Lindsey A. Schier, Ph.D. - US grants

DESCRIPTION (provided by applicant): The obesity epidemic is associated with excessive intake of calorie dense, palatable foods and fluids. Oral and postoral chemical signals are integrated in the central nervous system to adjust food and fluid selection, control meal size, and establish taste preferences. Yet little is known about precisely how these signals are integrated to change intake behavior. Progress has been hampered by the lack of available sensitive techniques that probe postoral chemosensory signals and link those to intake behaviors. Recently, chemoreceptors and associated signaling molecules involved in taste transduction (e.g., T1Rs, T2Rs, ¿ -gustducin) have been discovered in postoral GI cells, suggesting the interesting possibility that taste properties are among the information encoded in ascending postoral signals and may directly access and impact matching chemosensory signals arising from the oral cavity. Considering oral and postoral sensory signals ascend the central nervous system in roughly parallel pathways, it is especially surprising then that very little experimental attention has been paid to direct influence of postoral signals on primary taste sensory processing. As such, the presence of a common sensory system provides a framework for probing chemospecific influences of postoral signals on well characterized taste-guided behaviors. The present proposal seeks support to begin the psychophysical assessment of chemospecific influences of postoral signals on taste responsiveness in a rat model. Two taste-specific, and complementary, behavioral techniques will be used to assess the effects of intraduodenal chemical infusions on (a) hedonic evaluation of and (b) sensitivity to, independent of the hedonic valence of the stimulus, an oral taste stimulus. Specific Aim 1 tests the hypothesis that postgastric signals influence the hedonic evaluation of an oral taste stimulus in a chemospecific manner in the taste reactivity test. Specific Aim 2 tests the hypothesis that postgastric signals influence oral taste sensitivity in a chemospecific manner in the two response operant taste signal detection task. Not only will applying these psychophysical techniques identify novel, and potentially, important types of primary sensory integration, it will afford me training in new behavioral approaches and data analyses (e.g., psychometric functions) and expose me to a new area of conceptual expertise centered on gustatory function. Such psychophysical testing of GI taste signals through their specific impact on oral taste processing will direct future work on the underlying neural mechanisms, with the ultimate goal of identifying potential targets and strategies to augment sensory feedback crucial to the control of food intake.

PROJECT SUMMARY Obesity and diabetes are associated with the chronic overconsumption of high sugar foods and fluids, driven in large part by their palatable taste. A single heterodimeric G-protein coupled receptor (T1R2+3) found in mammalian taste cells is widely considered the principal means through which all simple sugars are detected and promote ingestion via the gustatory system. Yet, recent studies from our laboratory revealed that rodents come to respond more positively to the orosensory properties of glucose over fructose, when provided the opportunity to learn about their divergent metabolic consequences, and this phenomenon does not require the canonical T1R2+3 taste receptor. Collectively, these published studies point to the existence of a previously unknown taste receptor linked to glucose appetite. The preliminary findings included in this proposal now show that glucokinase, a phosphorylating enzyme involved in other glucosensing mechanisms, is expressed in murine taste cells. We further demonstrate that glucokinase levels in the taste tissue are regulated by energy state and dietary sugar exposure. Moreover, pharmacological activation of lingual glucokinase specifically bolsters licking behavior and neural responsiveness in the chorda tympani nerve for glucose, but not fructose or water. Our working hypothesis is that glucokinase is part of a T1R2+3-independent taste receptor that transduces glucose- specific signals in the gustatory system. The overall goal of this proposal is to further clarify the functional and molecular properties of this novel gustatory glucosensor. In Aim 1, we will combine genetic and pharmacological approaches to selectively disrupt and/or activate canonical ?sweet? taste inputs and lingual glucokinase while measuring taste-driven licking for various ?sweet? and ?non-sweet? tastants in sugar-naïve and sugar-exposed mice. With immunoblot and qPCR, we will further quantify changes in glucokinase and other sensory mechanisms linked to glucokinase in taste tissue as a function of dietary sugar exposure. In Aim 2, we will combine genetic and pharmacological approaches to psychophysically assess the discriminability of glucose, fructose, and other tastants in a series of two response operant discrimination tasks in order to fully elucidate the behavioral outputs functionally linked to gustatory glucosensors. In Aim 3, we will combine genetic and pharmacological approaches with electrophysiology to determine how T1R2+3-independent, glucokinase-linked taste signals are neurally-transmitted from tongue to brain. The outcomes of these aims will identify novel and potentially critical aspects of nutrient sensing, with the ultimate goal of identifying potential new strategies to curb appetite.