Ana Domingos - Academia.edu (original) (raw)

Papers by Ana Domingos

EMBO reports, 2014

People think they are in control of their own decisions: what to eat or drink, whom to marry or p... more People think they are in control of their own decisions: what to eat or drink, whom to marry or pick a fight with, where to live, what to buy. Behavioural economists and neurophysiologists have long studied decision-making behaviours. However, these behaviours have only recently been studied through the light of molecular genetics. Here, we review recent research in mice, Drosophila melanogaster and Caenorhabditis elegans, that analyses the molecular and cellular mechanisms underlying decision-making. These studies interrogate decision-making about food, sexual behaviour, aggression or foraging strategies, and add molecular and cell biology understanding onto the consilience of brain and decision.

eLife, 2013

Sugars that contain glucose, such as sucrose, are generally preferred to artificial sweeteners ow... more Sugars that contain glucose, such as sucrose, are generally preferred to artificial sweeteners owing to their post-ingestive rewarding effect, which elevates striatal dopamine (DA) release. While the post-ingestive rewarding effect, which artificial sweeteners do not have, signals the nutrient value of sugar and influences food preference, the neural circuitry that mediates the rewarding effect of glucose is unknown. In this study, we show that optogenetic activation of melanin-concentrating hormone (MCH) neurons during intake of the artificial sweetener sucralose increases striatal dopamine levels and inverts the normal preference for sucrose vs sucralose. Conversely, animals with ablation of MCH neurons no longer prefer sucrose to sucralose and show reduced striatal DA release upon sucrose ingestion. We further show that MCH neurons project to reward areas and are required for the post-ingestive rewarding effect of sucrose in sweet-blind Trpm5 −/− mice. These studies identify an essential component of the neural pathways linking nutrient sensing and food reward.

Molecular Metabolism, 2014

Leptin-deficient patients report higher "liking" ratings for food, and leptin replacement therapy... more Leptin-deficient patients report higher "liking" ratings for food, and leptin replacement therapy normalizes these ratings even before weight loss is achieved. Since animals cannot report their ratings, we studied the relationship between leptin and food reward in leptin-deficient ob/ob mice using a optogenetic assay that quantifies the reward value of sucrose. In this assay, mice chose between one sipper dispensing the artificial sweetener sucralose coupled to optogenetic activation of dopaminergic (DA) neurons, and another sipper dispensing sucrose. We found that the reward value of sucrose was high under a state of leptin deficiency, as well as at a dose of leptin that does not suppress food intake (12.5 ng/h). Treatment with higher doses of leptin decreased the reward value of sucrose before weight loss was achieved (100 ng/h), as seen in leptin-deficient patients. These results phenocopy in mice the behavior of leptin-deficient patients.

Nature Neuroscience, 2011

We developed an assay for quantifying the reward value of nutrient and used it to analyze the eff... more We developed an assay for quantifying the reward value of nutrient and used it to analyze the effects of metabolic state and leptin. In this assay, mice chose between two sippers, one of which dispensed water and was coupled to optogenetic activation of dopaminergic (DA) neurons and the other of which dispensed natural or artificial sweeteners. This assay measured the reward value of sweeteners relative to lick-induced optogenetic activation of DA neurons. Mice preferred optogenetic stimulation of DA neurons to sucralose, but not to sucrose. However, the mice preferred sucralose plus optogenetic stimulation versus sucrose. We found that food restriction increased the value of sucrose relative to sucralose plus optogenetic stimulation, and that leptin decreased it. Our data suggest that leptin suppresses the ability of sucrose to drive taste-independent DA neuronal activation and provide new insights into the mechanism of leptin's effects on food intake.

