GluD1, linked to schizophrenia, controls the burst firing of dopamine neurons

Human mutations of the GRID1 gene encoding the orphan delta1 glutamate receptor-channel (GluD1) are associated with schizophrenia but the explicit role of GluD1 in brain circuits is unknown. Based on the known function of its paralog GluD2 in cerebellum, we searched for a role of GluD1 in slow glutamatergic transmission mediated by metabotropic receptor mGlu1 in midbrain dopamine neurons, whose dysfunction is a hallmark of schizophrenia. We found that an mGlu1 agonist elicits a slow depolarizing current in HEK cells co-expressing mGlu1 and GluD1, but not in cells expressing mGlu1 or GluD1 alone. This current is abolished by additional co-expression of a dominant-negative GluD1 dead pore mutant. We then characterized mGlu1-dependent currents in dopamine neurons from midbrain slices. Both the agonist-evoked and the slow postsynaptic currents are abolished by expression of the dominant-negative GluD1 mutant, pointing to the involvement of native GluD1 channels in these currents. Likewise, both mGlu1-dependent currents are suppressed in GRID1 knockout mice, which reportedly display endophenotypes relevant for schizophrenia. It is known that mGlu1 activation triggers the transition from tonic to burst firing of dopamine neurons, which signals salient stimuli and encodes reward prediction. In vivo recordings of dopamine neurons showed that their spontaneous burst firing is abolished in GRID1 knockout mice or upon targeted expression of the dominant-negative GluD1 mutant in wild-type mice. Our results de-orphanize GluD1, unravel its key role in slow glutamatergic transmission and provide insights into how GRID1 gene alterations can lead to dopaminergic dysfunctions in schizophrenia

Allergic rhinitis: evidence for impact on asthma

BACKGROUND: This paper reviews the current evidence indicating that comorbid allergic rhinitis may have clinically relevant effects on asthma. DISCUSSION: Allergic rhinitis is very common in patients with asthma, with a reported prevalence of up to 100% in those with allergic asthma. While the temporal relation of allergic rhinitis and asthma diagnoses can be variable, the diagnosis of allergic rhinitis often precedes that of asthma. Rhinitis is an independent risk factor for the subsequent development of asthma in both atopic and nonatopic individuals. Controlled studies have provided conflicting results regarding the benefits for asthma symptoms of treating comorbid allergic rhinitis with intranasal corticosteroids. Effects of other treatments for comorbid allergic rhinitis, including antihistamines, allergen immunotherapy, systemic anti-IgE therapy, and antileukotriene agents, have been examined in a limited number of studies; anti-IgE therapy and antileukotriene agents such as the leukotriene receptor antagonists have benefits for treating both allergic rhinitis and asthma. Results of observational studies indicate that treating comorbid allergic rhinitis results in a lowered risk of asthma-related hospitalizations and emergency visits. Results of several retrospective database studies in the United States and in Europe indicate that, for patients with asthma, the presence of comorbid allergic rhinitis is associated with higher total annual medical costs, greater prescribing frequency of asthma-related medications, as well as increased likelihood of asthma-related hospital admissions and emergency visits. There is therefore evidence suggesting that comorbid allergic rhinitis is a marker for more difficult to control asthma and worsened asthma outcomes. CONCLUSION: These findings highlight the potential for improving asthma outcomes by following a combined therapeutic approach to comorbid allergic rhinitis and asthma rather than targeting each condition separately

