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News Article | April 25, 2017
Site: www.scientificamerican.com

Scientists have known for decades that what we eat can change the balance of microbes in our digestive tracts. Choosing between a BLT sandwich or a yogurt parfait for lunch can increase the populations of some types of bacteria and diminish others—and as their relative numbers change they secrete different substances, activate different genes and absorb different nutrients. And those food choices are probably a two-way street. Gut microbes have also been shown to influence diet and behavior as well as anxiety, depression, hypertension and a variety of other conditions. But exactly how these trillions of tiny guests—collectively called the microbiome—influence our decisions on which foods to stuff into our mouths has been a mystery. Now neuroscientists have found specific types of gut flora help a host animal detect which nutrients are missing in food, and then finely titrate how much of those nutrients the host really needs to eat. “What the bacteria do for appetite is kind of like optimizing how long a car can run without needing to add more petrol to the tank,” says senior author Carlos Ribeiro, who studies the eating behaviors of Drosophila melanogaster, a type of fruit fly, at Champalimaud Center for the Unknown in Lisbon. In a paper published Tuesday in PLoS Biology Ribeiro and his team demonstrated how the microbiome influences drosophila’s nutritional decisions. First, they fed one group of flies a sucrose solution containing all the necessary amino acids. Another group got a mix that had some of the amino acids needed to make protein but lacked essential amino acids that the host cannot synthesize by itself. For a third group of flies, the scientists removed essential amino acids from the food one by one to determine which was being detected by the microbiome. After 72 hours on the various diets, flies in the all three groups were presented with a buffet offering their normal sugary solution alongside  protein-rich yeast. The researchers found that flies in the two groups whose diet lacked any single essential amino acid got a strong craving for yeast to make up for the missing nutrients. But when scientists increased five different types of bacteria found in the flies’ digestive tracts—Lactobacillus plantarum, L. brevis, Acetobacter pomorum, Commensalibacter intestini and Enterococcus faecalis—the flies completely lost the urge to eat more protein. The researchers found the flies’ amino acid levels were still low, indicating the bacteria were not simply replacing nutrients missing from the flies’ diet by producing the amino acids themselves. Instead, the microbes were functioning as little metabolic factories, transforming the food they got into new chemicals: metabolites that the researchers believe might be telling the host animal it could carry on without the amino acids. As a result of this microbial trick, the flies were able to continue reproducing, for example—even though an amino acid deficiency usually hampers cell growth and regeneration, and therefore reproduction, Ribeiro explains. Two kinds of bacteria were particularly effective in influencing the appetite of flies this way: Acetobacter and Lactobacillus. Increasing both was enough to suppress the flies’ protein cravings and increase their appetite for sugar. These two bacteria also restored the flies’ reproductive abilities, indicating their bodies were carrying out normal functions that typically get restricted when there is a nutritional deficiency. “How the brain handles this trade-off of nutritional information is very fascinating, and our study shows that the microbiome plays a key role in telling the animal what to do,” Ribeiro says. Next the team removed an enzyme needed to process the amino acid tyrosine in flies, making it necessary for the flies to get tyrosine via their food, just like other essential amino acids. Surprisingly, they found that Acetobacter and Lactobacillus were unable to suppress the craving for tyrosine in the modified flies. “This shows that the gut microbiome has evolved to titrate only the normal essential amino acid intake,” Ribeiro explains. The research adds a new perspective on coevolution of microbes and their hosts. “The findings show that there is a unique pathway that has coevolved between animals and the resident bacteria in their gut, and there is a bottom-up communication about diet,” says Jane Foster, who is a neuroscientist at McMaster University in Ontario and not associated with the study. Although the study does not specify the exact mechanism of communication, Ribeiro thinks it could take various forms. Strong evidence from the study indicates microbially derived metabolites carry information from the gut to the brain, telling the host whether it needs a particular kind of food. “One of the big evolutionary mysteries is why we lost the ability to produce essential amino acids,” he says. “Maybe these metabolites gave animals more leeway to be independent of these nutrients, and to deal without them sometimes.” Microbes may also have their own evolutionary reasons for communicating with the brain, he adds. For one thing, they feed on whatever the host animal eats. For another, they need host animals to be social so the guests can spread through the population. The data is limited to animal models so far but Ribeiro believes that gut–brain communication can provide fertile ground for developing treatments for humans in the future. “It’s an interesting therapeutic window that could be utilized to improve behaviors related to diet one day,” he says.