Nature, 2012

Ventral tegmental area (VTA) dopamine neurons in the brain's reward circuit have a crucial role i... more Ventral tegmental area (VTA) dopamine neurons in the brain's reward circuit have a crucial role in mediating stress responses 1-4 , including determining susceptibility versus resilience to social-stress-induced behavioural abnormalities 5 . VTA dopamine neurons show two in vivo patterns of firing: low frequency tonic firing and high frequency phasic firing 6-8 . Phasic firing of the neurons, which is well known to encode reward signals 6,7,9 , is upregulated by repeated social-defeat stress, a highly validated mouse model of depression . Surprisingly, this pathophysiological effect is seen in susceptible mice only, with no apparent change in firing rate in resilient individuals 5,8 . However, direct evidence-in real time-linking dopamine neuron phasic firing in promoting the susceptible (depression-like) phenotype is lacking. Here we took advantage of the temporal precision and celltype and projection-pathway specificity of optogenetics to show that enhanced phasic firing of these neurons mediates susceptibility to social-defeat stress in freely behaving mice. We show that optogenetic induction of phasic, but not tonic, firing in VTA dopamine neurons of mice undergoing a subthreshold social-defeat paradigm rapidly induced a susceptible phenotype as measured by social avoidance and decreased sucrose preference. Optogenetic phasic stimulation of these neurons also quickly induced a susceptible phenotype in previously resilient mice that had been subjected to repeated social-defeat stress. Furthermore, we show differences in projection-pathway specificity in promoting stress susceptibility: phasic activation of VTA neurons projecting to the nucleus accumbens (NAc), but not to the medial prefrontal cortex (mPFC), induced susceptibility to socialdefeat stress. Conversely, optogenetic inhibition of the VTA-NAc projection induced resilience, whereas inhibition of the VTA-mPFC projection promoted susceptibility. Overall, these studies reveal novel firing-pattern-and neural-circuit-specific mechanisms of depression.

Current Biology, 2005

Background: Odorant receptors (ORs) are thought to act in a combinatorial fashion, in which odor ... more Background: Odorant receptors (ORs) are thought to act in a combinatorial fashion, in which odor identity is encoded by the activation of a subset of ORs and the olfactory sensory neurons (OSNs) that express them. The extent to which a single OR contributes to chemotaxis behavior is not known. We investigated this question in Drosophila larvae, which represent a powerful genetic system to analyze the contribution of individual OSNs to odor coding. Results: We identify 25 larval OR genes expressed in 21 OSNs and generate genetic tools that allow us to engineer larvae missing a single OSN or having only a single or a pair of functional OSNs. Ablation of single OSNs disrupts chemotaxis behavior to a small subset of the odors tested. Larvae with only a single functional OSN are able to chemotax robustly, demonstrating that chemotaxis is possible in the absence of the remaining elements of the combinatorial code. We provide behavioral evidence that an OSN not sufficient to support chemotaxis behavior alone can act in a combinatorial fashion to enhance chemotaxis along with a second OSN. Conclusions: We conclude that there is extensive functional redundancy in the olfactory system, such that a given OSN is necessary and sufficient for the perception of only a subset of odors. This study is the first behavioral demonstration that formation of olfactory percepts involves the combinatorial integration of information transmitted by multiple ORs.

Cell Metabolism, 2013

Comprehensive transcriptional profiling of glucosesensing neurons is challenging because of low e... more Comprehensive transcriptional profiling of glucosesensing neurons is challenging because of low expression levels of glucokinase (Gck) and other key proteins that transduce a glucose signal. To overcome this, we generated and validated transgenic mice with a neuronal/endocrine-specific Gck promoter driving cre expression and mated them to mice with cre-dependent expression of an EGFPtagged ribosomal protein construct (EEF1A1ÀLSL. EGFPL10) that can be used to map and profile cells. We found significant Gck expression in hypothalamic and limbic regions in cells that are activated following administration of glucose or 2-deoxyglucose. Transcriptional profiling from Gck-cre/EEF1A1ÀLSL. EGFPL10 mice enriched known and previously unknown glucose-sensing populations including neurons expressing growth hormone releasing hormone (GHRH). Electrophysiological recordings show that hypoglycemia activates GHRH neurons, suggesting a mechanistic link between hypoglycemia and growth hormone release. These studies provide a means for mapping glucose-sensitive neurons and for generating transcriptional profiles from other cell types expressing cre in a cell-specific manner.

