The influence of thyroid hormones, receptors, and transporters on brain structure and function

甲状腺激素不仅在发育过程中影响大脑的结构和功能，而且在甲状腺功能低下和甲亢的情况下，对成年机体的认知和神经过程也有深远的影响。在第一个资助期，我们使用了多模式成像电池(基于体素的形态测量、扩散张量成像、动脉自旋标记、静息状态功能磁共振成像、功能磁共振成像)和认知电池来区分甲亢和甲状腺功能减退的影响。此外，我们还发现，甲状腺激素受体α1基因和甲状腺激素转运蛋白MCT8基因的多态与注意和执行功能领域的行为影响有关。在第二个资助期，我们将在另外两个队列中应用已建立的测试组合：第一，我们将检查甲状腺激素β基因突变和甲状腺激素抵抗的患者，以描绘他们的认知和神经表型。其次，在一组新的具有THRA1基因多态的正常参与者中，我们将复制和扩展我们在认知和神经元表型方面的发现。此外，我们将扩展我们的方法，在将从合作项目中获得的转基因小鼠(Pax8-/-，Mct8/Oatp1c1 dKO)中添加多模式成像。我们的成像电池将包括静息状态功能磁共振成像、基于体素的形态测量和磁共振光谱。对正常甲状腺、甲状腺功能减退和甲状腺功能亢进Pax8-/-小鼠的检查将允许表征甲状腺激素对成年动物大脑结构和功能的影响，类似于我们对人类的方法。然而，在这些动物中，我们将能够在比人类更大的程度上控制甲状腺激素水平。Mct8/Oatp1c1双基因敲除小鼠是人类Allan-Herndon-Dudley综合征的模型，用三碘甲酸或二碘甲状腺丙酸治疗这些动物将使我们能够判断基因敲除对大脑结构和功能的影响在多大程度上是可逆的。这两种方法是互补的，并为我们了解甲状腺激素系统和中枢神经系统的相互作用的长期目标服务。

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.