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Cao G.,Yale University | Cao G.,University of Texas at Austin | Platisa J.,John B Pierce Laboratory | Platisa J.,University of Belgrade | And 5 more authors.
Cell | Year: 2013

Nervous systems process information by integrating the electrical activity of neurons in complex networks. This motivates the long-standing interest in using optical methods to simultaneously monitor the membrane potential of multiple genetically targeted neurons via expression of genetically encoded fluorescent voltage indicators (GEVIs) in intact neural circuits. No currently available GEVIs have demonstrated robust signals in intact brain tissue that enable reliable recording of individual electrical events simultaneously in multiple neurons. Here, we show that the recently developed "ArcLight" GEVI robustly reports both subthreshold events and action potentials in genetically targeted neurons in the intact Drosophila fruit fly brain and reveals electrical signals in neurite branches. In the same way that genetically encoded fluorescent sensors have revolutionized the study of intracellular Ca2+ signals, ArcLight now enables optical measurement in intact neural circuits of membrane potential, the key cellular parameter that underlies neuronal information processing. © 2013 Elsevier Inc.


Stice E.,Oregon Research Institute | Yokum S.,Oregon Research Institute | Burger K.S.,Oregon Research Institute | Epstein L.H.,State University of New York at Buffalo | And 2 more authors.
Journal of Neuroscience | Year: 2011

Obese humans, compared with normal-weight humans, have less striatalD2receptors and striatal response to food intake; weaker striatal response to food predicts weight gain for individuals at genetic risk for reduced dopamine (DA) signaling, consistent with the rewarddeficit theory of obesity. Yet these may not be initial vulnerability factors, as overeating reduces D2 receptor density, D2 sensitivity, reward sensitivity, and striatal response to food. Obese humans also show greater striatal, amygdalar, orbitofrontal cortex, and somatosensory region response to food images than normal-weight humans do, which predicts weight gain for those not at genetic risk for compromised dopamine signaling, consonant with the reward-surfeit theory of obesity. However, after pairings of palatable food intake and predictive cues, DA signaling increases in response to the cues, implying that eating palatable food contributes to increased responsivity. Using fMRI, we tested whether normal-weight adolescents at high- versus low-risk for obesity showed aberrant activation of reward circuitry in response to receipt and anticipated receipt of palatable food and monetary reward. High-risk youth showed greater activation in the caudate, parietal operculum, and frontal operculum in response to food intake and in the caudate, putamen, insula, thalamus, and orbitofrontal cortex in response to monetary reward. No differences emerged in response to anticipated food or monetary reward. Data indicate that youth at risk for obesity show elevated reward circuitry responsivity in general, coupled with elevated somatosensory region responsivity to food, which may lead to overeating that produces blunted dopamine signaling and elevated responsivity to food cues. Copyright © 2011 the authors.


Tellez L.A.,John B Pierce Laboratory | Tellez L.A.,Yale University | Medina S.,John B Pierce Laboratory | Han W.,John B Pierce Laboratory | And 11 more authors.
Science | Year: 2013

Excessive intake of dietary fats leads to diminished brain dopaminergic function. It has been proposed that dopamine deficiency exacerbates obesity by provoking compensatory overfeeding as one way to restore reward sensitivity. However, the physiological mechanisms linking prolonged high-fat intake to dopamine deficiency remain elusive. We show that administering oleoylethanolamine, a gastrointestinal lipid messenger whose synthesis is suppressed after prolonged high-fat exposure, is sufficient to restore gut-stimulated dopamine release in high-fat-fed mice. Administering oleoylethanolamine to high-fat-fed mice also eliminated motivation deficits during flavorless intragastric feeding and increased oral intake of low-fat emulsions. Our findings suggest that high-fat-induced gastrointestinal dysfunctions play a key role in dopamine deficiency and that restoring gut-generated lipid signaling may increase the reward value of less palatable, yet healthier, foods.


De Araujo I.E.,John B Pierce Laboratory | De Araujo I.E.,Yale University | Lin T.,John B Pierce Laboratory | Veldhuizen M.G.,John B Pierce Laboratory | And 3 more authors.
Current Biology | Year: 2013

Identification of energy sources depends upon the ability to form associations between food cues and nutritional value. As such, cues previously paired with calories elicit neuronal activation in the nucleus accumbens (NAcc), which reflects the reinforcing value of food [1-4]. The identity of the physiological signals regulating this response remains elusive. Using fMRI, we examined brain response to noncaloric versions of flavors that had been consumed in previous days with either 0 or 112.5 calories from undetected maltodextrin. We report a small but perceptually meaningful increase in liking for the flavor that had been paired with calories and find that change in liking was associated with changes in insular responses to this beverage. In contrast, NAcc and hypothalamic response to the calorie-paired flavor was unrelated to liking but was strongly associated with the changes in plasma glucose levels produced by ingestion of the beverage when consumed previously with calories. Importantly, because each participant ingested the same caloric dose, the change in plasma glucose depended upon individual differences in glucose metabolism. We conclude that glucose metabolism is a critical signal regulating NAcc and hypothalamic response to food cues, and that this process operates independently from the ability of calories to condition liking. © 2013 Elsevier Ltd.


