Age effect on thyroid hormone brain response in male mice
- 134 Downloads
Thyroid hormones (TH) are important for brain development and central nervous system (CNS) function. Disturbances of thyroid function occur with higher prevalence in the ageing population and may negatively impact brain function.
We investigated the age impact on behavior in young adult and old male mice (5 vs. 20 months) with chronic hypo- or hyper-thyroidism as well as in sham-treated controls. Expression of TH transporters and TH responsive genes was studied in CNS and pituitary by in situ hybridization and qRT-PCR, whereas TH serum concentrations were determined by immunoassay.
Serum TH levels were lower in old compared with young hyperthyroid mice, suggesting a milder hyperthyroid phenotype in the aged group. Likewise, elevated plus maze activity was reduced in old hyperthyroid animals. Under hypothyroid conditions, thyroxine serum concentrations did not differ in young and old mice. Both groups showed a comparable decline in activity and elevated anxiety levels. However, an attenuated increase in hypothalamic thyrotropin releasing hormone and pituitary thyroid stimulating hormone transcript expression was found in old hypothyroid mice. Brain expression of monocarboxylate transporter 8 and organic anion transporting polypeptide 1c1 was not affected by age or TH status.
In summary, ageing attenuates neurological phenotypes in hyperthyroid but not hypothyroid mice, which fits with age effects on TH serum levels in the animals. In contrast no changes in TH transporter expression were found in aged mouse brains with hyper- or hypo-thyroid state.
KeywordsAgeing Male mice Thyroid hormones Hypothyroidism Hyperthyroidism
The authors are grateful to A. Jaeger, S. Rehn, M. Schmidt for their dedicated technical support.
This work was supported by DFG FU356/7–1/2 to DF, MO1018/2–1/2 to LCM, and HE3418/8–1 to HH in the framework of SPP1629 and RTG1715 to HH/FK. Funding source was not involved in decisions about study design; collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All animal experiments were performed in accordance with the German regulations for Laboratory Animal Science (GVSOLAS) and the European Health Law of the Federation of Laboratory Animal Science Associations (FELASA). The protocols for animal studies were approved by the Landesamt für Natur, Umwelt und Verbraucherschutz Nordrhein-Westfalen (LANUV-NRW), Germany (AZ.84–02.04.2013.A188).
- 3.F.L. Yudiarto, L. Muliadi, D. Moeljanto, B. Hartono, Neuropsychological findings in hyperthyroid patients. Acta Med. Indones. 38(1), 6–10 (2006)Google Scholar
- 5.S. Gulseren, L. Gulseren, Z. Hekimsoy, P. Cetinay, C. Ozen, B. Tokatlioglu, Depression, anxiety, health-related quality of life, and disability in patients with overt and subclinical thyroid dysfunction. Arch. Med. Res. 37(1), 133–139 (2006). https://doi.org/10.1016/j.arcmed.2005.05.008 CrossRefGoogle Scholar
- 7.M.F. Schreckenberger, U.T. Egle, S. Drecker, H.G. Buchholz, M.M. Weber, P. Bartenstein, G.J. Kahaly, Positron emission tomography reveals correlations between brain metabolism and mood changes in hyperthyroidism. J. Clin. Endocrinol. Metab. 91(12), 4786–4791 (2006). https://doi.org/10.1210/jc.2006-0573 CrossRefGoogle Scholar
- 8.W. Zhang, X. Liu, Y. Zhang, L. Song, J. Hou, B. Chen, M. He, P. Cai, H. Lii, Disrupted functional connectivity of the hippocampus in patients with hyperthyroidism: evidence from resting-state fMRI. Eur. J. Radiol. 83(10), 1907–1913 (2014). https://doi.org/10.1016/j.ejrad.2014.07.003 CrossRefGoogle Scholar
- 10.A. Gobel, M. Heldmann, A. Sartorius, M. Gottlich, A.L. Dirk, G. Brabant, T.F. Munte, Mild thyrotoxicosis leads to brain perfusion changes: an arterial spin labelling study. J. Neuroendocrinol. 29(1), (2017). https://doi.org/10.1111/jne.12446
- 12.S. Barez-Lopez, D. Bosch-Garcia, D. Gomez-Andres, I. Pulido-Valdeolivas, A. Montero-Pedrazuela, M.J. Obregon, A. Guadano-Ferraz, Abnormal motor phenotype at adult stages in mice lacking type 2 deiodinase. PLoS ONE 9(8), e103857 (2014). https://doi.org/10.1371/journal.pone.0103857 CrossRefGoogle Scholar
- 14.J.P. Stohn, M.E. Martinez, A. Hernandez, Decreased anxiety- and depression-like behaviors and hyperactivity in a type 3 deiodinase-deficient mouse showing brain thyrotoxicosis and peripheral hypothyroidism. Psychoneuroendocrinology 74, 46–56 (2016). https://doi.org/10.1016/j.psyneuen.2016.08.021 CrossRefGoogle Scholar
- 15.C. Venero, A. Guadano-Ferraz, A.I. Herrero, K. Nordstrom, J. Manzano, G.M. de Escobar, J. Bernal, B. Vennstrom, Anxiety, memory impairment, and locomotor dysfunction caused by a mutant thyroid hormone receptor alpha1 can be ameliorated by T3 treatment. Genes Dev. 19(18), 2152–2163 (2005). https://doi.org/10.1101/gad.346105 CrossRefGoogle Scholar
- 19.H. Heuer, M.K. Maier, S. Iden, J. Mittag, E.C. Friesema, T.J. Visser, K. Bauer, The monocarboxylate transporter 8 linked to human psychomotor retardation is highly expressed in thyroid hormone-sensitive neuron populations. Endocrinology 146(4), 1701–1706 (2005). https://doi.org/10.1210/en.2004-1179 CrossRefGoogle Scholar
- 22.D. Spano, I. Branchi, A. Rosica, M.T. Pirro, A. Riccio, P. Mithbaokar, A. Affuso, C. Arra, P. Campolongo, D. Terracciano, V. Macchia, J. Bernal, E. Alleva, R. Di Lauro, Rhes is involved in striatal function. Mol. Cell Biol. 24(13), 5788–5796 (2004). https://doi.org/10.1128/MCB.24.13.5788-5796.2004 CrossRefGoogle Scholar
- 23.P. Gil-Ibanez, J. Bernal, B. Morte, Thyroid hormone regulation of gene expression in primary cerebrocortical cells: role of thyroid hormone receptor subtypes and interactions with retinoic acid and glucocorticoids. PLoS ONE 9(3), e91692 (2014). https://doi.org/10.1371/journal.pone.0091692 CrossRefGoogle Scholar
- 25.C.G. Vasilopoulou, C. Constantinou, D. Giannakopoulou, P. Giompres, M. Margarity, Effect of adult onset hypothyroidism on behavioral parameters and acetylcholinesterase isoforms activity in specific brain regions of male mice. Physiol. Behav. 164(Pt A), 284–291 (2016). https://doi.org/10.1016/j.physbeh.2016.06.016 CrossRefGoogle Scholar
- 26.K. Wallis, M. Sjogren, M. van Hogerlinden, G. Silberberg, A. Fisahn, K. Nordstrom, L. Larsson, H. Westerblad, G. de Escobar Morreale, O. Shupliakov, B. Vennstrom, Locomotor deficiencies and aberrant development of subtype-specific GABAergic interneurons caused by an unliganded thyroid hormone receptor alpha1. J. Neurosci. 28(8), 1904–1915 (2008). https://doi.org/10.1523/JNEUROSCI.5163-07.2008 CrossRefGoogle Scholar