mGluR5 positive allosteric modulation prevents MK-801 induced increases in extracellular glutamate in the rat medial prefrontal cortex.

Potentiation of metabotropic glutamate receptor subtype 5 (mGluR5) function produces antipsychotic-like and pro-cognitive effects in animal models of schizophrenia and can reverse cognitive deficits induced by N-methyl-D-aspartate type glutamate receptor (NMDAR) antagonists. However, it is currently unknown if mGluR5 positive allosteric modulators (PAMs) can modulate NMDAR antagonist-induced alterations in extracellular glutamate levels in regions underlying these cognitive and behavioral effects, such as the medial prefrontal cortex. We therefore assessed the ability of the mGluR5 PAM, 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB), to reduce elevated extracellular glutamate levels induced by the NMDAR antagonist, dizocilpine (MK-801), in the medial prefrontal cortex. Male Sprague-Dawley rats were implanted with a guide cannula aimed at the medial prefrontal cortex and treated for ten consecutive days with MK-801 and CDPPB or their corresponding vehicles. CDPPB or vehicle was administered thirty minutes before MK-801 or vehicle each day. On the final day of treatment, in vivo microdialysis was performed, and samples were collected every thirty minutes to analyze extracellular glutamate levels. Compared to animals receiving only vehicle, administration of MK-801 alone significantly increased extracellular levels of glutamate in the mPFC. This effect was not observed in animals administered CDPPB before MK-801, nor in those administered CDPPB alone, indicating that CDPPB decreased extracellular glutamate release stimulated by MK-801. Results indicate that CDPPB attenuates MK-801 induced elevations in extracellular glutamate in the medial prefrontal cortex. This effect of CDPPB may underlie neurochemical adaptations associated with the pro-cognitive effects of mGluR5 PAMs in rodent models of schizophrenia.

SAMPL is a high-throughput solution to study unconstrained vertical behavior in small animals.

Balance and movement are impaired in many neurological disorders. Recent advances in behavioral monitoring provide unprecedented access to posture and locomotor kinematics but without the throughput and scalability necessary to screen candidate genes/potential therapeutics. Here, we present a scalable apparatus to measure posture and locomotion (SAMPL). SAMPL includes extensible hardware and open-source software with real-time processing and can acquire data from D. melanogaster, C. elegans, and D. rerio as they move vertically. Using SAMPL, we define how zebrafish balance as they navigate vertically and discover small but systematic variations among kinematic parameters between genetic backgrounds. We demonstrate SAMPL's ability to resolve differences in posture and navigation as a function of effect size and data gathered, providing key data for screens. SAMPL is therefore both a tool to model balance and locomotor disorders and an exemplar of how to scale apparatus to support screens.

Scalable Apparatus to Measure Posture and Locomotion (SAMPL): a high-throughput solution to study unconstrained vertical behavior in small animals.

Balance and movement are impaired in a wide variety of neurological disorders. Recent advances in behavioral monitoring provide unprecedented access to posture and locomotor kinematics, but without the throughput and scalability necessary to screen candidate genes / potential therapeutics. We present a powerful solution: a Scalable Apparatus to Measure Posture and Locomotion (SAMPL). SAMPL includes extensible imaging hardware and low-cost open-source acquisition software with real-time processing. We first demonstrate that SAMPL's hardware and acquisition software can acquire data from from D. melanogaster, C. elegans, and D. rerio as they move vertically. Next, we leverage SAMPL's throughput to rapidly (two weeks) gather a new zebrafish dataset. We use SAMPL's analysis and visualization tools to replicate and extend our current understanding of how zebrafish balance as they navigate through a vertical environment. Next, we discover (1) that key kinematic parameters vary systematically with genetic background, and (2) that such background variation is small relative to the changes that accompany early development. Finally, we simulate SAMPL's ability to resolve differences in posture or vertical navigation as a function of affect size and data gathered -- key data for screens. Taken together, our apparatus, data, and analysis provide a powerful solution for labs using small animals to investigate balance and locomotor disorders at scale. More broadly, SAMPL is both an adaptable resource for labs looking process videographic measures of behavior in real-time, and an exemplar of how to scale hardware to enable the throughput necessary for screening.

Effect of caffeine on alcohol drinking in mice.