Neuron, 2004

electrophysiology has demonstrated that the characteristic odor response profile of a given OSN i... more electrophysiology has demonstrated that the characteristic odor response profile of a given OSN is governed by the selective expression of one or more members of the family of 61 OR genes in that neuron (Dobritsa et al., One member of the OR gene family, Or83b, is strikingly 1230 York Avenue different from the other OR genes. Unlike the conven-New York, New York 10021 tional ORs, it has clear homologs in other insect species that share nearly 70% amino acid identity with Or83b (Hill et al., 2002; Krieger et al., 2003; Pitts et al., 2004). Summary Or83b and its homologs in other insects are coexpressed with conventional ORs in a large proportion of Fruit flies are attracted by a diversity of odors that OSNs (Vosshall et al., 1999, 2000; Elmore et al., 2003; signal the presence of food, potential mates, or attrac-Krieger et al., 2003; Pitts et al., 2004). tive egg-laying sites. Most Drosophila olfactory neu-Based on these observations, two models could acrons express two types of odorant receptor genes: count for Or83b function in insect olfaction. Or83b could Or83b, a broadly expressed receptor of unknown funcbind distinct ligands independently of the other OR tion, and one or more members of a family of 61 selecgenes coexpressed with it in a given OSN, or it could tively expressed receptors. While the conventional act in concert with conventional ORs to recognize a odorant receptors are highly divergent, Or83b is rewide variety of odors. markably conserved between insect species. Two In the first model, Or83b might act in most OSNs to models could account for Or83b function: it could inrecognize and report the presence in the environment teract with specific odor stimuli independent of conof an important odor signifying danger or a particularly ventional odorant receptors, or it could act in concert rich food source. Insects have evolved a diversity of with these receptors to mediate responses to all food preferences and inhabit many different ecological odors. Our results support the second model. Denniches. However, the vast majority of insects have an dritic localization of conventional odorant receptors important relationship to plants, either as food sources, is abolished in Or83b mutants. Consistent with this sites for egg-laying, habitat for prey, or shelter. Green cellular defect, the Or83b mutation disrupts behavioral leaf volatiles such as E2-hexenal and linalool are proand electrophysiological responses to many odorants. duced by many different plants and elicit physiological Or83b therefore encodes an atypical odorant receptor and behavioral responses in insects as varied as moths, that plays an essential general role in olfaction. mosquitoes, and Drosophila (Rostelien et al., 2000; de Bruyne et al., 2001; Kline et al., 2003). Therefore, Or83b Introduction might interact selectively with various plant volatiles and transmit the same information to insects of diverse tax-The olfactory system has evolved the capacity to recogonomy: that they are in the presence of plants. Alternanize and discriminate an inordinate number of chemitively, Or83b could interact with a single odorant that cally distinct odors that signal the presence of food, has different meanings to different insects. For instance, predators, or mating partners. The initial steps in odor isoamyl acetate is a key component of rotting fruit and detection involve the binding of a volatile odor to odorant signifies food to Drosophila (Stensmyr et al., 2003), while receptor (OR) proteins displayed on ciliated dendrites the same odorant is produced by honeybees as an alarm of specialized olfactory sensory neurons (OSNs) that are and aggregation pheromone (Galizia et al., 1998). In both exposed to the external environment. The OR genes cases, the stimulus is of great importance to these inthat mediate odor detection in Drosophila fruit flies are sects, and dedicating a broadly expressed receptor like expressed in subpopulations of OSNs (Clyne et al., 1999; Or83b to detecting it might be adaptive for each insect. Gao and Chess, 1999; Vosshall et al., 1999, 2000; Do-In either variation of this first model, animals lacking britsa et al., 2003; Elmore et al., 2003) and are members

