Thyrotrophin signalling at the core of photoperiodic time-measurement

地球上的生命必须应对不断变化的环境。其中一些变化是可以预测的，因为每天的明暗周期，或者每年的季节变化周期，动物已经进化出生物钟来优化它们对有节奏的环境的反应。这些时钟主要通过对环境照明的反应来同步。在哺乳动物中，季节性调整过程的一个关键部分是松果体产生一种叫做褪黑激素的激素。褪黑素仅在夜间产生，其产生和分泌模式的变化反映了夜间的长度，已知是动物在繁殖、换毛和冬眠的季节性循环过程中的关键部分。由于预计全球温度变化会对季节时序产生深远的破坏性影响，因此了解这种生理学背后的遗传机制元素变得越来越重要。这个项目的重点是提出褪黑激素在哺乳动物中的作用机制，实际上取决于褪黑激素对大脑对另一种激素——甲状腺激素的敏感性的影响。众所周知，甲状腺激素会影响动物的“代谢率”——它们的生存率，这基本上是季节变化的最终焦点，比如进入冬眠。因此，季节性变化取决于甲状腺激素影响的调节的概念直观上很有吸引力。我们感兴趣的褪黑素的作用实际上高度定位于大脑的底部，在下丘脑和脑垂体之间的界面。大脑的这个区域特别与代谢控制和繁殖时间有关。在这里，我们已经确定了垂体中褪黑激素敏感细胞和邻近下丘脑中控制该区域甲状腺激素水平的细胞之间的联系。这种联系是由褪黑激素反应细胞产生的另一种激素——促甲状腺激素（TSH），这种激素作用于邻近的下丘脑脑细胞，下丘脑脑细胞携带专门的促甲状腺激素“受体”。该项目希望探索这种联系的重要性，就褪黑激素控制TSH产生的方式以及TSH作用于邻近下丘脑的后果而言。这个项目非常有趣，因为我们正在探索的机制似乎与鸟类和两栖动物的机制有共同的特征，这表明它可能是一个古老的核心机制。此外，我们描述的TSH局部作用的新概念具有生物医学意义，因为包括格雷夫斯病在内的几种代谢紊乱都源于异常的TSH信号传导。

Life on Earth has to cope with constantly changing environments. Some of this change is predictable, due to the daily light dark cycle, or to the annual cycle of seasonal change, and animals have evolved biological clocks to optimise their responses to rhythmic environments. These clocks are synchronised primarily through their responses to environmental lighting. In mammals, a key part of the seasonal timing process is the production of a hormone, called melatonin, by the pineal gland. Melatonin is only produced at night, in a temporal pattern that reflects the night-length, and changes in its pattern of production and secretion are known to be a key part of the process whereby animals time seasonal cycles of breeding, moulting and hibernation. Understanding of the genetic mechanisms elements underlying this physiology is of increasing importance since global changes in temperature are predicted to have profound disruptive effects on seasonal timing. This project focusses on the proposal that the mechanisms of melatonin action in mammals, actually depend on melatonin's effects on brain sensitivity to another hormone called thyroid hormone. Thyroid hormone is well known for its effects on animals' 'metabolic rate' - their rate of living, which is essentially the ultimate focus of seasonal changes such as entry into hibernation. So the concept that seasonal changes depend on modulation of the influence of thyroid hormone is intuitively attractive. The effects of melatonin in which we are interested are actually highly localised to the base of the brain, at the interface between the hypothalamus and the pituitary. This region of the brain is specifically concerned with metabolic control, and the timing of breeding. Here, we have identified a link between melatonin-sensitive cells in the pituitary and cells in the adjacent hypothalamus which control thyroid hormone levels in this area. This link is the local production of another hormone called thyroid stimulating hormone (TSH) by melatonin responsive cells, which acts on adjacent hypothalamic brain cells carrying specialised 'receptors' for TSH. The project wishes to explore the importance of this link, in terms of the ways in which melatonin controls TSH production, and the consequences of TSH acting on the adjacent hypothalmus. This project is of considerable interest because the mechanism we are exploring appears to have features in common with that in birds and amphibians, suggesting that it may be an ancient core mechanism. Additionally the novel concept of local actions of TSH by the route we describe has biomedical relevance since several metabolic disorders, including Grave's Disease, stem from abnormal TSH signalling.