SPP 1629, Subproject: The influence of thyroid hormones, receptors, and transporters on brain structure and function

Thyroid hormones influence brain structure and function not only during development but also have profound effects on cognitive and neural processes in the adult organism in the conditions of hypo- and hyperthyroidism. In the first funding period we used a multimodal imaging battery (voxel-based morphometry, diffusion-tensor-imaging, arterial spin labeling, resting state fMRI, fMRI) and cognitive battery to delinate the effects of hyper- and hypothyroidism. In addition, we have shown that polymorphisms in the thyroid hormone receptor alpha1 gene as well as in the thyroid hormone transporter MCT8 are associated with behavioral effects in the attention and executive function domains. In the second funding period we will apply the established test-battery in two additional cohorts: First, we will examine patients with a mutation in the thyroid hormone beta gene and thyroid hormone resistance to delineate their cognitive and neuronal phenotype. Second, in a new group of normal participants with the polymorphism in the THRA1-gene we will replicate and extend our findings on the cognitive and neuronal phenotype. In addition, we will extend our approach by adding multimodal imaging in transgenic mice (Pax8-/-, Mct8/Oatp1c1 dko) that will be obtained from cooperating projects. Our imaging battery will include resting state fMRI, voxel-based morphometry, and magnetic resonance spectroscopy. The examination of euthyroid, hypothyroid and hyperthyroid Pax8-/- mice will allow the characterization of thyroid hormone effects on brain structure and function in the adult animal similar to our approach in humans. In these animals we will be able to manipulate thyroid hormone levels to a greater extent than in the human, however. Mct8/Oatp1c1 double knock-out mice serve as a model for the human Allan-Herndon-Dudley-Syndrome, and the treatment of these animals with triiodothyroacetic acid or diiodothyropropionic acid will allow us to judge to what extent the effects of the knock-out on brain structure and function are reversible by treatment. Both approaches are complementary and serve our long-term goal to understand the interaction of the thyroid hormone system and the central nervous system.