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Neuroanatomical Visualization of the Impaired Striatal Connectivity in Huntington’s Disease Mouse Model

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Abstract

Huntington’s disease (HD) is a movement disorder characterized by the early selective degeneration of striatum. For motor control, the striatum receives excitatory inputs from multiple brain regions and projects the information to other basal ganglia nuclei. Despite the pathological importance of the striatal degeneration in HD, there are little anatomical data that show impaired striatal connectivity in HD. For the anatomical mapping of the striatum, we injected here a neurotracer DiD to the dorsal striatum of HD mouse model (YAC128). Compared with littermate controls, the number of the traced inputs to the striatum was reduced dramatically in YAC128 mice at 12 months of age suggesting massive destruction of the striatal connections. Basal ganglia inputs were significantly damaged in HD mice by showing 61 % decrease in substantia nigra pars compacta, 85 % decrease in thalamic centromedian nucleus, and 55 % decrease in thalamic parafascicular nucleus. Cortical inputs were also greatly decreased by 43 % in motor cortex, 48 % in somatosensory cortex, and 72 % in visual cortex. Besides the known striatal connections, the neurotracer DiD also traced inputs from amygdala and the amygdala inputs were decreased by 68 % in YAC128 mice. Considering the role of amygdala in emotion processing, the impairment in amygdalostriatal connectivity strongly suggests that emotional disturbances could occur in HD mice. Indeed, open-field tests further indicated that YAC128 mice exhibited changes in emotional behaviors related to symptoms of depression and anxiety. Although onset of HD is clinically determined on the basis of motor abnormality, emotional deficits are also common features of the disease. Therefore, our anatomical connectivity mapping of the striatum provides a new insight to interpret brain dysfunction in HD.

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Acknowledgments

This work was supported by an intramural funding from the Korea Institute of Science and Technology (2E25023 and 2 V03400 to Y.K.) and the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST), the National Research Foundation of Korea (2012R1A2A2A02118 38 to Y.K. and 2011-0030928, 2011-0030049 and 2012-003338 to H.S.). This study was also supported by the National Institutes of Health (NIH) Grant (R01 NS067283 to H.R.)

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Authors and Affiliations

  1. Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Hwarangno 14-gil 5, Seongbuk-gu, Seoul, 136-791, South Korea

    Dohee Kim, Dong Jin Kim, Hoon Ryu & Yun Kyung Kim

  2. Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, 120-749, South Korea

    Dohee Kim & Eunji Cheong

  3. Department of Molecular and Life Sciences, Hanyang University, Gyeonggi-do, 426-791, South Korea

    Jeha Jeon & Hyemyung Seo

  4. Boston University Alzheimer’s Disease Center, Boston University School of Medicine, Boston, MA, USA

    Hoon Ryu

  5. Biological Chemistry, University of Science and Technology (UST), Daejeon, 305-333, South Korea

    Yun Kyung Kim

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  1. Dohee Kim
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Correspondence to Yun Kyung Kim.

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Dohee Kim and Jeha Jeon contributed equally to this work.

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Fig. S1

Striatal degeneration and motor deficits in YAC128 mice. a YAC128 mice showed neuronal loss in striatum by showing 28 % decrease of DARPP-32 (dopamine- and cAMP-regulated phosphoprotein, MW 32 kDa)-positive neurons. Scale bar: 100 μm. b Rotarod test indicates that YAC128 mice show significantly shortened latency to fall on the rod (DOC 428 kb)

Fig. S2

Photomicrography of brain slices presenting two types of DiD-labeled patterns. a VL region shows the amorphous shading pattern of DiD fluorescence and CM region shows DiD-labeled somata. b SNr region shows the amorphous shading pattern of DiD fluorescence, and SNc region shows DiD-labeled somata. Scale bars: 200 μm. VL ventrolateral nucleus, CM centromedian nucleus, SNc substantia nigra pars compacta, SNr substantia nigra pars reticulata (DOC 739 kb)

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Kim, D., Jeon, J., Cheong, E. et al. Neuroanatomical Visualization of the Impaired Striatal Connectivity in Huntington’s Disease Mouse Model. Mol Neurobiol 53, 2276–2286 (2016). https://doi.org/10.1007/s12035-015-9214-2

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