EMBO reports, 2014

People think they are in control of their own decisions: what to eat or drink, whom to marry or p... more People think they are in control of their own decisions: what to eat or drink, whom to marry or pick a fight with, where to live, what to buy. Behavioural economists and neurophysiologists have long studied decision-making behaviours. However, these behaviours have only recently been studied through the light of molecular genetics. Here, we review recent research in mice, Drosophila melanogaster and Caenorhabditis elegans, that analyses the molecular and cellular mechanisms underlying decision-making. These studies interrogate decision-making about food, sexual behaviour, aggression or foraging strategies, and add molecular and cell biology understanding onto the consilience of brain and decision.

eLife, 2013

Sugars that contain glucose, such as sucrose, are generally preferred to artificial sweeteners ow... more Sugars that contain glucose, such as sucrose, are generally preferred to artificial sweeteners owing to their post-ingestive rewarding effect, which elevates striatal dopamine (DA) release. While the post-ingestive rewarding effect, which artificial sweeteners do not have, signals the nutrient value of sugar and influences food preference, the neural circuitry that mediates the rewarding effect of glucose is unknown. In this study, we show that optogenetic activation of melanin-concentrating hormone (MCH) neurons during intake of the artificial sweetener sucralose increases striatal dopamine levels and inverts the normal preference for sucrose vs sucralose. Conversely, animals with ablation of MCH neurons no longer prefer sucrose to sucralose and show reduced striatal DA release upon sucrose ingestion. We further show that MCH neurons project to reward areas and are required for the post-ingestive rewarding effect of sucrose in sweet-blind Trpm5 −/− mice. These studies identify an essential component of the neural pathways linking nutrient sensing and food reward.

Molecular Metabolism, 2014

Leptin-deficient patients report higher "liking" ratings for food, and leptin replacement therapy... more Leptin-deficient patients report higher "liking" ratings for food, and leptin replacement therapy normalizes these ratings even before weight loss is achieved. Since animals cannot report their ratings, we studied the relationship between leptin and food reward in leptin-deficient ob/ob mice using a optogenetic assay that quantifies the reward value of sucrose. In this assay, mice chose between one sipper dispensing the artificial sweetener sucralose coupled to optogenetic activation of dopaminergic (DA) neurons, and another sipper dispensing sucrose. We found that the reward value of sucrose was high under a state of leptin deficiency, as well as at a dose of leptin that does not suppress food intake (12.5 ng/h). Treatment with higher doses of leptin decreased the reward value of sucrose before weight loss was achieved (100 ng/h), as seen in leptin-deficient patients. These results phenocopy in mice the behavior of leptin-deficient patients.

Nature Neuroscience, 2011

We developed an assay for quantifying the reward value of nutrient and used it to analyze the eff... more We developed an assay for quantifying the reward value of nutrient and used it to analyze the effects of metabolic state and leptin. In this assay, mice chose between two sippers, one of which dispensed water and was coupled to optogenetic activation of dopaminergic (DA) neurons and the other of which dispensed natural or artificial sweeteners. This assay measured the reward value of sweeteners relative to lick-induced optogenetic activation of DA neurons. Mice preferred optogenetic stimulation of DA neurons to sucralose, but not to sucrose. However, the mice preferred sucralose plus optogenetic stimulation versus sucrose. We found that food restriction increased the value of sucrose relative to sucralose plus optogenetic stimulation, and that leptin decreased it. Our data suggest that leptin suppresses the ability of sucrose to drive taste-independent DA neuronal activation and provide new insights into the mechanism of leptin's effects on food intake.

