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Scholarly Works (4 results)

  • Thesis
  • Peer Reviewed
UCLA Electronic Theses and Dissertations (2015)

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.

    Cover page: Brain Behavior Interactions in Avian Models for Speech Disorders
    • Article
    • Peer Reviewed
    UCLA Previously Published Works (2013)
    Humans and songbirds are among the rare animal groups that exhibit socially learned vocalizations: speech and song, respectively. These vocal-learning capacities share a reliance on audition and cortico-basal ganglia circuitry, as well as neurogenetic mechanisms. Notably, the transcription factors Forkhead box proteins 1 and 2 (FoxP1, FoxP2) exhibit similar expression patterns in the cortex and basal ganglia of humans and the zebra finch species of songbird, among other brain regions. Mutations in either gene are associated with language disorders in humans. Experimental knock-down of FoxP2 in the basal ganglia song control region Area X during song development leads to imprecise copying of tutor songs. Moreover, FoxP2 levels decrease naturally within Area X when zebra finches sing. Here, we examined neural expression patterns of FoxP1 and FoxP2 mRNA in adult Bengalese finches, a songbird species whose songs exhibit greater sequence complexity and increased reliance on audition for maintaining their quality. We found that FoxP1 and FoxP2 expression in Bengalese finches is similar to that in zebra finches, including strong mRNA signals for both factors in multiple song control nuclei and enhancement of FoxP1 in these regions relative to surrounding brain tissue. As with zebra finches, when Bengalese finches sing, FoxP2 is behaviorally downregulated within basal ganglia 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.
      Cover page: Expression analysis of the speech-related genes FoxP1 and FoxP2 and their relation to singing behavior in two songbird species
      • Article
      • Peer Reviewed
      UCLA Previously Published Works (2015)
      The forkhead domain FOXP2 and FOXP1 transcription factors are implicated in several cognitive disorders with language deficits, notably autism, and thus play a central role in learned vocal motor behavior in humans. Although a similar role for FoxP2 and FoxP1 is proposed for other vertebrate species, including songbirds, the neurodevelopmental expression of these genes are unknown in a species with lifelong vocal learning abilities. Like humans, budgerigars (Melopsittacus undulatus) learn new vocalizations throughout their entire lifetime. Like songbirds, budgerigars have distinct brain nuclei for vocal learning, which include the magnocellular nucleus of the medial striatum (MMSt), a basal ganglia region that is considered developmentally and functionally analogous to Area X in songbirds. Here, we used in situ hybridization and immunohistochemistry to investigate FoxP2 and FoxP1 expression in the MMSt of juvenile and adult budgerigars. We found FoxP2 mRNA and protein expression levels in the MMSt that were lower than the surrounding striatum throughout development and adulthood. In contrast, FoxP1 mRNA and protein had an elevated MMSt/striatum expression ratio as birds matured, regardless of their sex. These results show that life-long vocal plasticity in budgerigars is associated with persistent low-level FoxP2 expression in the budgerigar MMSt, and suggests the possibility that FoxP1 plays an organizational role in the neurodevelopment of vocal motor circuitry. Thus, developmental regulation of the FoxP2 and FoxP1 genes in the basal ganglia appears essential for vocal mimicry in a range of species that possess this relatively rare trait.
        Cover page: Differential FoxP2 and FoxP1 expression in a vocal learning nucleus of the developing budgerigar
        • Article
        • Peer Reviewed
        UCLA Previously Published Works (2015)
        Vocal learning underlies acquisition of both language in humans and vocal signals in some avian taxa. These bird groups and humans exhibit convergent developmental phases and associated brain pathways for vocal communication. The transcription factor FoxP2 plays critical roles in vocal learning in humans and songbirds. Another member of the forkhead box gene family, FoxP1 also shows high expression in brain areas involved in vocal learning and production. Here, we investigate FoxP2 and FoxP1 mRNA and protein in adult male budgerigars (Melopsittacus undulatus), a parrot species that exhibits vocal learning as both juveniles and adults. To examine these molecules in adult vocal learners, we compared their expression patterns in the budgerigar striatal nucleus involved in vocal learning, magnocellular nucleus of the medial striatum (MMSt), across birds with different vocal states, such as vocalizing to a female (directed), vocalizing alone (undirected), and non-vocalizing. We found that both FoxP2 mRNA and protein expressions were consistently lower in MMSt than in the adjacent striatum regardless of the vocal states, whereas previous work has shown that songbirds exhibit down-regulation in the homologous region, Area X, only after singing alone. In contrast, FoxP1 levels were high in MMSt compared to the adjacent striatum in all groups. Taken together these results strengthen the general hypothesis that FoxP2 and FoxP1 have specialized expression in vocal nuclei across a range of taxa, and suggest that the adult vocal plasticity seen in budgerigars may be a product of persistent down-regulation of FoxP2 in MMSt.
          Cover page: Neural FoxP2 and FoxP1 expression in the budgerigar, an avian species with adult vocal learning
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