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.

Public Health Relevance

Individuals who suffer from certain mental disorders such as autism fail to develop normal language, which has devastating consequences on social integration. To understand the neural basis for these deficits, and thus formulate novel approaches to improve them, we use songbirds, the only practical laboratory animal for investigating the vocal learning subcomponent of language. We will examine the role of FoxP2, a molecule whose single mutation causes a human language disorder, in complex socially-learned vocal communication.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Neurobiology of Learning and Memory Study Section (LAM)
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Panchision, David M
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University of California Los Angeles
Schools of Arts and Sciences
Los Angeles
United States
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Fraley, E R; Burkett, Z D; Day, N F et al. (2016) Mice with Dab1 or Vldlr insufficiency exhibit abnormal neonatal vocalization patterns. Sci Rep 6:25807
Berg, Jamee M; Lee, Changhoon; Chen, Leslie et al. (2015) JAKMIP1, a Novel Regulator of Neuronal Translation, Modulates Synaptic Function and Autistic-like Behaviors in Mouse. Neuron 88:1173-91
Heston, Jonathan B; White, Stephanie A (2015) Behavior-linked FoxP2 regulation enables zebra finch vocal learning. J Neurosci 35:2885-94
Burkett, Zachary D; Day, Nancy F; Peñagarikano, Olga et al. (2015) VoICE: A semi-automated pipeline for standardizing vocal analysis across models. Sci Rep 5:10237
Hara, Erina; Perez, Jemima M; Whitney, Osceola et al. (2015) Neural FoxP2 and FoxP1 expression in the budgerigar, an avian species with adult vocal learning. Behav Brain Res 283:22-9
Whitney, Osceola; Voyles, Tawni; Hara, Erina et al. (2015) Differential FoxP2 and FoxP1 expression in a vocal learning nucleus of the developing budgerigar. Dev Neurobiol 75:778-90
Grant, Laura M; Richter, Franziska; Miller, Julie E et al. (2014) Vocalization deficits in mice over-expressing alpha-synuclein, a model of pre-manifest Parkinson's disease. Behav Neurosci 128:110-21
Condro, Michael C; White, Stephanie A (2014) Recent Advances in the Genetics of Vocal Learning. Comp Cogn Behav Rev 9:75-98
Chen, Qianqian; Heston, Jonathan B; Burkett, Zachary D et al. (2013) Expression analysis of the speech-related genes FoxP1 and FoxP2 and their relation to singing behavior in two songbird species. J Exp Biol 216:3682-92
Hilliard, Austin T; Miller, Julie E; Fraley, Elizabeth R et al. (2012) Molecular microcircuitry underlies functional specification in a basal ganglia circuit dedicated to vocal learning. Neuron 73:537-52

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