Interactions between learning and immunity in Drosophila melanogaster

Learning and immunity are two adaptive traits with roles in central aspects of an organism's life: learning allows adjusting behaviours in changing environments, while immunity protects the body integrity against parasites and pathogens. While we know a lot about how these two traits interact in vertebrates, the interactions between learning and immunity remain poorly explored in insects. During my PhD, I studied three possible ways in which these two traits interact in the model system Drosophila melanogaster, a model organism in the study of learning and in the study of immunity. Learning can affect the behavioural defences against parasites and pathogens through the acquisition of new aversions for contaminated food for instance. This type of learning relies on the ability to associate a food-related cue with the visceral sickness following ingestion of contaminated food. Despite its potential implication in infection prevention, the existence of pathogen avoidance learning has been rarely explored in invertebrates. In a first part of my PhD, I tested whether D. melanogaster, which feed on food enriched in microorganisms, innately avoid the orally-acquired 'novel' virulent pathogen Pseudomonas entomophila, and whether it can learn to avoid it. Although flies did not innately avoid this pathogen, they decreased their preference for contaminated food over time, suggesting the existence of a form of learning based likely on infection-induced sickness. I further found that flies may be able to learn to avoid an odorant which was previously associated with the pathogen, but this requires confirmation with additional data. If this is confirmed, this would be the first time, to my knowledge, that pathogen avoidance learning is reported in an insect. The detrimental effect of infection on cognition and more specifically on learning ability is well documented in vertebrates and in social insects. While the underlying mechanisms are described in detail in vertebrates, experimental investigations are lacking in invertebrates. In a second part of my PhD, I tested the effect of an oral infection with natural pathogens on associative learning of D. melanogaster. By contrast with previous studies in insects, I found that flies orally infected with the virulent P. entomophila learned better the association of an odorant with mechanical shock than uninfected flies. The effect seems to be specific to a gut infection, and so far I have not been able to draw conclusions on the respective contributions of the pathogen's virulence and of the flies' immune activity in this effect. Interestingly, infected flies may display an increased sensitivity to physical pain. If the learning improvement observed in infected flies was due partially to the activity of the immune system, my results would suggest the existence of physiological connections between the immune system and the nervous system. The basis of these connections would then need to be addressed. Learning and immunity are linked at the physiological level in social insects. Physiological links between traits often result from the expression of genetic links between these traits. However, in social insects, there is no evidence that learning and immunity may be involved in an evolutionary trade-off. I previously reported a positive effect of infection on learning in D. melanogaster. This might suggest that a positive genetic link could exist between learning and immunity. We tested this hypothesis with two approaches: the diallel cross design with inbred lines, and the isofemale lines design. The two approaches provided consistent results: we found no additive genetic correlation between learning and resistance to infection with the diallel cross, and no genetic correlation in flies which are not yet adapted to laboratory conditions in isofemale lines. Consistently with the literature, the two studies suggested that the positive effect of infection on learning I observed might not be reflected by a positive evolutionary link between learning and immunity. Nevertheless, the existence of complex genetic relationships between the two traits cannot be excluded. - L'apprentissage et l'immunité sont deux caractères à valeur adaptative impliqués dans des aspects centraux de la vie d'un organisme : l'apprentissage permet d'ajuster les comportements pour faire face aux changements de l'environnement, tandis que l'immunité protège l'intégrité