Temperature Sensation and Its Behavioral Consequences

描述(申请人提供)：体温对动物生物学的各个方面都有深远的影响。哺乳动物有能力通过调节它们的生理(例如，不颤抖的产热、出汗)和行为措施(例如，挤在一起，定位更有利的温度或趋热区域)来控制体温。这个过程被认为涉及一个内部设定点和复杂的反馈回路，依赖于皮肤和下丘脑中的温度感受器神经元。我们对这种温度感受器神经元和运动中枢之间的联系的理解充其量也是不完整的。对于感觉运动整合在短期和长期适应过程中负责行为体温调节及其修改的机制，人们更是知之甚少。相比之下，在线虫中，一对温度感受器神经元与对温度梯度(趋热性)的行为反应的变化有关。它们与中间神经元的联系，并最终与运动神经元的联系是已知的。因此，在线虫中，可以理解热感受器神经元信号如何影响行为的细节，这在哺乳动物中是不可能的。在这个探索性的建议中，我们试图通过研究突变可以破坏这种联系的机制和开发新的工具来改变神经元功能，来扩大对温度感觉和行为之间联系的理解。我们专注于我们实验室分离的一个突变体，它在感觉运动整合中显示出一个耐人寻味的缺陷。我们试图通过筛选负责神经元发育和/或功能的基因来扩展这项工作，这些基因将温度感觉与运动输出联系起来，并开发新的工具来分析对神经元激活的行为反应。一般的策略是将经典遗传学与定量行为分析和在体全细胞膜片钳记录相结合，以阐明温度感觉与其行为后果之间的关系。建议的长期目标是建立线虫作为研究行为体温调节和感觉运动整合的新模型。这个项目与人类健康的相关性在于它有可能揭示感觉-运动整合中的通用基序，并为热失调提供洞察。 所有动物，包括人类，都有能力通过移动到环境中有利的区域来调节自己的体温。这种能力依赖于感觉温度并与神经系统沟通的神经细胞，以产生所需的运动。人们对这一复杂的过程知之甚少。为了加深理解，我们将研究一种只有302个神经元的简单蛔虫。其中两个神经元感知温度，似乎有助于某种形式的体温调节。这项研究将阐明温度感觉和学习的基本机制，并可能提高对温度调节及其在疾病和对摇头丸等娱乐药物的反应中的功能障碍的理解。

DESCRIPTION (provided by applicant): Body temperature has profound influences on all aspects of animal biology. Mammals have the ability to control body temperature by adjusting their physiology (e.g. non-shivering thermogenesis, perspiration) and by behavioral measures (e.g. huddling, locating areas of more favorable temperatures or thermotaxis). This process is thought to involve an internal set point and complex feedback loops that rely on thermoreceptor neurons in the skin and in the hypothalamus. Our understanding of the connections between such thermoreceptor neurons and motor centers is incomplete at best. Even less is known about the mechanisms of sensorimotor integration responsible for behavioral thermoregulation and its modification during short-term and long-term acclimation. In the nematode C. elegans, by contrast, a single pair of thermoreceptor neurons is linked to changes in behavioral responses to thermal gradients (thermotaxis). Their connections with interneurons and, ultimately, with motor neurons are known. Thus, in C. elegans, it is possible to understand how thermoreceptor neuron signaling affects behavior at a level of detail that is not possible in mammals. In this exploratory proposal, we seek to expand understanding of the link between temperature sensation and behavior by investigating the mechanism by which mutations can disrupt this link and by developing new tools for altering neuronal function. We focus on a mutant isolated in our laboratory that exhibits an intriguing defect in sensorimotor integration. We seek to extend this work by screening for genes responsible for the development and/or function of neurons that link thermosensation to motor output and to develop new tools for analyzing behavioral responses to neuron activation. The general strategy is to combine classical genetics with quantitative behavioral analysis and in vivo whole-cell patch-clamp recording in order to elucidate the relationship between temperature sensation and its behavioral consequences. The long-term objective of the proposed is to establish C. elegans as a new model for the study of behavioral thermoregulation and sensorimotor integration. The relevance of this project to human health lies in its potential to uncover universal motifs in sensorimotor integration and to provide insight into thermal dysregulation. All animals, including humans, have the ability to regulate their body temperature by moving to favorable areas in the environment. This ability relies on nerve cells that sense temperature and communicate with the nervous system to produce the needed movements. This complex process is only poorly understood. To improve understanding, we will study a simple roundworm that has only 302 neurons. Two of these neurons sense temperature and appear to aid a form of thermoregulation. What is learned from this study will clarify basic mechanisms of temperature sensation as well as learning and could improve understanding of thermoregulation and its dysfunction in disease and in response to recreational drugs such as ecstasy.