Diversité des signaux d'avertissement, spéciation et diversification

The display of warning signals by unpalatable (or otherwise defended) prey provides a wonderful opportunity for establishing an integrative view of biological diversification. Warning signals are known to be under strong natural and sexual selection. On the one hand, the sampling strategy of predators, characterized by a learned avoidance of signals associated with unpalatability, generates natural selection in favour of warning signals in high frequency in the prey community. Such positive frequency-dependent selection favours phenotypic uniformity and causes unpalatable species to converge on common warning signals (mutualistic "Müllerian" mimicry), as seen in a large panel of taxa. On the other hand, warning signals are used as a phenotypic cue for mate choice, generating sexual selection with important consequences for reproductive isolation and speciation. Paradoxically, despite powerful selection favouring phenotypic convergence, warning signals are fantastically diverse, both within and between species, and this morphological diversification is often associated with extensive species diversification at the clade level. In this thesis, I tackle this apparent paradox from the ground up and I thereby refine our understanding of the role of positive frequency-dependent selection and mutualistic interactions for evolutionary diversification at micro- and macroevolutionary scales. First, I show that the predator sampling strategy can favour the emergence of diversity of warning signals despite positive frequency-dependent selection. Second, I dissect the conditions allowing the evolution of strong and stable reproductive isolation, necessary for speciation to occur, in a number of ecological situations where warning signals are under natural and sexual selection. Third, I highlight important indirect effects of frequency-dependent selection on diversification at macro-evolutionary scale via spatial constraints and by-product ecological convergence.Les signaux d'avertissement que portent les proies toxiques (ou autrement défendues) offrent une opportunité unique de développer une vision intégrative de la diversification biologique. Ces signaux sont soumis à une forte sélection naturelle et sexuelle. D'une part, la stratégie d'échantillonnage utilisée par les prédateurs, caractérisée par l'apprentissage des signaux associés à la toxicité, protège les signaux en forte fréquence dans la communauté de proies. Cette sélection fréquence-dépendante positive favorise l'uniformité des phénotypes et la convergence de signaux entre espèces toxiques (mimétisme mutualiste dit "Müllerien") dans de nombreux taxons. D'autre part, les signaux d'avertissement sont utilisés comme critères de choix entre partenaires sexuels et sont donc soumis à de la sélection sexuelle avec des conséquences importantes pour l'émergence de l'isolement reproducteur et la spéciation. Paradoxalement, malgré une forte sélection naturelle favorisant la convergence, les signaux d'avertissement sont incroyablement diversifiés, à la fois au sein de la même espèce et entre espèces. Cette diversification morphologique est souvent associée à une importante diversification des espèces à l'échelle des clades. Dans cette thèse, j'apporte quelques explications à ce paradoxe et j'affine ainsi notre compréhension de l'effet de la sélection fréquence-dépendante positive et du mutualisme sur la diversification à l'échelle micro- et macro-évolutive. Premièrement, je montre que la stratégie d'échantillonnage des prédateurs peut favoriser la diversification des signaux d'avertissement malgré une sélection fréquence-dépendante positive. Deuxièmement, je dissèque les conditions permettant l'évolution d'un isolement reproducteur stable, nécessaire à la spéciation, dans certaines situations écologiques où les signaux mimétiques sont sous sélection naturelle et sexuelle. Troisièmement, je décris des effets indirect de la sélection fréquence-dépendante sur la diversification à l'échelle macro-évolutive par le biais de contraintes spatiales et de convergences écologiques secondaires

Coevolution of male and female mate choice can destabilize reproductive isolation

Sexual interactions play an important role in the evolution of reproductive isolation, with important consequences for speciation. Theoretical studies have focused on the evolution of mate preferences in each sex separately. However, mounting empirical evidence suggests that premating isolation often involves mutual mate choice. Here, using a population genetic model, we investigate how female and male mate choice coevolve under a phenotype matching rule and how this affects reproductive isolation. We show that the evolution of female preferences increases the mating success of males with reciprocal preferences, favouring mutual mate choice. However, the evolution of male preferences weakens indirect selection on female preferences and, with weak genetic drift, the coevolution of female and male mate choice leads to periodic episodes of random mating with increased hybridization (deterministic ‘preference cycling’ triggered by stochasticity). Thus, counterintuitively, the process of establishing premating isolation proves rather fragile if both male and female mate choice contribute to assortative mating

Data from: Diversity in Müllerian mimicry: the optimal predator sampling strategy explains both local and regional polymorphism in prey

The convergent evolution of warning signals in unpalatable species, known as Müllerian mimicry, has been observed in a wide variety of taxonomic groups. This form of mimicry is generally thought to have arisen as a consequence of local frequency-dependent selection imposed by sampling predators. However, despite clear evidence for local selection against rare warning signals, there appears an almost embarrassing amount of polymorphism in natural warning colors, both within and among populations. Because the model of predator cognition widely invoked to explain Müllerian mimicry (Müller’s “fixed nk” model) is highly simplified and has not been empirically supported; here, we explore the dynamical consequences of the optimal strategy for sampling unfamiliar prey. This strategy, based on a classical exploration–exploitation trade-off, not only allows for a variable number of prey sampled, but also accounts for predator neophobia under some conditions. In contrast to Müller’s “fixed nk” sampling rule, the optimal sampling strategy is capable of generating a variety of dynamical outcomes, including mimicry but also regional and local polymorphism. Moreover, the heterogeneity of predator behavior across space and time that a more nuanced foraging strategy allows, can even further facilitate the emergence of both local and regional polymorphism in prey warning color