corporelle contre les attaques des parasites et des pathogènes. Alors que les interactions entre l'apprentissage et l'immunité sont bien documentées chez les vertébrés, ces interactions ont été très peu étudiées chez les insectes. Pendant ma thèse, je me suis intéressée à trois aspects des interactions possibles entre l'apprentissage et l'immunité chez la mouche du vinaigre Drosophila melanogaster, qui est un organisme modèle dans l'étude à la fois de l'apprentissage et de l'immunité. L'apprentissage peut affecter les défenses comportementales contre les parasites et les pathogènes par l'acquisition de nouvelles aversions pour la nourriture contaminée par exemple. Ce type d'apprentissage repose sur la capacité à associer une caractéristique de la nourriture avec la maladie qui suit l'ingestion de cette nourriture. Malgré les implications potentielles pour la prévention des infections, l'évitement appris des pathogènes a été rarement étudié chez les invertébrés. Dans une première partie de ma thèse, j'ai testé si les mouches, qui se nourrissent sur des milieux enrichis en micro-organismes, évitent de façon innée un 'nouveau' pathogène virulent Pseudomonas entomophila, et si elles ont la capacité d'apprendre à l'éviter. Bien que les mouches ne montrent pas d'évitement inné pour ce pathogène, elles diminuent leur préférence pour de la nourriture contaminée dans le temps, suggérant l'existence d'une forme d'apprentissage basée vraisemblablement sur la maladie générée par l'infection. J'ai ensuite observé que les mouches semblent être capables d'apprendre à éviter une odeur qui était au préalable associée avec ce pathogène, mais cela reste à confirmer par la collecte de données supplémentaires. Si cette observation est confirmée, cela sera la première fois, à ma connaissance, que l'évitement appris des pathogènes est décrit chez un insecte. L'effet détrimental des infections sur la cognition et plus particulièrement sur les capacités d'apprentissage est bien documenté chez les vertébrés et les insectes sociaux. Alors que les mécanismes sous-jacents sont détaillés chez les vertébrés, des études expérimentales font défaut chez les insectes. Dans une seconde partie de ma thèse, j'ai mesuré les effets d'une infection orale par des pathogènes naturels sur les capacités d'apprentissage associatif de la drosophile. Contrairement aux études précédentes chez les insectes, j'ai trouvé que les mouches infectées par le pathogène virulent P. entomophila apprennent mieux à associer une odeur avec des chocs mécaniques que des mouches non infectées. Cet effet semble spécifique à l'infection orale, et jusqu'à présent je n'ai pas pu conclure sur les contributions respectives de la virulence du pathogène et de l'activité immunitaire des mouches dans cet effet. De façon intéressante, les mouches infectées pourraient montrer une plus grande réactivité à la douleur physique. Si l'amélioration de l'apprentissage observée chez les mouches infectées était due en partie à l'activité du système immunitaire, mes résultats suggéreraient l'existence de connections physiologiques entre le système immunitaire et le système nerveux. Les mécanismes de ces connections seraient à explorer. L'apprentissage et l'immunité sont liés sur un plan physiologique chez les insectes sociaux. Les liens physiologiques entre les caractères résultent souvent de l'expression de liens entre ces caractères au niveau génétique. Cependant, chez les insectes sociaux, il n'y a pas de preuve que l'apprentissage et l'immunité soient liés par un compromis évolutif. J'ai précédemment rapporté un effet positif de l'infection sur l'apprentissage chez la drosophile. Cela pourrait suggérer qu'une relation génétique positive existerait entre l'apprentissage et l'immunité. Nous avons testé cette hypothèse par deux approches : le croisement diallèle avec des lignées consanguines, et les lignées isofemelles. Les deux approches ont fournies des résultats similaires : nous n'avons pas détecté de corrélation génétique additive entre l'apprentissage et la résistance à l'infection avec le croisement diallèle, et pas de corrélation génétique chez des mouches non adaptées aux conditions de laboratoire avec les lignées isofemelles. En ligne avec la littérature, ces deux études suggèrent que l'effet positif de l'infection sur l'apprentissage que j'ai précédemment observé ne refléterait pas un lien évolutif positif entre l'apprentissage et l'immunité. Néanmoins, l'existence de relations génétiques complexes n'est pas exclue.

