BackgroundMutations in the FOXP2 transcription factor lead to language disorders with developmental onset. Accompanying structural abnormalities in cortico-striatal circuitry indicate that at least a portion of the behavioral phenotype is due to organizational deficits. We previously found parallel FoxP2 expression patterns in human and songbird cortico/pallio-striatal circuits important for learned vocalizations, suggesting that FoxP2's function in birdsong may generalize to speech.Methodology/Principal FindingsWe used zebra finches to address the question of whether FoxP2 is additionally important in the post-organizational function of these circuits. In both humans and songbirds, vocal learning depends on auditory guidance to achieve and maintain optimal vocal output. We tested whether deafening prior to or during the sensorimotor phase of song learning disrupted FoxP2 expression in song circuitry. As expected, the songs of deafened juveniles were abnormal, however basal FoxP2 levels were unaffected. In contrast, when hearing or deaf juveniles sang for two hours in the morning, FoxP2 was acutely down-regulated in the striatal song nucleus, area X. The extent of down-regulation was similar between hearing and deaf birds. Interestingly, levels of FoxP2 and singing were correlated only in hearing birds.Conclusions/SignificanceHearing appears to link FoxP2 levels to the amount of vocal practice. As juvenile birds spent more time practicing than did adults, their FoxP2 levels are likely to be low more often. Behaviorally-driven reductions in the mRNA encoding this transcription factor could ultimately affect downstream molecules that function in vocal exploration, especially during sensorimotor learning.
Synaptotagmins are a family of proteins that function in membrane fusion events, including synaptic vesicle exocytosis. Within this family, synaptotagmin IV (Syt IV) is unique in being a depolarization-induced immediate early gene (IEG). Experimental perturbation of Syt IV modulates neurotransmitter release in mice, flies, and PC12 cells, and modulates learning in mice. Despite these features, induction of Syt IV expression by a natural behavior has not been previously reported. We used the zebra finch, a songbird species, to investigate Syt IV because song is a naturally learned behavior whose neuroanatomical basis is largely identified. We observed that, similar to rodents, Syt IV is inducible in songbirds. This induction was selective and depended on the nature of neuronal depolarization. Generalized seizures caused by the GABA(A) receptor antagonist, metrazole, induced the IEG, ZENK, in zebra finch brain. However, these same seizures failed to induce Syt IV in song control areas. In contrast, when nontreated birds sang, three song control areas showed striking Syt IV induction. Further, this induction appeared sensitive to the social context in which song was sung. Together, these data suggest that neural activity during singing can drive Syt IV expression within song circuitry whereas generalized seizure activity fails to do so even though song control areas are depolarized. Our findings indicate that, within this neural circuit for a procedurally learned sensorimotor behavior, Syt IV is selective and requires precisely patterned neural activity and/or neuromodulation associated with singing.
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