Altered cerebellum development and dopamine distribution in a rat genetic model with congenital hypothyroidism

N. Shimokawa, B. Yousefi, S. Morioka, S. Yamaguchi, A. Ohsawa, H. Hayashi, A. Azuma, H. Mizuno, M. Kasagi, H. Masuda, H. Jingu, S. I. Furudate, A. Haijima, Y. Takatsuru, T. Iwasaki, M. Umezu, N. Koibuchi*

*この研究の対応する著者

研究成果: Article査読

25 被引用数 (Scopus)

抄録

Thyroid hormones play crucial roles in the development and functional maintenance of the central nervous system. Despite extensive studies of the neural function of thyroid hormones, little is known about the effects of hypothyroidism on behavioural traits and the mechanisms underlying such effects. In the present study, we report an investigation of congenitally hypothyroid mutant rdw rats, revealing a novel function of thyroid hormones in the central nervous system. The rdw rats were subjected to behavioural analyses such as the rotarod test, open field test and circadian activity measurement. To determine the cause of behavioural disorders, cerebellar morphogenesis was examined by immunohistochemical analysis, and the axonal transport of dopamine in the nigrostriatal pathway was analysed by high-performance liquid chromatography and western blotting. The effects of thyroxine administration to the rdw rats were examined by behavioural analysis. The rdw rats showed severe impairment of motor coordination and balance. This could be explained by the fact that the rats showed severe retardation of cerebellar morphogenesis, which correlates with the small somata and poor dendritic arborisation of Purkinje cells and retarded migration of granule cells particularly during the first two postnatal weeks. Moreover, the rdw rats showed hypoactivity, characterised by decreased circadian locomotor activity. After weaning, thyroxine administration improved the dwarfism in rdw rats but had no effect on cerebellar function. In addition, the rdw rats showed anxiety and depression intrinsically to novel surroundings. Interestingly, the rdw rats showed high levels of dopamine in the substantia nigra and low levels in the striatum, an important centre for the coordination of behaviour. Furthermore, low levels of tubulin in the striatum were detected, indicating the aberrant axonal transport of dopamine in the nigrostriatal pathway as a result of the reduced delivery of microtubules. These findings indicate an important function of thyroid hormones in cerebellar formation and in the regulation of axonal transport of dopamine. Moreover, rdw rats will be useful for studies of brain function and behavioural disorders in congenital hypothyroidism.

本文言語English
ページ(範囲)164-175
ページ数12
ジャーナルJournal of Neuroendocrinology
26
3
DOI
出版ステータスPublished - 2014 3月
外部発表はい

ASJC Scopus subject areas

  • 内分泌学、糖尿病および代謝内科学
  • 内分泌学
  • 内分泌系および自律システム
  • 細胞および分子神経科学

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