Nature, 2012

Ventral tegmental area (VTA) dopamine neurons in the brain's reward circuit have a crucial role i... more Ventral tegmental area (VTA) dopamine neurons in the brain's reward circuit have a crucial role in mediating stress responses 1-4 , including determining susceptibility versus resilience to social-stress-induced behavioural abnormalities 5 . VTA dopamine neurons show two in vivo patterns of firing: low frequency tonic firing and high frequency phasic firing 6-8 . Phasic firing of the neurons, which is well known to encode reward signals 6,7,9 , is upregulated by repeated social-defeat stress, a highly validated mouse model of depression . Surprisingly, this pathophysiological effect is seen in susceptible mice only, with no apparent change in firing rate in resilient individuals 5,8 . However, direct evidence-in real time-linking dopamine neuron phasic firing in promoting the susceptible (depression-like) phenotype is lacking. Here we took advantage of the temporal precision and celltype and projection-pathway specificity of optogenetics to show that enhanced phasic firing of these neurons mediates susceptibility to social-defeat stress in freely behaving mice. We show that optogenetic induction of phasic, but not tonic, firing in VTA dopamine neurons of mice undergoing a subthreshold social-defeat paradigm rapidly induced a susceptible phenotype as measured by social avoidance and decreased sucrose preference. Optogenetic phasic stimulation of these neurons also quickly induced a susceptible phenotype in previously resilient mice that had been subjected to repeated social-defeat stress. Furthermore, we show differences in projection-pathway specificity in promoting stress susceptibility: phasic activation of VTA neurons projecting to the nucleus accumbens (NAc), but not to the medial prefrontal cortex (mPFC), induced susceptibility to socialdefeat stress. Conversely, optogenetic inhibition of the VTA-NAc projection induced resilience, whereas inhibition of the VTA-mPFC projection promoted susceptibility. Overall, these studies reveal novel firing-pattern-and neural-circuit-specific mechanisms of depression.

Current Biology, 2005

Background: Odorant receptors (ORs) are thought to act in a combinatorial fashion, in which odor ... more Background: Odorant receptors (ORs) are thought to act in a combinatorial fashion, in which odor identity is encoded by the activation of a subset of ORs and the olfactory sensory neurons (OSNs) that express them. The extent to which a single OR contributes to chemotaxis behavior is not known. We investigated this question in Drosophila larvae, which represent a powerful genetic system to analyze the contribution of individual OSNs to odor coding. Results: We identify 25 larval OR genes expressed in 21 OSNs and generate genetic tools that allow us to engineer larvae missing a single OSN or having only a single or a pair of functional OSNs. Ablation of single OSNs disrupts chemotaxis behavior to a small subset of the odors tested. Larvae with only a single functional OSN are able to chemotax robustly, demonstrating that chemotaxis is possible in the absence of the remaining elements of the combinatorial code. We provide behavioral evidence that an OSN not sufficient to support chemotaxis behavior alone can act in a combinatorial fashion to enhance chemotaxis along with a second OSN. Conclusions: We conclude that there is extensive functional redundancy in the olfactory system, such that a given OSN is necessary and sufficient for the perception of only a subset of odors. This study is the first behavioral demonstration that formation of olfactory percepts involves the combinatorial integration of information transmitted by multiple ORs.

Cell Metabolism, 2013

Comprehensive transcriptional profiling of glucosesensing neurons is challenging because of low e... more Comprehensive transcriptional profiling of glucosesensing neurons is challenging because of low expression levels of glucokinase (Gck) and other key proteins that transduce a glucose signal. To overcome this, we generated and validated transgenic mice with a neuronal/endocrine-specific Gck promoter driving cre expression and mated them to mice with cre-dependent expression of an EGFPtagged ribosomal protein construct (EEF1A1ÀLSL. EGFPL10) that can be used to map and profile cells. We found significant Gck expression in hypothalamic and limbic regions in cells that are activated following administration of glucose or 2-deoxyglucose. Transcriptional profiling from Gck-cre/EEF1A1ÀLSL. EGFPL10 mice enriched known and previously unknown glucose-sensing populations including neurons expressing growth hormone releasing hormone (GHRH). Electrophysiological recordings show that hypoglycemia activates GHRH neurons, suggesting a mechanistic link between hypoglycemia and growth hormone release. These studies provide a means for mapping glucose-sensitive neurons and for generating transcriptional profiles from other cell types expressing cre in a cell-specific manner.