Meyniel F.,University Paris - Sud | Sigman M.,Torcuato Di Tella University | Mainen Z.F.,Champalimaud Center for the Unknown
Neuron | Year: 2015

Research on confidence spreads across several sub-fields of psychology and neuroscience. Here, we explore how a definition of confidence as Bayesian probability can unify these viewpoints. This computational view entails that there are distinct forms in which confidence is represented and used in the brain, including distributional confidence, pertaining to neural representations of probability distributions, and summary confidence, pertaining to scalar summaries of those distributions. Summary confidence is, normatively, derived or "read out" from distributional confidence. Neural implementations of readout will trade off optimality versus flexibility of routing across brain systems, allowing confidence to serve diverse cognitive functions. © 2015 Elsevier Inc.

French C.A.,Champalimaud Center for the Unknown | Fisher S.E.,Max Planck Institute for Psycholinguistics | Fisher S.E.,Donders Institute for Brain
Current Opinion in Neurobiology | Year: 2014

Disruptions of the FOXP2 gene cause a rare speech and language disorder, a discovery that has opened up novel avenues for investigating the relevant neural pathways. FOXP2 shows remarkably high conservation of sequence and neural expression in diverse vertebrates, suggesting that studies in other species are useful in elucidating its functions. Here we describe how investigations of mice that carry disruptions of Foxp2 provide insights at multiple levels: molecules, cells, circuits and behaviour. Work thus far has implicated the gene in key processes including neurite outgrowth, synaptic plasticity, sensorimotor integration and motor-skill learning. © 2014 Elsevier Ltd.

Kepecs A.,Cold Spring Harbor Laboratory | Mainen Z.F.,Champalimaud Center for the Unknown
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2012

Confidence judgements, self-assessments about the quality of a subject's knowledge, are considered a central example of metacognition. Prima facie, introspection and self-report appear the only way to access the subjective sense of confidence or uncertainty. Contrary to this notion, overt behavioural measures can be used to study confidence judgements by animals trained in decision-making tasks with perceptual or mnemonic uncertainty. Here, we suggest that a computational approach can clarify the issues involved in interpreting these tasks and provide a much needed springboard for advancing the scientific understanding of confidence. We first review relevant theories of probabilistic inference and decision-making. We then critically discuss behavioural tasks employed to measure confidence in animals and show how quantitative models can help to constrain the computational strategies underlying confidence-reporting behaviours. In our view, post-decision wagering tasks with continuous measures of confidence appear to offer the best available metrics of confidence. Since behavioural reports alone provide a limited window into mechanism, we argue that progress calls for measuring the neural representations and identifying the computations underlying confidence reports. We present a case study using such a computational approach to study the neural correlates of decision confidence in rats. This work shows that confidence assessments may be considered higher order, but can be generated using elementary neural computations that are available to a wide range of species. Finally, we discuss the relationship of confidence judgements to the wider behavioural uses of confidence and uncertainty. © 2012 The Royal Society.

Deneve S.,Ecole Normale Superieure de Paris | Machens C.K.,Champalimaud Center for the Unknown
Nature Neuroscience | Year: 2016

Recent years have seen a growing interest in inhibitory interneurons and their circuits. A striking property of cortical inhibition is how tightly it balances excitation. Inhibitory currents not only match excitatory currents on average, but track them on a millisecond time scale, whether they are caused by external stimuli or spontaneous fluctuations. We review, together with experimental evidence, recent theoretical approaches that investigate the advantages of such tight balance for coding and computation. These studies suggest a possible revision of the dominant view that neurons represent information with firing rates corrupted by Poisson noise. Instead, tight excitatory/inhibitory balance may be a signature of a highly cooperative code, orders of magnitude more precise than a Poisson rate code. Moreover, tight balance may provide a template that allows cortical neurons to construct high-dimensional population codes and learn complex functions of their inputs. © 2016 Nature America, Inc. All rights reserved.

Ahrens M.B.,Howard Hughes Medical Institute | Orger M.B.,Champalimaud Center for the Unknown | Robson D.N.,Harvard University | Li J.M.,Harvard University | Keller P.J.,Howard Hughes Medical Institute
Nature Methods | Year: 2013

Brain function relies on communication between large populations of neurons across multiple brain areas, a full understanding of which would require knowledge of the time-varying activity of all neurons in the central nervous system. Here we use light-sheet microscopy to record activity, reported through the genetically encoded calcium indicator GCaMP5G, from the entire volume of the brain of the larval zebrafish in vivo at 0.8 Hz, capturing more than 80% of all neurons at single-cell resolution. Demonstrating how this technique can be used to reveal functionally defined circuits across the brain, we identify two populations of neurons with correlated activity patterns. One circuit consists of hindbrain neurons functionally coupled to spinal cord neuropil. The other consists of an anatomically symmetric population in the anterior hindbrain, with activity in the left and right halves oscillating in antiphase, on a timescale of 20 s, and coupled to equally slow oscillations in the inferior olive. © 2013 Nature America, Inc. All rights reserved.

