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的气候中，通常在冬季的几个月里每天定期体温和代谢率下降，以此作为一种节能策略。这些每日的麻木发作由大脑的神经通路控制，并由生物钟计时。我们几乎对这些动物是如何实现代谢调节这一非凡壮举一无所知。我们早就知道甲状腺激素对季节生理节律的正确时机至关重要，而且这些激素对体温调节也是至关重要的。本项目的目的是研究甲状腺激素及其代谢物在昏迷过程中的作用。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’(来自甲状腺)的酶，并将其转化为一种名为T3的活性形式(已有一个碘分子被‘脱碘酶-2’酶去除)。另一条途径是利用另一种酶--脱碘酶-3，调节T4转化为不活跃的“反向”T3分子。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自然产生的化合物，称为胸腺胺或T1AMT1AM是一种有效的抑制小鼠体温的药物，似乎会使它们陷入麻木。我们已经证明，这也发生在西伯利亚仓鼠身上。如果西伯利亚仓鼠的日照时间很短，室管膜细胞中的脱碘酶3水平就会急剧上升。在这个项目中，我们的目标是了解脱碘酶3基因表达的这些自然发生的变化是否对大脑中T1AM表达水平的变化负责。我们将通过与其发现者合作测量T1AM，并评估夏季和冬季仓鼠对T1AM治疗的麻木反应来研究这一点。然后，我们将看看是否可以通过使用病毒将基因传递到大脑中酶工作的区域来改变脱碘酶3的表达。这些病毒将导致该基因比正常或被抑制的更强的表达，通过这种方法，我们的目的是证明脱碘酶活性的改变是否是季节性麻木机制的主要原因。最后，我们将研究两个小鼠的遗传模型，在这些模型中，更容易操纵基因表达。首先，我们将研究一种我们已知的受体的基因移除是否会导致这些小鼠的麻木倾向导致T1AM合成的改变。其次，我们将使用一只自然脱碘酶3基因过度表达的小鼠，这会导致这种酶产生过多。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新陈代谢的基本机制是如何控制的。这对人类的研究有明显的影响，也许长期使用这种化合物来改变医疗目的或甚至长期太空飞行的全身新陈代谢的可能性。

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.