2006 — 2018 |
Small, Dana M |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cognitive and Affective Influences On Taste Processing
DESCRIPTION (provided by applicant): It is well established that there are individual differences in taste intensity perception resulting from genetic variation in taste receptors or other peripheral taste physiology [1-8]. Much less explored is the possibility for other sources of variability. Guided by new evidence from the prior project period which indicates that the gustatory system is an integrated oral sensory system that exhibits both transient and long-term plasticity, the proposed work will combine psychophysics and neuroimaging methods in humans to investigate central as well as peripheral neural mechanisms that influence taste sensitivity. In aim 1 we will test the hypothesis that a central gain mechanism plays a significant role in individual differences in taste perception in humans. Whereas peripheral explanations of variance in sensitivity are often specific to a particular quality or chemical, we propose to develop and validate a neurobiological model of brain circuitry that determines overall taste system sensitivity. In aim 2 we will investigate whether prolonged directed attention to oral but not extra-oral sensations increases taste and flavor sensitivity via modulation of the anterior insula or the proposed central gain mechanism. In the first period of this project we identified a higher-order cortical network that modulates processing in gustatory cortex in the service of goal directed behaviors [9-12]. New pilot data suggests that engaging in a psychophysical task that demands prolonged attention may modulate this mechanism. We will test this hypothesis by comparing changes in taste intensity and the blood oxygen level dependent (BOLD) responses in gustatory circuits before and after tasks requiring directed attention to flavors vs. visual stimuli. In aim 3 we investigate the possibility of a dietary influence on gustatory sensitivity. Significant controversy surrounds the possibility that consumption of artificial sweeteners (AFS) leads to weight gain. Some studies have found correlations between AFS use and weight gain and/or diabetes [13-16] while others have indicated that AFSs may aid in weight loss [17] or have no effects on body mass index (BMI) [18]. Given that the five FDA approved AFSs are found in thousands of foods [19] this marks a clear and significant gap in knowledge. Our preliminary data demonstrate a 3-fold decrease in sweet taste sensitivity following consumption of a beverage sweetened with two packets of Splenda for just 10 days. These data provide strong evidence that repeated exposure to sucralose reduces perception of sweet taste intensity, most likely by down regulation of the sweet taste receptor. Overall, identifying central mechanisms of taste modulation related to gain modulation and directed attention, as well as a possible peripheral mechanism triggered by consumption of an AFS, the proposed work will advance understanding of sources of individual differences in taste that are relevant to food choice and consumption.
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2017 — 2021 |
Caprio, Sonia Small, Dana M |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Neurocognition in Youth With Prediabetes
SUMMARY Accumulating evidence links human obesity and diabetes with cognitive dysfunction and dementia 1-51. While the causality is unknown in humans, and likely bi-directional, it is clear from work in rodents that diet induced obesity and associated metabolic dysfunction cause impaired cognition52-56. The mechanisms supporting this effect and the relative contribution of adiposity, diet and metabolic dysfunction remain unknown. Of particular interest to the funding opportunity announcement to which we respond is elucidating the link between glucose regulation and cognition. Although glucose intolerance is diagnostic of type 2 diabetes (T2D), a recent systematic review of 86 papers examining T2D and cognition only found a weak association between glycaemia and cognition 68 and there is even less evidence for an association with other measures of peripheral glucose regulation (e.g., insulin concentration, insulin action, insulin resistance)68. This represents a major gap in knowledge because it impedes the development of strategies to mitigate the risk of neurocognitive complications. The proposed research directly addresses this gap in knowledge. More specifically, we aim to provide a definitive test of the role of peripheral glucose intolerance on neurocognition, by longitudinal evaluation of cognitive and brain function in youth enrolled in the Pathogenesis of Youth Onset Diabetes (PYOD) study (R01DK111038) who are either glucose tolerant or intolerant but matched for age, gender, BMI and central adiposity. The PYOD cohort provides an exceptional opportunity to study cognitive impairment in T2D because the participants are pre-diabetic and thus do not suffer from chronic conditions associated with T2D. We also propose to use a new neuroimaging paradigm developed to assess central insulin resistance (IR) so that we may disentangle the effects of central and peripheral IR on neurocognition 46 and an indirect marker of striatal dopamine signaling to investigate the relation between IR, dopamine and neurocognition. More specifically, our aims are to (1) To test whether impaired peripheral glucose tolerance (IGT) and/or central IR influence neurocognitive function independently from adiposity; (2) To test whether change in glucose metabolism and/or adiposity predicts and precedes change in neurocognition; and (3) To test whether cognitive dysfunction and decline is associated with dopamine signaling. We anticipate that these results will inform the development of strategies to mitigate the risk of developing neurocognitive impairment, aid in the identification of individuals who are at-risk and who might benefit from additional therapy, provide a novel therapeutic target for pharmacological intervention and provide critical information about the rate of cognitive decline.
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2021 |
Small, Dana M |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Targeting the Gut-Brain Axis to Facilitate Weight Loss in High Fat Diet Consumers
Current therapies for obesity treatment are effective at producing weight loss but weight loss maintenance remains a significant challenge (Franz et al., 2007; Sawamoto et al., 2017; Wing and Phelan, 2005). The proposed work takes a precision medicine approach to obesity treatment and focuses specifically on weight loss maintenance and identification of biomarkers for weight loss outcomes. Our overarching goal is to test the hypothesis that individuals with overweight and obesity (OW/OB) who regularly consume a high fat diet (HFD) are able to lose more weight and maintain greater weight loss following a gold standard behavioral weight loss intervention if they supplement daily with the gut lipid messenger oleoylthanolamide (OEA) compared to a placebo and compared to OW/OB individuals who do not consume a HFD. The rationale for this hypothesis stems from preclinical work showing that a vagal afferent pathway critical for sensing dietary lipids regulating the reinforcing value of fat is blunted by a high fat diet (HFD) in the absence of weight gain, resulting in reduced preference for low fat foods and severe blunting of dopamine (DA) response to the infusion of lipids directly to the gut of mice (Tellez et al., 2013). This DA blunting is immediately reversed upon OEA infusion with concomitant shifts to greater preferences of low-fat food. Preliminary data from our laboratory provide strong evidence that these effects translate to humans and in a pilot randomized control trial (RCT) we found a very strong modulatory effect of baseline self-reported fat intake on weight loss. Specifically, the high fat subgroup on the supplement maintained a 15 lbs weight loss on average (~7% body weight-loss) 4 months after completing a weight loss program, relative to the effect of treatment in the low-fat subgroup, p=0.006. Our aims are therefore to (1) conduct an RCT in OW/OB individuals to determine if dietary fat intake moderates the ability of OEA to improve weight loss and weight loss maintenance after a gold standard behavioral weight-loss treatment; (2) identify biomarkers that predict outcome and optimize a stratification strategy; and (3) test a model underlying OEAs effectiveness. If successful, this work will identify a novel gut-brain target for weight- loss maintenance and support a precision medicine approach to behavioral weight-loss + supplementation that is easy and inexpensive to implement.
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