Thermal sensory mechanisms involved in body temperature regulation

在寒冷的环境中，哺乳动物减少流向皮肤的血液以保存热量，而在炎热的环境中，出汗会降低体温。众所周知，寒冷环境中皮肤血流量的减少是由去甲肾上腺素能交感神经介导的，去甲肾上腺素能交感神经支配血管并释放去甲肾上腺素，以引起血管收缩。相反，胆碱能交感神经支配汗腺，在炎热的环境中产生凉爽。然而，驱动交感神经系统这两个部分活动的热和冷敏感机制--“恒温器”--是未知的。在初步实验中，我们在交感神经元中发现了一种离子通道，该通道可被寒冷直接激活，而在副交感神经元中表达的另一种离子通道是胆碱能的，它可被温暖直接激活。这些反应背后的热和冷敏感离子通道是新的热敏机制，因为它们不被任何已知热敏离子通道的激动剂激活。这些新的热敏机制的发现现在将使我们能够表征它们的电学性质。然后，我们将继续使用RNA测序来确定它们的分子基础，在这一过程中，我们将比较特定的冷敏感和温敏神经元群体中表达的mRNA，并将其与类似的非热敏感群体进行比较，从而确定哪些离子通道mRNAs存在差异表达。最后，我们将克隆和表达我们鉴定的离子通道，以检查克隆的基因的性质是否与在温度敏感神经元中表达的相同。同时，我们将研究决定哺乳动物核心体温的温度敏感机制。温暖激活的神经元存在于下丘脑前视前核，在调节体温方面起重要作用。我们将从这个区域分离神经元，并研究它们在热刺激下的激活。这种机制与我们在胆碱能神经元中发现的温激活机制相同吗？我们将使用原位杂交来检测这些神经元中表达的mRNA，如果表达了相同的通道，那么我们将对生物学中的一个重要问题有一个答案，即哺乳动物如何感知它们的核心温度。如果机制不同，我们将从热敏感神经元群体中分离出mRNA，并将其与相邻的非热敏感神经元中的mRNA丰度进行比较，以类似于上面概述的方法来克隆温度调节基因。

In a cold environment mammals reduce blood flow to the skin in order to conserve heat, while in a hot environment sweating reduces body temperature. It is well established that the reduction in skin blood flow in a cold environment is mediated by noradrenergic sympathetic nerves, which innervate blood vessels and release noradrenaline in order to cause vasoconstriction in response to cold. Conversely, cholinergic sympathetic nerves innervate sweat glands to produce cooling in a hot environment. The heat and cold-sensitive mechanisms - the "thermostats" - which drive activity in these two divisions of the sympathetic nervous system are, however, unknown. In preliminary experiments we have found an ion channel in sympathetic neurons which is directly activated by cold, while a different ion channel expressed in parasympathetic neurons, which are cholinergic, is directly activated by warmth. The heat and cold-sensitive ion channels underlying these responses are novel thermosensory mechanisms, as they are not activated by any of the agonists for known thermally sensitive ion channels. The discovery of these novel thermally sensitive mechanisms will now allow us to characterize their electrical properties. We will then proceed to determine their molecular basis using RNA sequencing, in which we will compare the mRNA expressed in specific cold-sensitive and warm-sensitive neuronal populations with similar populations which are not thermally sensitive, and so will determine which ion channel mRNAs are differentially expressed. Finally, we will clone and express the ion channels that we have identified in order to check that the properties of the cloned gene are the same as those expressed in thermally-sensitive neurons.In parallel we will investigate the thermally sensitive mechanism which determines the mammalian core body temperature. Warmth-activated neurons are known to be present in the pre-optic nucleus of the anterior hypothalamus and to be important in regulating body temperature. We will isolate neurons from this region and will study their activation by thermal stimuli. Is the mechanism the same as the warmth-activated mechanism that we have discovered in cholinergic neurons? We will examine the mRNA expressed in these neurons using in situ hybridization, and if the same channels are expressed then we will have an answer to an important problem in biology, namely how mammals sense their core temperature. If the mechanism is not the same then we will isolate mRNA from populations of thermally sensitive neurons and will compare the mRNA abundance with that in adjacent non-thermally sensitive to clone the thermoregulatory gene in a similar approach to that outlined above.