Mixing alcohol (ethanol) with caffeinated beverages continues to be a common and risky practice. Energy drinks are one type of caffeinated beverage that may be especially problematic when used as mixers, due to their relatively high caffeine content in combination with their highly sweetened flavor profile. The present study used a mouse model of limited-access drinking and lickometer circuitry to examine the effects of an energy drink anid its caffeine content on ethanol consumption. Predictably, the highly sweetened energy drink significantly increased ethanol intake compared to a plain ethanol solution (6.34 ± 0.2 vs. 5.01 ± 0.3 g/kg; Cohen's d = 1.79). Interestingly, adulterating a plain ethanol solution with the same concentration of caffeine (without sweetener) found in the energy drink also increased ethanol intake (5.47 ± 0.3 vs. 4.11 ± 0.3 g/kg; Cohen's d = 1.4). A lower concentration of caffeine was without effect on ethanol drinking. Interestingly, plain caffeine solutions at both tested concentrations provoked high numbers of bottle contacts, indicating that the mice found the solution palatable. These findings suggest that altering the bitterness profile of an ethanol solution with the addition of caffeine can increase intake in a similar manner as sweetening the solution. Further, the findings underscore the importance of taste in motivating ethanol consumption and the potential role that caffeine can have in this process.

Confection Confusion: Interplay Between Diet, Taste, and Nutrition.

Although genetics shapes our sense of taste to prefer some foods over others, taste sensation is plastic and changes with age, disease state, and nutrition. We have known for decades that diet composition can influence the way we perceive foods, but many questions remain unanswered, particularly regarding the effects of chemosensory plasticity on feeding behavior. Here, we review recent evidence on the effects of high-nutrient diets, especially high dietary sugar, on sweet taste in vinegar flies, rodents, and humans, and discuss open questions about molecular and neural mechanisms and research priorities. We also consider ways in which diet-dependent chemosensory plasticity may influence food intake and play a role in the etiology of obesity and metabolic disease. Understanding the interplay between nutrition, taste sensation, and feeding will help us define the role of the food environment in mediating chronic disease and design better public health strategies to combat it.

Persistent epigenetic reprogramming of sweet taste by diet.

Diets rich in sugar, salt, and fat alter taste perception and food preference, contributing to obesity and metabolic disorders, but the molecular mechanisms through which this occurs are unknown. Here, we show that in response to a high sugar diet, the epigenetic regulator Polycomb Repressive Complex 2.1 (PRC2.1) persistently reprograms the sensory neurons of Drosophila melanogaster flies to reduce sweet sensation and promote obesity. In animals fed high sugar, the binding of PRC2.1 to the chromatin of the sweet gustatory neurons is redistributed to repress a developmental transcriptional network that modulates the responsiveness of these cells to sweet stimuli, reducing sweet sensation. Half of these transcriptional changes persist despite returning the animals to a control diet, causing a permanent decrease in sweet taste. Our results uncover a new epigenetic mechanism that, in response to the dietary environment, regulates neural plasticity and feeding behavior to promote obesity.

Dietary sugar inhibits satiation by decreasing the central processing of sweet taste.

From humans to vinegar flies, exposure to diets rich in sugar and fat lowers taste sensation, changes food choices, and promotes feeding. However, how these peripheral alterations influence eating is unknown. Here we used the genetically tractable organism D. melanogaster to define the neural mechanisms through which this occurs. We characterized a population of protocerebral anterior medial dopaminergic neurons (PAM DANs) that innervates the ß'2 compartment of the mushroom body and responds to sweet taste. In animals fed a high sugar diet, the response of PAM-ß'2 to sweet stimuli was reduced and delayed, and sensitive to the strength of the signal transmission out of the sensory neurons. We found that PAM-ß'2 DANs activity controls feeding rate and satiation: closed-loop optogenetic activation of ß'2 DANs restored normal eating in animals fed high sucrose. These data argue that diet-dependent alterations in taste weaken satiation by impairing the central processing of sensory signals.

Obesity is a major health problem affecting over 650 million adults worldwide. It is typically caused by overeating high-energy foods, which often contain a lot of sugar. Consuming sugary foods triggers the production of a reward signal called dopamine in the brains of insects and mammals, which reinforces sugar-consuming behavior. The brain balances this with a process called 'sensory-enhanced satiety', which makes foods that provide a stronger sensation of sweetness better at reducing hunger and further eating. High-energy food was scarce for most of human evolution, but over the past century sugar has become readily available in our diet leading to an increase in obesity. Last year, a study in fruit flies reported that a sugary diet reduces the sensitivity to sweet flavors, which leads to overeating and weight gain. It appears that this sensitivity is linked to the effectiveness of sensory-enhanced satiety. However, the mechanism linking diets high in sugar and overeating is still poorly understood. One hypothesis is that fruit flies estimate the energy content of food based on the degree of dopamine released in response to the sugar. May et al. compared the responses of neurons in fruit flies fed a normal diet to those in flies fed a diet high in sugar. As expected, both groups activated the neurons involved in the dopamine reward response when they tasted sugar. However, when the flies were on a sugar-heavy diet, these neurons were less active. This was because the neurons responsible for tasting sweetness were activated less in flies fed a high-sugar diet, leading to a lowered response by the neurons that produce dopamine. The flies in these experiments were genetically engineered so that the dopamine-producing neurons could be artificially activated in response to light, a technique called optogenetics. When May et al. applied this technique to the flies on a sugar-heavy diet, they were able to stop these flies from overeating. These findings provide further evidence to support the idea that a sugary diet reduces the brain's sensitivity to overeating. Given the significant healthcare cost of obesity to society, this improved understanding could help public health initiatives focusing on manufacturing food that is lower in sugar.

