果蝇冷觉感受机制研究

Many animals, including mammals and the fruit fly Drosophila melanogaster, are very sensitive to small differences in ambient temperature and seek out their preferred temperature within their thermal landscape. Many disease-transmitting insects, such as those that spread malaria, dengue and yellow fever, use thermotaxis as one of the critical strategies to find their human hosts. Thus, substances that perturb this behavior may reduce the incidence of insect-borne diseases. However, the molecules that are responsible for thermotactic behavior are largely unknown. One exception to this is the class of channels, referred to as Transient Receptor Potential (TRP) channels, which are critical for thermosensation in mice and have recently been reported to function in Drosophila thermotaxis as well. In this proposal, we study the roles of TRP channels in Drosophila larval cool/cold sensation. We reported that a TRPV channel IAV is required for larval cold avoidance, though the channel itself is not thermosensitive. In this study, based on our preliminary data, we propose that IAV forms a heteromultimeric cold receptor together with another TRPV channel NAN. This might be the first cold receptor discovered in flies. We will investigate whether that the two channels could interact in vivo and are required for the neuronal physiological calcium increase and behavioral avoidance to cold temperatures. Furthermore, we suggest that assembling non-thermosensitive TRPs into a thermosensitive one might be a shared strategy in fruit flies and mammals to increase thermoreceptor numbers without evolving new protein families, which is insightful for finding additional thermoreceptors.

许多动物，包括哺乳动物和果蝇，都对环境中微小的温度变化非常敏感，都积极寻找适合自己生存的温度区间。很多病原传播体，比如传播疟疾、登革热和黄热病的蚊蝇，都利用宿主体温来寻找宿主。因此，如果干扰温度趋向行为，则可能可以降低虫媒疾病的发生。然而我们对介导温度趋向行为的分子了解的很有限。不过有一特例就是TRP离子通道：它们被发现在小鼠和果蝇的温度趋向行为中都发挥着重要作用。本课题将重点研究TRP在果蝇幼虫低温感受中的作用。我们曾报道一个TRPV通道IAV在幼虫规避低温中起重要作用，尽管它本身不能被冷激活。现在，结合初步实验结果，我们提议：IAV与另一个TRPV通道NAN一起，共同形成一个对冷敏感的异源寡聚受体，共同介导幼虫的低温规避行为。这将会是果蝇中发现的首个低温受体，并且它的组装模式比较新颖。这种模式或许是果蝇和哺乳动物所共有的一种快速增加受体数目的方法，我们希望它能给更多受体的发现提供思路。

动物对环境温度信号的处理包括了初级的温度感受和高级的温度（体温）调节。本项目针对温度感受和温度调节的重要问题展开，第一部分利用果蝇为模型发现和验证了新型的低温受体，第二部分利用小鼠模型研究了由温度刺激所诱发的体温调节机制。具体地，我们发现了果蝇中两个TRP离子通道（iav、nan）的突变体不能规避低温。这两个通道本身对温度并不敏感，而是共同组成一个异源多聚体，从而变成温度敏感性离子通道。之后，我们对表达此二通道的神经元进行活性记录，发现这些神经元能被低温激活。跟其突变体的表型相吻合的是，这种冷刺激所引起的活性依赖于此二通道，敲除此二通道的神经元不再能够被冷刺激所激活。因此，我们鉴定出了一种新型低温受体，我们推测哺乳动物也存在类似的温度感受机制。更进一步地，我们利用小鼠作为模型，研究了温度刺激所激活的温度调节机制。我们系统性的分析了温度刺激所激活的神经元的分布，确认了下丘脑是主要的调节中枢。下丘脑负责接收环境的冷热温度信息的传入，从而启动相应的体温调节过程。我们进一步针对冷刺激所激活的神经元进行了研究，发现下丘脑背内侧核（DMH）响应环境的冷刺激，启动脂肪产热和增加运动度，从而增加体温；而视前区（POA）则正好相反，响应热刺激并下调体温。很有意思的是，我们发现视前区（POA）散热神经元可抑制背内侧核（DMH）产热神经元的活性，抑制产热和运动度。因此，我们描绘出了冷热温度调节的初步神经环路模型，为进一步理解温度调节机制提供了基础。总之，本项目发现了新的温度受体，找到了新的体温调节环路，为理解温度感受和温度调节等重要的生理学问题打下了坚实的基础，为驱虫剂的药物设计和温度调节疾病的防治提供了新的思路。