Neuron, 2004

electrophysiology has demonstrated that the characteristic odor response profile of a given OSN i... more electrophysiology has demonstrated that the characteristic odor response profile of a given OSN is governed by the selective expression of one or more members of the family of 61 OR genes in that neuron (Dobritsa et al., One member of the OR gene family, Or83b, is strikingly 1230 York Avenue different from the other OR genes. Unlike the conven-New York, New York 10021 tional ORs, it has clear homologs in other insect species that share nearly 70% amino acid identity with Or83b (Hill et al., 2002; Krieger et al., 2003; Pitts et al., 2004). Summary Or83b and its homologs in other insects are coexpressed with conventional ORs in a large proportion of Fruit flies are attracted by a diversity of odors that OSNs (Vosshall et al., 1999, 2000; Elmore et al., 2003; signal the presence of food, potential mates, or attrac-Krieger et al., 2003; Pitts et al., 2004). tive egg-laying sites. Most Drosophila olfactory neu-Based on these observations, two models could acrons express two types of odorant receptor genes: count for Or83b function in insect olfaction. Or83b could Or83b, a broadly expressed receptor of unknown funcbind distinct ligands independently of the other OR tion, and one or more members of a family of 61 selecgenes coexpressed with it in a given OSN, or it could tively expressed receptors. While the conventional act in concert with conventional ORs to recognize a odorant receptors are highly divergent, Or83b is rewide variety of odors. markably conserved between insect species. Two In the first model, Or83b might act in most OSNs to models could account for Or83b function: it could inrecognize and report the presence in the environment teract with specific odor stimuli independent of conof an important odor signifying danger or a particularly ventional odorant receptors, or it could act in concert rich food source. Insects have evolved a diversity of with these receptors to mediate responses to all food preferences and inhabit many different ecological odors. Our results support the second model. Denniches. However, the vast majority of insects have an dritic localization of conventional odorant receptors important relationship to plants, either as food sources, is abolished in Or83b mutants. Consistent with this sites for egg-laying, habitat for prey, or shelter. Green cellular defect, the Or83b mutation disrupts behavioral leaf volatiles such as E2-hexenal and linalool are proand electrophysiological responses to many odorants. duced by many different plants and elicit physiological Or83b therefore encodes an atypical odorant receptor and behavioral responses in insects as varied as moths, that plays an essential general role in olfaction. mosquitoes, and Drosophila (Rostelien et al., 2000; de Bruyne et al., 2001; Kline et al., 2003). Therefore, Or83b Introduction might interact selectively with various plant volatiles and transmit the same information to insects of diverse tax-The olfactory system has evolved the capacity to recogonomy: that they are in the presence of plants. Alternanize and discriminate an inordinate number of chemitively, Or83b could interact with a single odorant that cally distinct odors that signal the presence of food, has different meanings to different insects. For instance, predators, or mating partners. The initial steps in odor isoamyl acetate is a key component of rotting fruit and detection involve the binding of a volatile odor to odorant signifies food to Drosophila (Stensmyr et al., 2003), while receptor (OR) proteins displayed on ciliated dendrites the same odorant is produced by honeybees as an alarm of specialized olfactory sensory neurons (OSNs) that are and aggregation pheromone (Galizia et al., 1998). In both exposed to the external environment. The OR genes cases, the stimulus is of great importance to these inthat mediate odor detection in Drosophila fruit flies are sects, and dedicating a broadly expressed receptor like expressed in subpopulations of OSNs (Clyne et al., 1999; Or83b to detecting it might be adaptive for each insect. Gao and Chess, 1999; Vosshall et al., 1999, 2000; Do-In either variation of this first model, animals lacking britsa et al., 2003; Elmore et al., 2003) and are members