Central Control of Cardiovascular Function and Energy Expenditure by Thyroid Hormone

甲状腺激素对大脑发育和功能，调节行为以及心血管特性和能量稳态的中心控制很重要。然而，潜在的细胞和分子机制尚不完全清楚。第一期资助项目旨在利用甲状腺激素及其受体TRa1在中枢神经系统中的重要性，以更好地了解心血管和代谢功能的自主控制。我们的研究表明，母体TRa1信号是雄性野生型后代腹内侧下丘脑大麻素受体1表达的正确胎儿编程所必需的，从而调节其代谢和运动活动。在第二个资助期，我们现在的目标是研究母体TRb信号和甲状腺功能亢进对野生型后代的作用。我们的初步数据表明，心血管和体温调节发生了严重变化，但甲状腺激素经济性没有改变。通过使用最先进的无线电遥测技术和代谢谱分析这些甲状腺功能亢进母亲的后代的外周和中枢改变，我们旨在更多地了解心血管功能和能量消耗的中枢控制。在该项目的第二部分，我们分析了甲状腺激素对控制心率和血压的下丘脑小白蛋白神经元群的作用。利用tr1和TRb突变小鼠以及怀孕期间甲状腺激素水平高的母亲，我们发现这两种TR亚型对这些神经元的发育都至关重要：未配体的TRb似乎是维持前体细胞增殖直到E12的必要条件，而配体的TRa1是E12之后直到出生的分化所必需的。在第二个资助期，我们现在希望在这些发现的基础上，用甲状腺激素治疗从受孕到E12以及从E12到出生的怀孕女性，并分析对下丘脑小白蛋白神经元发育以及后代心血管功能的影响。此外，通过立体定向注射腺相关病毒载体，我们的目标是在这些神经元中特异性表达显性阴性和组成性活性甲状腺激素受体，以阐明甲状腺激素信号在成年动物这些细胞中的作用。我们的结果将有助于更好地理解甲状腺激素在母亲以及成年后代中对自主神经功能（如心率、血压和能量消耗）的中枢控制的作用。此外，它们可以揭示以前未知的心血管疾病和肥胖的表观遗传风险因素。

Thyroid hormone is important for brain development and function, modulating behavior as well as the central control of cardiovascular properties and energy homeostasis. However, the underlying cellular and molecular mechanisms are not completely understood. The project of the first funding period aimed to exploit the importance of thyroid hormone and its receptor TRa1 in the central nervous system to obtain a better understanding of the autonomic control of cardiovascular and metabolic functions. Our studies revealed that maternal TRa1 signaling is required for correct fetal programming of cannabinoid receptor 1 expression in the ventromedial hypothalamus of the male wildtype offspring, which regulates their metabolic and locomotor activity. In the second funding period we now aim to study the role of maternal TRb signaling and hyperthyroidism for wildtype offspring. Our preliminary data indicate severe alterations in the cardiovascular and thermoregulatory regulation without alterations in thyroid hormone economy. By dissecting the peripheral and central alterations in these offspring of hyperthyroid mothers using state-of-the-art radiotelemetry and metabolic profiling, we aim to understand more about the central control of cardiovascular functions and energy expenditure.In the second part of the project, we analyzed the role of thyroid hormone for a population of hypothalamic parvalbumin neurons that control heart rate and blood pressure. Using a combination of TRa1 and TRb mutant mice as well as mothers with high thyroid hormone levels during pregnancy, we revealed that both TR isoforms are crucial for the development of these neurons: unliganded TRb seems required for maintaining the proliferation of the precursors cells until E12, whereas liganded TRa1 is necessary for the differentiation after E12 until birth. In the second funding period we now want to build on these findings and treat pregnant females from conception to E12 as well as from E12 to birth with thyroid hormone and analyze the consequences for hypothalamic parvalbumin neuron development as well as cardiovascular function in the offspring. Moreover, using stereotaxic injection of adeno-associated virus vectors, we aim to express dominant-negative and constitutively active thyroid hormone receptors specifically in these neurons to elucidate the role of thyroid hormone signaling for these cells in the adult animal. Our results will contribute to a better understanding of the role of thyroid hormone in the mother as well as the adult offspring for the central control of autonomic functions such as heart rate, blood pressure and exergy expenditure. Moreover, they can reveal previously unknown epigenetic risk factors for cardiovascular disease and obesity.