Senescence evolution under the catastrophic accumulation of deleterious mutations

For aging to evolve, selection against mortality must decrease with age. This prevailing view in the evolutionary theory of senescence posits that mutations with deleterious effects happening late in life—when purging selection is weak—may become fixed via genetic drift in the germline, and produce a senescent phenotype. Theory, however, has focused primarily on growing populations and the fate of single deleterious mutations. In a mathematical model, we demonstrate that relaxing both of these simplifying assumptions leads to unrealistic outcomes. In density-regulated populations, previously fixed deleterious mutations should promote the fixation of other deleterious mutations that lead to senescence at ever younger ages, until death necessarily occurs at sexual maturity. This sequential fixation of deleterious mutations is not promoted by a decrease in population size, but is due to a change in the strength of selection. In an individual-based model, we also show that such evolutionary dynamics should lead to the extinction of most populations. Our models therefore make rather unrealistic predictions, underlining the need for a reappraisal of current theories. In this respect, we have further assumed in our models that the deleterious effects of mutations can only occur at certain ages, marked, for instance, by somatic or physiological changes. Under this condition, we show that the catastrophic accumulation of deleterious mutations in the germline can stop. This new finding emphasizes the importance of investigating somatic factors, as well as other mechanisms underlying the deleterious effects of mutations, to understand senescence evolution. More generally, our model therefore establishes that patterns of senescence in nature depend not only on the decrease in selection strength with age but also on any mechanism that stops the catastrophic accumulation of mutations.ISSN:2056-374

Balancing quality and quantity of social relationships in volatile social environments

Cooperative interactions do not occur in a vacuum, but develop over time in social groups that undergo demographic changes. Intuition suggests that stable social environments might favour individuals that develop few but strong reciprocal relationships (a ‘focused’ strategy), while volatile social environments do the opposite and favour individuals with more but weaker social relationships (a ‘diversifying’ strategy). We model reciprocal investments under a tradeoff between quantity and quality of social relationships, and reveal that this intuition is fallible. We find that volatile social environments particularly favour a focused cooperative strategy. This result can be explained by applying the theory of antagonistic pleiotropy, originally developed for senescence, to cooperative strategies. Diversifying social investments benefits late-life individuals that already have their social network built up, but is detrimental early in life when networks must be built from scratch. Under volatile social environments, the age structure of a population remains generally young, and this emphasizes strategies that do well early in life: a focused strategy which makes the individual form its first few social bonds happen quickly. Overall, our model highlights the importance of pleiotropy and population age structure for the evolution of cooperative strategies and other social traits

Transmissible cancers and the evolution of sex under the Red Queen hypothesis

The predominance of sexual reproduction in eukaryotes remains paradoxical in evolutionary theory. Of the hypotheses proposed to resolve this paradox, the ‘Red Queen hypothesis’ emphasises the potential of antagonistic interactions to cause fluctuating selection, which favours the evolution and maintenance of sex. Whereas empirical and theoretical developments have focused on host-parasite interactions, the premises of the Red Queen theory apply equally well to any type of antagonistic interactions. Recently, it has been suggested that early multicellular organisms with basic anticancer defences were presumably plagued by antagonistic interactions with transmissible cancers and that this could have played a pivotal role in the evolution of sex. Here, we dissect this argument using a population genetic model. One fundamental aspect distinguishing transmissible cancers from other parasites is the continual production of cancerous cell lines from hosts’ own tissues. We show that this influx dampens fluctuating selection and therefore makes the evolution of sex more difficult than in standard Red Queen models. Although coevolutionary cycling can remain sufficient to select for sex under some parameter regions of our model, we show that the size of those regions shrinks once we account for epidemiological constraints. Altogether, our results suggest that horizontal transmission of cancerous cells is unlikely to cause fluctuating selection favouring sexual reproduction. Nonetheless, we confirm that vertical transmission of cancerous cells can promote the evolution of sex through a separate mechanism, known as similarity selection, that does not depend on coevolutionary fluctuations

C++ and R code

You'll find the C++ code to simulate the evolutionary dynamics of mimetic organisms, and the R code used to analyse the outputs (format : .csv) of the simulations