Uchida N.,Harvard University | Poo C.,Champalimaud Center for the Unknown | Haddad R.,Harvard University | Haddad R.,Bar - Ilan University
Annual Review of Neuroscience | Year: 2014

How is sensory information represented in the brain? A long-standing debate in neural coding is whether and how timing of spikes conveys information to downstream neurons. Although we know that neurons in the olfactory bulb (OB) exhibit rich temporal dynamics, the functional relevance of temporal coding remains hotly debated. Recent recording experiments in awake behaving animals have elucidated highly organized temporal structures of activity in the OB. In addition, the analysis of neural circuits in the piriform cortex (PC) demonstrated the importance of not only OB afferent inputs but also intrinsic PC neural circuits in shaping odor responses. Furthermore, new experiments involving stimulation of the OB with specific temporal patterns allowed for testing the relevance of temporal codes. Together, these studies suggest that the relative timing of neuronal activity in the OB conveys odor information and that neural circuits in the PC possess various mechanisms to decode temporal patterns of OB input. © Copyright ©2014 by Annual Reviews. All rights reserved.

Itskov P.M.,Champalimaud Center for the Unknown | Ribeiro C.,Champalimaud Center for the Unknown
Frontiers in Neuroscience | Year: 2013

To survive and successfully reproduce animals need to maintain a balanced intake of nutrients and energy. The nervous system of insects has evolved multiple mechanisms to regulate feeding behavior. When animals are faced with the choice to feed, several decisions must be made: whether or not to eat, how much to eat, what to eat, and when to eat. Using Drosophila melanogaster substantial progress has been achieved in understanding the neuronal and molecular mechanisms controlling feeding decisions. These feeding decisions are implemented in the nervous system on multiple levels, from alterations in the sensitivity of peripheral sensory organs to the modulation of memory systems. This review discusses methodologies developed in order to study insect feeding, the effects of neuropeptides and neuromodulators on feeding behavior, behavioral evidence supporting the existence of internal energy sensors, neuronal and molecular mechanisms controlling protein intake, and finally the regulation of feeding by circadian rhythms and sleep. From the discussed data a conceptual framework starts to emerge which aims to explain the molecular and neuronal processes maintaining the stability of the internal milieu. © 2013 Itskov and Ribeiro.

Fonseca M.S.,Champalimaud Center for the Unknown | Murakami M.,Champalimaud Center for the Unknown | Mainen Z.F.,Champalimaud Center for the Unknown
Current Biology | Year: 2015

Background The central neuromodulator serotonin (5-HT) has been implicated in a wide range of behaviors and affective disorders, but the principles underlying its function remain elusive. One influential line of research has implicated 5-HT in response inhibition and impulse control. Another has suggested a role in affective processing. However, whether and how these effects relate to each other is still unclear. Results Here, we report that optogenetic activation of 5-HT neurons in the dorsal raphe nucleus (DRN) produces a dose-dependent increase in mice's ability to withhold premature responding in a task that requires them to wait several seconds for a randomly delayed tone. The 5-HT effect had a rapid onset and was maintained throughout the stimulation period. In addition, movement speed was slowed, but photostimulation did not affect reaction time or time spent at the reward port. Using similar photostimulation protocols in place preference and value-based choice tests, we found no evidence of either appetitive or aversive effects of DRN 5-HT neuron activation. Conclusions These results provide strong evidence that the efficacy of DRN 5-HT neurons in promoting waiting for delayed reward is independent of appetitive or aversive effects and support the importance of 5-HT in behavioral persistence and impulse control. © 2015 Elsevier Ltd

Murakami M.,Champalimaud Center for the Unknown | Vicente M.I.,Champalimaud Center for the Unknown | Costa G.M.,Champalimaud Center for the Unknown | Mainen Z.F.,Champalimaud Center for the Unknown
Nature Neuroscience | Year: 2014

The neural origins of spontaneous or self-initiated actions are not well understood and their interpretation is controversial. To address these issues, we used a task in which rats decide when to abort waiting for a delayed tone. We recorded neurons in the secondary motor cortex (M2) and interpreted our findings in light of an integration-to-bound decision model. A first population of M2 neurons ramped to a constant threshold at rates proportional to waiting time, strongly resembling integrator output. A second population, which we propose provide input to the integrator, fired in sequences and showed trial-to-trial rate fluctuations correlated with waiting times. An integration model fit to these data also quantitatively predicted the observed inter-neuronal correlations. Together, these results reinforce the generality of the integration-to-bound model of decision-making. These models identify the initial intention to act as the moment of threshold crossing while explaining how antecedent subthreshold neural activity can influence an action without implying a decision. © 2014 Nature America, Inc.

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