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Brain Behavior Interactions in Avian Models for Speech Disorders

  • Author(s): Chen, Qianqian
  • Advisor(s): White, Stephanie A
  • et al.
Abstract

Humans and songbirds are among the rare animal groups that exhibit socially learned vocalizations. These vocal-learning capacities share a reliance on audition and cortico-basal ganglia circuitry, as well as neurogenetic mechanisms. Thus, songbirds can serve as relevant models in which to study the mechanisms of human speech disorders. Mutations in the transcription factors Forkhead box proteins 1 and 2 (FoxP1, FoxP2) are associated with language disorders in humans. Both genes exhibit similar expression patterns in the cortex and basal ganglia of humans and songbirds, among other brain regions. Here, I examined neural expression patterns of FoxP1 and P2 mRNA in two adult songbird species. I found that FoxP1 and P2 expression is similarly expressed in both species, including strong mRNA signals for both factors in multiple song control nuclei. With both species, when the birds sing, FoxP2 is behaviorally down-regulated within the basal ganglia song control nucleus, Area X, over a similar time course, and expression negatively correlates with the amount of singing. This study confirms that in multiple songbird species, FoxP1 expression highlights song control regions, and regulation of FoxP2 is associated with motor control of song. Mutations in contactin associated protein-like 2 (Cntnap2), a FoxP2 target gene, are associated with cortical dysplasia- focal epilepsy, autism spectrum disorder, and specific language impairment. We have previously characterized the expression of Cntnap2 in zebra finch (Taeniopygia guttata), a songbird species. Within the robust nucleus of the arcopallium (RA), the primary vocal motor control nucleus in zebra finch brain, Cntnap2 expression becomes sexually dimorphic over the course of song learning. RA shares striking similarities with the laryngeal motor cortex, a language control region in the human brain, both in terms of gene expression profiles and in making direct neuronal projections onto the motor neurons that control the muscles of phonation. To further test the function of Cntnap2, I developed shRNA constructs to specifically knock down zebra finch Cntnap2. I stereotaxically injected an adeno-associated virus (AAV) bearing the shRNA constructs into zebra finch RA to attenuate the Cntnap2 expression during the sensorimotor phase of vocal learning. I found that knocking down Cntnap2 in RA caused inaccurate imitation and a high percentage of omission of the tutor song but did not interfere with the bird’s ability to modify its song over the course of sensorimotor learning. These results suggest that among Cntnap2’s many functions within the nervous system, its expression within the cortical vocal control region alone is critical for accurate vocal imitation. In summary, these studies provide ongoing support for using songbirds to investigate the neurogenetic mechanisms of human speech and language.

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