Felsted J.A.,John B Pierce Laboratory | Ren X.,John B Pierce Laboratory | Ren X.,Yale University | Chouinard-Decorte F.,John B Pierce Laboratory | And 2 more authors.
Journal of Neuroscience | Year: 2010

Combining genetic and neuroimaging techniques may elucidate the biological underpinnings of individual differences in neurophysiology and potential vulnerabilities to disease. The TaqIA A1 variant is associated with diminished dopamine D2 receptor density, higher body mass, and food reinforcement. It also moderates the relationship between brain response to food and future weight gain. This suggests that the polymorphism is associated with a fundamental difference in the neurophysiology of food that may predispose toward overeating. An alternative possibility is that factors, such as impulsivity, eating style, reward drive, and perception, which may covary with the polymorphism, influence reward coding and eating behavior. To distinguish between these alternatives, we used functional magnetic resonance imaging to measure neural response to the ingestion of palatable and caloric milkshakes in healthy subjects with (A1+; n=13) and without (A1-; n=13) the TaqIA A1 allele. The groups were selected from a larger group to be matched for linked individual factors such as age, gender, education, body mass index, impulsivity, eating style, and perceptual responses to the milkshake. We demonstrate an interaction between genotype (A1+ vs A1-) and stimulus (milkshake vs a tasteless/odorless baseline) in the midbrain, thalamus, and orbital frontal cortex; whereas A1-shows increased responses to milkshake, A1+shows decreased responses to milkshake relative to baseline. This interaction occurs despite similar ratings of milkshake pleasantness, intensity, and familiarity. We therefore conclude that there is a specific association between the TaqIA A1 polymorphism and brain response during ingestion of a palatable food. Copyright © 2010 the authors.


Rudenga K.J.,Yale University | Rudenga K.J.,John B Pierce Laboratory | Sinha R.,Yale University | Small D.M.,John B Pierce Laboratory | Small D.M.,Yale University
International Journal of Obesity | Year: 2013

Objective: Stress is associated with an increased intake of palatable foods and with weight gain, particularly in overweight women. Stress, food and body mass index (BMI) have been separately shown to affect amygdala activity. However, it is not known whether stress influences amygdala responses to palatable foods, and whether this response is associated with chronic stress or BMI. Design: A total of 14 overweight and obese women participated in a functional magnetic resonance imaging (fMRI) scan as they consumed a palatable milkshake during script-driven, autobiographical, guided imagery of stressful and neutral-relaxing scenarios. Results: We report that a network including insula, somatomotor mouth area, ventral striatum and thalamus responds to milkshake receipt, but none of these areas are affected by stress. In contrast, whereas the left amygdala responds to milkshake irrespective of condition, the right amygdala responds to milkshake only under stressful conditions. Moreover, this right amygdala response is positively associated with basal cortisol levels, an objective measure of chronic stress. We also found a positive relationship between BMI and stress-related increased response to milkshake in the orbitofrontal cortex (OFC). Conclusion: These results demonstrate that acute stress potentiates response to food in the right amygdala and OFC as a function of chronic stress and body weight, respectively. This suggests that the influence of acute stress in potentiating amygdala and OFC responses to food is dependent upon individual factors like BMI and chronic stress. We conclude that BMI and chronic stress play a significant role in brain response to food and in stress-related eating. © 2013 Macmillan Publishers Limited All rights reserved.


Jastreboff A.M.,Yale University | Sinha R.,Yale University | Lacadie C.,Yale University | Small D.M.,Yale University | And 3 more authors.
Diabetes Care | Year: 2013

OBJECTIVE-Obesity is associated with alterations in corticolimbic-striatal brain regions involved in food motivation and reward. Stress and the presence of food cues may each motivate eating and engage corticolimibic-striatal neurocircuitry. It is unknown how these factors interact to influence brain responses and whether these interactions are influenced by obesity, insulin levels, and insulin sensitivity. We hypothesized that obese individuals would show greater responses in corticolimbic-striatal neurocircuitry after exposure to stress and food cues and that brain activations would correlate with subjective food craving, insulin levels, and HOMA-IR. RESEARCH DESIGN AND METHODS-Fasting insulin levels were assessed in obese and lean subjects who were exposed to individualized stress and favorite-food cues during functional MRI. RESULTS-Obese, but not lean, individuals exhibited increased activation in striatal, insular, and hypothalamic regions during exposure to favorite-food and stress cues. In obese but not lean individuals, food craving, insulin, and HOMA-IR levels correlated positively with neural activity in corticolimbic-striatal brain regions during favorite-food and stress cues. The relationship between insulin resistance and food craving in obese individuals was mediated by activity in motivation-reward regions including the striatum, insula, and thalamus. CONCLUSIONS-These findings demonstrate that obese, but not lean, individuals exhibit increased corticolimbic-striatal activation in response to favorite-food and stress cues and that these brain responses mediate the relationship between HOMA-IR and food craving. Improving insulin sensitivity and in turn reducing corticolimbic-striatal reactivity to food cues and stress may diminish food craving and affect eating behavior in obesity.© 2013 by the American Diabetes Association.


