Formation and Function of Circuitry for Vocal Learning

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DESCRIPTION (provided by applicant): The long term objective of this proposal is to discover the neural basis for socially-learned vocal communication, a form of implicit learning. Deficits in implicit learning, including language disorders, have devastating consequences for social integration. To treat or prevent these deficits, the neural mechanisms for learned vocal communication, currently unknown, must be understood. Language is uniquely human, but other species possess subcomponents of language enabling controlled molecular, physiological and behavioral studies. Songbirds are a useful model because they learn their songs through social interactions in a manner that exhibits significant parallels to human speech development. We use songbirds to investigate FoxP2- a conserved transcription factor whose mutation causes a severe language disorder as an entry point into the neuromolecular networks for vocal learning. Humans and songbirds possess full length and truncated FoxP2 isoforms. The latter lacks the DNA binding domain but includes a dimerization domain whereby it could interfere with transcriptional activity. These forms will serve as tools to augment or decrease FoxP2 function and determine bidirectional changes in gene coregulatory networks, neurophysiology and behavior. In addition to organizing brain structures, FoxP2 has post-organizational roles, as observed within area X, the basal ganglia sub-region dedicated to song. Area X FoxP2 levels are robust early in development, but when juvenile or adult birds practice their songs, FoxP2 is acutely down-regulated. We hypothesize that FoxP2 acts as a molecular gate of neural and behavioral plasticity even in the adult: Behaviorally driven reduction of FoxP2 during song learning and adult practice enables vocal adjustments. Conversely, high FoxP2 levels promote brain organization and reinforce optimal neural activity and behavior later in life. To test this, FoxP2 function will be augmented and reduced via viral driven expression of the two isoforms during periods of brain organization, and during song learning and adult maintenance. Molecular networks will be identified using RNAseq and a powerful systems level technique known as weighted gene co-expression network analysis, to highlight behaviorally significant relationships. Electrophysiological recordings from cultured neurons and acute brain slices will be used to examine emergent neurophysiological changes. Behavioral effects on song learning and on deafening-induced song deterioration in adulthood will be tested. This work is relevant to the NIMH's programmatic goals of developing and exploiting animal models for mental disorders in which social-learning deficits are a major component, including but not limited to autism spectrum disorder. By investigating an animal that learns its vocalizations, we can illuminate how molecules linked to human language disorders disrupt neural function, providing critical insight for the development of be- havioral and pharmacological interventions. These studies will provide basic but critical information about the neural processes underlying a complex socially-learned behavior.