Neural and molecular pathways regulating torpor in mammals

季节性繁殖的哺乳动物，如西伯利亚仓鼠，生活在极端纬度和寒冷气候中，通常在冬季的几个月里，体温和代谢率每天都会有规律地下降，这是一种节能策略。这些每天的昏睡发作是由大脑的神经通路控制的，并由生物钟计时。我们几乎不知道这些动物是如何实现这种新陈代谢调节的非凡壮举的。我们早就知道，甲状腺激素对季节性生理节律的正确计时至关重要，而且这些激素对体温调节也至关重要。本项目旨在探讨甲状腺激素及其代谢物在冬眠过程中的作用。在大脑内部，排列在第三脑室的细胞构成了一个关键结构。这些“室管膜”细胞含有作用于甲状腺素或“T4”的酶（它起源于甲状腺），并将其转化为一种名为T3的活性形式（其中一个碘分子被“脱碘酶-2”酶去除）。另一种途径利用另一种酶脱碘酶-3调节T4向非活性“反向”T3分子的转化。最近的研究表明，这种反向的T3分子可以进一步转化为一种天然存在的化合物，叫做甲状腺素胺或T1AM。T1AM在小鼠体内是一种有效的体温抑制剂，似乎会使它们进入麻木状态。我们已经证明，这也发生在西伯利亚仓鼠身上。如果让西伯利亚仓鼠保持较短的“冬季”白昼长度，室管膜细胞中的脱碘酶3水平会急剧上升。在这个项目中，我们的目标是了解这些自然发生的脱碘酶3基因表达的变化是否负责调节大脑中T1AM表达水平的改变。我们将通过与其发现者合作测量T1AM来研究这一点，并评估仓鼠在夏天和冬季对T1AM治疗的麻木反应。然后，我们将看看是否可以通过使用病毒将基因传递到酶起作用的大脑区域来改变去碘酶3的表达。这些病毒将导致基因比正常情况下更强烈地表达或抑制，通过这种方式，我们的目标是证明改变的去碘酶活性是否是季节性迟钝机制的主要原因。最后，我们将在小鼠中研究两种更容易操纵基因表达的遗传模型。首先，我们将研究基因去除一种受体是否会导致这些小鼠“嗜睡”，从而改变T1AM的合成。其次，我们将使用一只天然脱碘酶3基因“过度表达”的老鼠，导致这种酶的过量产生。这将使我们能够确定这一途径的改变是否是控制麻木的必要先决条件。这项研究的好处是我们希望了解调节身体代谢的基本机制是如何被控制的。这对人类的研究有明显的影响，也许从长远来看，使用这些化合物来改变人体的新陈代谢，用于医疗目的，甚至是长期的太空飞行。

Seasonally breeding mammals such as Siberian hamsters live in extreme latitudes and cold climates, and commonly undergo regular daily drops of body temperature and metabolic rate in the winter months as an energy saving strategy. These daily torpor bouts are controlled by neural pathways from the brain, and are timed by the circadian clock. We know almost nothing of how such animals achieve this remarkable feat of metabolic adjustment. We have known for some time that thyroid hormones are crucial for correct timing of seasonal physiological rhythms, and that these hormones are also crucial for body temperature regulation. The purpose of this project is to investigate the role of thyroid hormones and their metabolites in the torpor process. Within the brain, the cells that line the third ventricle form a key structure. These 'ependymal' cells contain enzymes that act on thyroxine or 'T4' (which originates from the thyroid gland) and converts it to an active form called T3 (which has had one iodine molecule removed by a 'deiodinase-2' enzyme). An additional pathway regulates conversion of T4 to an inactive 'reverse' T3 molecule, using another enzyme, deiodinase-3. Recent studies now show that this reverse T3 molecule can be further converted to a naturally occurring compound called thyronamine or T1AM. T1AM is a potent suppressor of body temperature in mice and appears to drive them into torpor. We have shown that this also occurs in Siberian hamsters. Deiodinase 3 levels in the ependymal cells rise sharply if Siberian hamsters are kept on short 'winter-like' day lengths. In this project, we aim to see whether these naturally occurring changes in expression of the gene for deiodinase 3 are responsible for regulating altered levels of expression of T1AM in the brain. We will investigate this by measuring T1AM in collaboration with its discoverer, and assessing torpor responses of hamsters on summer and winter day lengths to T1AM treatment. We will then see whether we can alter expression of de-iodinase 3 by using viruses to deliver genes to the region of the brain where the enzyme operates. These viruses will cause the gene to be more strongly expressed than normal or suppressed and by this means we aim to demonstrate whether altered de-iodinase activity is a prime cause of the seasonal torpor mechanism. Finally, we will study two genetic models in mice, where it is easier to manipulate gene expression. In the first, we will study whether genetic removal of a receptor that we know makes these mice 'torpor-prone' results in altered T1AM synthesis. Secondly, we will use a mouse in which the natural deiodinase 3 gene is 'over-expressed' causing excessive amounts of this enzyme to be produced. This will allow us to establish whether alterations in this pathway are an essential pre-requisite for the control of torpor. The benefits of this research are that we hope to understand how fundamental mechanisms regulating body metabolism are controlled. There are clear implications to the study of man, and perhaps the possibility longer term of using such compounds to alter whole-body metabolism for medical purposes or even long-term space flights.