Geha P.Y.,John B Pierce Laboratory | Geha P.Y.,Yale University | Aschenbrenner K.,John B Pierce Laboratory | Felsted J.,John B Pierce Laboratory | And 3 more authors.
American Journal of Clinical Nutrition | Year: 2013

Background: Smoking cessation is often followed by weight gain. Eating behaviors and weight change have been linked to the brain response to food, but it is unknown whether smoking influences this response. Objective: We determined the influence of smoking status (smokers compared with nonsmokers) on the brain response to food in regions associated with weight changes in nonsmokers. Design: In study 1, we used functional MRI (fMRI) to identify regions of the brain associated with weight change in nonsmokers. BMI and the brain response to a milk shake, which is a palatable and energy-dense food, were measured in a group of 27 nonsmokers (5 men). Sixteen subjects (3 men) returned 1 y later for BMI reassessment. The change in BMI was regressed against the brain response to isolate regions associated with weight change. In study 2, to determine whether smokers showed altered responses in regions associated with weight change, we assessed the brain response to a milk shake in 11 smokers. The brain response to a milk shake compared with a tasteless control solution was assessed in 11 smokers (5 men) in comparison with a group of age-, sex- and body weight-matched nonsmokers selected from the pool of nonsmokers who participated in study 1. Results: The response in the midbrain, hypothalamus, thalamus, and ventral striatum was positively associated with weight change at the 1-y follow-up in 16 nonsmokers. Compared with nonsmokers, smokers had a greater response to milk shakes in the hypothalamus. Conclusion: Smokers display an altered brain response to food in the hypothalamus, which is an area associated with long-term weight change in nonsmokers. © 2013 American Society for Nutrition.


Sikand P.,Yale University | Shimada S.G.,Yale University | Green B.G.,Yale University | Green B.G.,John B Pierce Laboratory | Lamotte R.H.,Yale University
Pain | Year: 2011

A punctate, cutaneous application of capsaicin or histamine by means of a cowhage spicule elicits itch accompanied by pricking/stinging, burning, and typically, one or more areas of dysesthesia (alloknesis, hyperalgesia, hyperknesis). When applied over a wider and deeper area of skin by means of intradermal injection, histamine evokes the same sensory effects, but capsaicin evokes pain and hyperalgesia with allodynia instead of alloknesis. To examine the sensory effects of the spatial spread, depth, and amount of capsaicin and histamine, we applied different amounts of capsaicin or histamine by intradermal injection or by single vs multiple spicules within a circular cutaneous region of ∼5 mm. Subjects rated the perceived intensity of itch, pricking/stinging, and burning for 20 minutes. Histamine injections or multiple spicules of capsaicin or histamine that resulted in a greater area of flare than a single spicule of each chemical evoked no greater magnitudes of sensation or areas of dysesthesia. Capsaicin injections elicited a dose-dependent increase in the magnitude of nociceptive sensations, areas of dysesthesia, and flare. However, there was little or no itch; and allodynia replaced alloknesis. Yet, hyperalgesia was typically accompanied by hyperknesis. We conclude that the pruritic sensory responses produced by capsaicin/histamine spicules and histamine injections may be due to activation of common nerve fibers, possibly different from those mediating the flare, and that capsaicin injections may activate additional fibers whose effects mask the sensory effects of fibers mediating itch and alloknesis but not hyperknesis. © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.


Stachenfeld N.S.,John B Pierce Laboratory | Stachenfeld N.S.,Yale University
Reproductive Sciences | Year: 2014

Reproductive surgeries leave women more susceptible to postoperative hypervolemic hyponatremia because during this period women can retain water at an accelerated pace and much faster than they do sodium. This review proposes that estrogen and progestogen exposure play an important role in the increased risk of hyponatremia in menopausal women. Estrogen and progesterone exposure have important effects on both body fluid regulation and cardiovascular function and both of these reproductive hormones impact blood pressure responses to sodium loads. This article provides information on the effects of female reproductive hormones and hormone therapy (HT) on fluid regulation and cardiovascular function during menopause. Thirst- and fluid-regulating hormones respond to both osmotic and volume stimuli. Aging women maintain thirst sensitivity to osmotic stimuli but lose some thirst sensitivity to changes in central body fluid volume. Thus, older adults are more at risk of dehydration because they may replenish fluids at a slower rate. Estrogen therapy increases osmotic sensitivity for mechanisms to retain body water so may help menopausal women control body fluids and avoid dehydration. Some progestogens can mitigate estradiol effects on water and sodium retention through competition with aldosterone for the mineralocorticoid receptor and attenuating aldosterone-mediated sodium retention in the distal tubule. However, some progestogens can increase cardiovascular risks. Appropriate balance of these hormones within HT is important to avoid the negative consequences of body fluid and sodium retention, including edema and hypertension. © The Author(s) 2013.

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