Psychophysical Evaluation of Taste Function

描述（由申请人提供）：味觉与进食后生理相互作用来控制摄食和饮水行为是毫无争议的，因此味觉过程的异常可能会影响更复杂的临床疾病，包括营养状况、水矿物质平衡和肥胖。因此，动物模型的发展，其中味觉系统可以实验操作，是必不可少的，以获得对正常和异常味觉功能的潜在神经生物学的理解。任何非人类动物的感觉和知觉的心理物理评估都是具有挑战性的，但对于旨在理解感觉功能的神经生物学的整体分析策略来说，这是绝对必要的组成部分。没有这些知识，就不可能将感觉系统的生理学和分子生物学与最终的功能结果-行为联系起来。所提出的实验的总体目的是使用严格的心理物理学方法来评估g蛋白偶联味觉受体T1R家族个体成员对正常味觉感知的必要性。T1R1和T1R3亚基结合形成味觉受体细胞中的异聚体，与l -氨基酸结合，T1R2和T1R3亚基结合形成异聚体，与糖、人工甜味剂和d -氨基酸亚基结合。尽管基因缺失了各种T1R亚基的敲除（KO）小鼠似乎对相应的配体缺乏味觉反应，但现有的数据在功能范围上受到严重限制，有理由相信这些动物可能并不完全对相应的化合物敏感。事实上，野生型（WT）小鼠对糖和l -氨基酸的感知特性仍然存在许多问题。使用WT、T1R1、T1R2、T1R3和T1R2+3 KO小鼠，我们将评估每个T1R亚基对1)味觉检测和2)典型T1R配体味觉识别的相对必要性，并验证这些KO小鼠中存在残余味觉功能的假设。使用基于操作性的味觉泛化任务，我们还将确定那些可检测的T1R配体的定性特征，从而构建WT和KO动物的感知图。这些实验将从心理物理学的角度定义一类重要的味觉受体对小鼠正常味觉功能的贡献，这被广泛应用于哺乳动物化学感觉过程的研究。

DESCRIPTION (provided by applicant): It is uncontested that taste interacts with postingestive physiology to control feeding and drinking behavior, and thus it follows that abnormalities in gustatory processes likely influence more complex clinical disorders nvolving nutritional status, hydromineral balance, and obesity. Accordingly, the development of animal models, in which the gustatory system can be experimentally manipulated, is essential to gain an understanding of the underlying neurobiology of normal and abnormal taste function. The psychophysical assessment of sensation and perception in any nonhuman animal is challenging, but an absolutely necessary component to the overall analytical strategy aimed at understanding the neurobiology of sensory function. Without such knowledge, it is impossible to link the physiology and molecular biology of the sensory system to the ultimate functional outcome - behavior. The overall aim of the proposed experiments is to use rigorous psychophysical methodology to assess the necessity of indivdual members of the T1R family of G-protein coupled taste receptors to normal taste perception. The T1R1 and T1R3 subunits combine to form a heteromer in taste receptor cells that binds with L-amino acids, and the T1R2 and T1R3 subunits combine to form a heteromer that binds with sugars, artificial sweetners and a subset of D-amino acids. Although knock-out (KO) mice that have had various T1R subunits genetically deleted appear to lack taste responsiveness to the corresponding ligands, the existing body of data is severely limited in functional scope, and there is reason to believe that these animals may not be entirely aguesic to the respective compounds. Indeed, many questions remain regarding the perceptual characteristics of sugars and L-amino acids in wild type (WT) mice. Using WT, T1R1 , T1R2, T1R3, and T1R2+3 KO mice, we will assess the relative necessity of each T1R subunit for 1) taste detection and 2) taste discrimination of prototypical T1R ligands and test the hypothesis that residual taste function is present in these KO mice. Using an operantly based taste generalization task, we will also determine the qualitative characteristics of those T1R ligands that are detectable and thus construct a perceptual map for WT and KO animals. These experiments will psychophysically define the contribution of an important class of taste receptors to normal gustatory function in the mouse model, which is becoming widely adopted for study of mammalian chemosensory processes.