High Dietary Sugar Reshapes Sweet Taste to Promote Feeding Behavior in Drosophila melanogaster.

Recent studies find that sugar tastes less intense to humans with obesity, but whether this sensory change is a cause or a consequence of obesity is unclear. To tackle this question, we study the effects of a high sugar diet on sweet taste sensation and feeding behavior in Drosophila melanogaster. On this diet, fruit flies have lower taste responses to sweet stimuli, overconsume food, and develop obesity. Excess dietary sugar, but not obesity or dietary sweetness alone, caused taste deficits and overeating via the cell-autonomous action of the sugar sensor O-linked N-Acetylglucosamine (O-GlcNAc) transferase (OGT) in the sweet-sensing neurons. Correcting taste deficits by manipulating the excitability of the sweet gustatory neurons or the levels of OGT protected animals from diet-induced obesity. Our work demonstrates that the reshaping of sweet taste sensation by excess dietary sugar drives obesity and highlights the role of glucose metabolism in neural activity and behavior.

Sensitization and Tolerance Following Repeated Exposure to Caffeine and Alcohol in Mice.

BACKGROUND: Energy drinks are popular mixers with alcohol. While energy drinks contain many ingredients, caffeine is an important pharmacologically active component and is generally present in larger amounts than in other caffeinated beverages. In these studies, we investigated the hypothesis that caffeine would influence the effects of alcohol (ethanol [EtOH]) on conditioned taste aversion (CTA), ataxia, and locomotor activity (LA) after repeated exposure. METHODS: Four groups of mice were exposed by oral gavage twice daily to vehicle, EtOH (4 g/kg), caffeine (15 mg/kg), or the EtOH/caffeine combination. CTA to saccharin and ataxia in the parallel rod task was evaluated after 8 or 16 gavages, respectively, using EtOH (1 to 3 g/kg) or EtOH/caffeine (3 mg/kg + 2 g/kg) challenges. In addition, LA was evaluated initially and after repeated exposure to oral gavage of these drugs and doses. RESULTS: Repeated oral gavage of EtOH produced significant locomotor sensitization, with those mice increasing total distance traveled by 2-fold. The locomotor response to caffeine, while significantly greater than vehicle gavage, did not change with repeated exposure. On the other hand, repeated gavage of caffeine/EtOH combination produced a substantial increase in total distance traveled after repeated exposure (~4-fold increase). After repeated EtOH exposure, there was significant tolerance to EtOH in the CTA and parallel rod tests. However, neither a history of caffeine exposure nor including caffeine influenced EtOH-induced CTA. Interestingly, a history of caffeine exposure increased the ataxic response to the caffeine/EtOH combination and appeared to reduce the ataxic response to high doses of EtOH. CONCLUSIONS: The data support the general hypothesis that repeated exposure to caffeine influences the response to EtOH. Together with previously published work, these data indicate that caffeine influences some EtOH-related behaviors, notably locomotion and ataxia, but appears not to influence the expression of conditioned behaviors.

Conditioned reinforcement and locomotor activating effects of caffeine and ethanol combinations in mice.

A growing trend among ethanol drinkers, especially young adults, is to combine caffeinated energy drinks with ethanol during a drinking episode. The primary active ingredient of these mixers is caffeine, which may significantly interact with ethanol. We tested the two hypotheses that caffeine would enhance ethanol-conditioned place preference and also enhance ethanol-stimulated locomotor activity. The interactive pharmacology of ethanol and caffeine was examined in C57BL/6J (B6) mice in a conditioned place preference procedure with 1.75 g/kg ethanol and 3 mg/kg caffeine. Additionally, we used B6 mice to evaluate ethanol/caffeine combinations on locomotor activity using 3 doses of ethanol (1.75, 2.5 and 3.25 g/kg) and 2 two doses of caffeine (3 and 15 mg/kg). Both ethanol and caffeine administered alone increased preference for the drug paired side, although the effect of caffeine was more modest than that of ethanol. The drug combination produced significant place preference itself, but this was not greater than that for ethanol alone. Additionally, the combination of caffeine and ethanol significantly increased locomotion compared to giving either drug alone. The effect was strongest with a stimulatory dose of ethanol (1.75 g/kg) and waned with increasing doses of ethanol. Thus, combinations of caffeine and ethanol had significant conditioned reinforcing and locomotor activating effects in mice.