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结构和功能，而且在甲状腺功能低下和甲状腺功能亢进的成年机体中对认知和神经过程产生深远的影响。在第一个资助期，我们使用了多模态成像电池（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fMRI、fMRI）和认知电池来描绘甲状腺功能亢进和甲状腺功能减退的影响。此外，我们已经证明，甲状腺激素受体α 1基因和甲状腺激素转运体MCT8基因的多态性与注意力和执行功能域的行为影响有关。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电池：首先，我们将检查甲状腺激素β基因突变和甲状腺激素抗性的患者，以描述他们的认知和神经元表型。其次，在一组具有thra1基因多态性的新正常参与者中，我们将复制并扩展我们在认知和神经元表型上的发现。此外，我们将通过在合作项目中获得的转基因小鼠（Pax8-/-, Mct8/Oatp1c1 dko）中添加多模态成像来扩展我们的方法。我们的成像电池将包括静息状态fMRI，基于体素的形态测量和磁共振波谱。对甲状腺功能正常、甲状腺功能低下和甲状腺功能亢进的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，类似于我们在人类中的方法。然而，在这些动物身上，我们将能够比在人类身上更大程度地操纵甲状腺激素水平。Mct8/Oatp1c1双敲除小鼠作为人类Allan-Herndon-Dudley-Syndrome的模型，用三碘甲状乙酸或二碘甲状丙酸治疗这些动物将使我们能够判断敲除对大脑结构和功能的影响在多大程度上通过治疗是可逆的。这两种方法是互补的，并为我们的长期目标服务，以了解甲状腺激素系统和中枢神经系统的相互作用。

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.