Cedrick Dotson - US grants

[unreadable] DESCRIPTION (provided by applicant): Psychophysical and behavioral studies with humans and non-verbal animals have lead researchers to propose that many natural sugars, a subset of amino acids, and some synthetic compounds produce qualitatively indiscriminable percepts. Recently, it has been suggested that in taste cells a family of receptors called the T1Rs mediates signal transduction of these "sweeteners." However, not all of these compounds bind with the same receptor in this family, providing a possible neural basis for discriminability. The experiments proposed here are designed to explicitly test the ability of mice to distinguish between sucrose, glucose, glycine, L-serine, L-alanine, and D-trytophan in operant taste discrimination tasks. The proposed experiments will help characterize the qualitative similarities and differences between these taste stimuli and thus provide data critical in constructing a qualitative perceptual space related to these "sweeteners" in this important animal model. As such these behavioral experiments will provide a functional context to guide the interpretation of findings from more molecular levels of analysis. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Two paradigm-shifting discoveries in taste research in recent years have realigned our thinking as to how taste perception is linked to mechanisms of appetite and satiety. The first was that many cells in the gut express the same molecular machinery required for nutrient detection as that found in taste cells. We now know these receptors in the gut detect ingested nutrients and mediate the secretion of gastric hormones. More recently, it was learned that these 'gastric' hormones together with their cognate receptors are also expressed in taste cells in the peripheral gustatory system. This latest discovery has raised a fundamental challenge to the field to understand how these peripheral 'gastric' hormones affect taste function and ingestive behavior. Given the worldwide rising incidence of diabetes, obesity and related metabolic disorders, we are proposing research that addresses our dearth of knowledge regarding the hormonal modulation of chemosensory perception and how disruption of hormonal signaling in the taste system can impact upon food intake and energy homeostasis. We have recently reported that the gut hormone, glucagon-like peptide 1 (GLP-1), can modulate sweet taste sensitivity. We have also reported that another GI peptide, glucagon, which plays a major role in the regulation of glucose homeostasis, can also act to modulate taste sensitivity to sweeteners. These results, when placed in the context of our preliminary findings on the hormone peptide YY (PYY) suggest that the gustatory system is indeed being dynamically modulated through hormonal action. The neuropeptide Y (NPY) family peptides, NPY and PYY, play a major role in the regulation of satiety when expressed by gut cells and/or in CNS tissues. Currently, PYY is being viewed as a candidate treatment for obesity and has been through clinical trials because of its ability to reduce food intake. However, unfortunately, high doses of PYY given systemically also cause conditioned taste aversion (CTA). Our data suggesting that PYY introduced into the oral cavity, while leading to significant weight loss in animal models, does not induce CTA, reintroduces PYY as a putative treatment for obesity. The presence of these NPY family peptides in the oral cavity, along with the expression of their cognate receptor(s) in gustatory tissues suggests that they may be influencing ingestive behavior by affecting the functioning of the peripheral gustatory system. Using a combination of genetic and pharmacological models, the proposed studies focus on investigating the general hypothesis that taste-related behavior can be modulated by metabolic hormones such as PYY and/or NPY.