Altered Cerebellum Development and Dopamine Distribution in a Rat Genetic Model with Congenital Hypothyroidism. (March 2014)

• Record Type: Journal Article
• Authors: Shimokawa, N.; Yousefi, B.; Morioka, S.; Yamaguchi, S.; Ohsawa, A.; Hayashi, H.; Azuma, A.; Mizuno, H.; Kasagi, M.; Masuda, H.; Jingu, H.; Furudate, S.‐I.; Haijima, A.; Takatsuru, Y.; Iwasaki, T.; Umezu, M.; Koibuchi, N.
• Is Part Of: Journal of neuroendocrinology. Volume 26:Number 3(2014:Mar.)
• Page Start: 164
• Page End: 175
• Publication Date: 2014-03
• Subjects: Neuroendocrinology -- Periodicals; 616.4
• DOI: 10.1111/jne.12135
• Languages: English
• ISSNs: 0953-8194

Abstract

<abstract abstract-type="main" id="jne12135-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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 <italic>rdw</italic> rats, revealing a novel function of thyroid hormones in the central nervous system. The <italic>rdw</italic> 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 <italic>rdw</italic> rats were examined by behavioural analysis. The <italic>rdw</italic> 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 <italic>rdw</italic> rats showed hypoactivity, characterised by decreased circadian locomotor activity. After weaning, thyroxine administration improved the dwarfism in <italic>rdw</italic> rats but had no effect on cerebellar function. In addition, the <italic>rdw</italic> rats showed anxiety and depression intrinsically to novel surroundings. Interestingly, the <italic>rdw</italic> 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, <italic>rdw</italic> rats will be useful for studies of brain function and behavioural disorders in congenital hypothyroidism.</p> </abstract>