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Nat Neurosci. 2015 Nov;18(11):1617-22. doi: 10.1038/nn.4133. Epub 2015 Oct 5.

Human mutant huntingtin disrupts vocal learning in transgenic songbirds.

Author information

Laboratory of Animal Behavior, The Rockefeller University, New York, New York, USA.
Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, New York, USA.
Neurodegeneration Laboratory, University of California, San Diego, La Jolla, California, USA.
Vector Development Core Lab, UCSD School of Medicine, La Jolla, California, USA.
CHDI Management Inc., New York, New York, USA.


Speech and vocal impairments characterize many neurological disorders. However, the neurogenetic mechanisms of these disorders are not well understood, and current animal models do not have the necessary circuitry to recapitulate vocal learning deficits. We developed germline transgenic songbirds, zebra finches (Taneiopygia guttata) expressing human mutant huntingtin (mHTT), a protein responsible for the progressive deterioration of motor and cognitive function in Huntington's disease (HD). Although generally healthy, the mutant songbirds had severe vocal disorders, including poor vocal imitation, stuttering, and progressive syntax and syllable degradation. Their song abnormalities were associated with HD-related neuropathology and dysfunction of the cortical-basal ganglia (CBG) song circuit. These transgenics are, to the best of our knowledge, the first experimentally created, functional mutant songbirds. Their progressive and quantifiable vocal disorder, combined with circuit dysfunction in the CBG song system, offers a model for genetic manipulation and the development of therapeutic strategies for CBG-related vocal and motor disorders.

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