for sensorimotor learning and song maintenance. These findings will significantly advance our understanding of the formation and function of vocal-learning circuitry. Discovery of FoxP function in songbirds, the only experimentally tractable vocal learner, will additionally provide essential information regarding human disorders linked to FOXP mutations