ELECTROCORTICAL DYNAMICS OF MOTOR INHIBITORY CONTROL WITH AGING

Motor inhibitory control plays a central role in adaptive behaviors during the entire lifespan. Inhibitory motor control refers to the ability to stop all (global) or a part (selective) of a planned or ongoing motor action. Although the neural processing underlying the global inhibitory control has received much attention from cognitive neuroscientists, brain modulations that occur during selective inhibitory motor control remain unknown. The aim of the present thesis is to investigate the spatio-temporal brain processes of selective inhibitory motor control in young and old adults using high-density electroencephalography. In the first part, we focus on early (preparatory period) spatio-temporal brain processes involved in selective and global inhibitory control in young (study I) and old adults (study II) using a modified Go/No-go task. In study I, we distinguished global from selective inhibition in the early attentional stage of inhibitory control and provided neurophysiological evidence in favor of the combination model. In study II, we showed an under-recruitment of neural resources associated with preservation of performance in old adults during selective inhibition, suggesting efficient cerebral and behavioral adaptations to environmental changes. In the second part, we investigate beta oscillations in the late (post-execution period) spatio-temporal brain processes of selective inhibition during a motor Switching task (i.e., tapping movement from bimanual to unimanual) in young (study III) and old adults (study IV). In study III, we identified concomitant beta synchronization related (i) to sensory reafference processes, which enabled the stabilization of the movement that was perturbed after switching, and (ii) to active inhibition processes that prevented movement of the stopping hand. In study IV, we demonstrated a larger beta synchronization in frontal and parietal regions in old adults compared to young adults, suggesting age-related brain modulations in active inhibition processes. Apart from contributing to a basic understanding of the electrocortical dynamics underlying inhibitory motor control, the findings of the present studies contribute to knowledge regarding the further establishment of specific trainings with aging. -- Le contrôle de l'inhibition motrice joue un rôle central dans les adaptations comportementales quel que soit l'âge. L'inhibition motrice se réfère à la capacité à arrêter entièrement (globale) ou en partie (sélective) une action motrice planifiée ou en cours. Bien que les processus neuronaux sous-jacents de l'inhibition globale aient suscité un grand intérêt auprès des neurosciences cognitives, les modulations cérébrales dans le contrôle de l'inhibition motrice sélective sont encore peu connues. Le but de cette thèse est d'étudier les processus cérébraux spatio-temporels du contrôle de l'inhibition motrice sélective chez les adultes jeunes et âgés en utilisant l'électroencéphalogramme à haute densité. Dans la première partie, nous comparons les processus cérébraux spatio-temporels précoces (préparation motrice) de l'inhibition sélective et globale chez des adultes jeunes (étude I) et âgés (étude II) en utilisant une tâche Go/No-go modifiée. Dans l'étude I, nous avons distingué l'inhibition globale et sélective au niveau des processus attentionnels précoces du contrôle de l'inhibition et nous avons apporté des preuves neurophysiologiques de l'existence d'un modèle de combinaison. Dans l'étude II, nous avons montré une sous-activation neuronale associée à un maintien de la performance dans l'inhibition sélective chez les adultes âgés, suggérant des adaptations cérébrales et comportementales aux contraintes environnementales. Dans la seconde partie, nous examinons les processus cérébraux spatio-temporels tardifs (post-exécution motrice) de l'inhibition sélective pendant une tâche de Switching (tapping bimanuel vers un tapping unimanuel) chez des adultes jeunes (étude III) et âgés (étude IV). Dans l'étude III, nous avons distingué des synchronisations beta liées (i) au traitement des réafférences sensorielles permettant de stabiliser le mouvement perturbé après le switching, et (ii) aux processus d'inhibition active afin d'empêcher les mouvements de la main arrêtée. Dans l'étude IV, cette synchronisation beta était plus forte dans les régions frontales et pariétales chez les âgés par rapport aux jeunes adultes suggérant des modulations cérébrales de l'inhibition active avec l'âge. Outre la contribution fondamentale sur la compréhension des dynamiques électrocorticales dans le contrôle de l'inhibition motrice, les résultats de ces études contribuent à développer les connaissances pour la mise en place de programmes d'entraînements adaptés aux personnes âgées.

Reduced learning ability as a consequence of evolutionary adaptation to nutritional stress in Drosophila melanogaster

1. Dietary conditions affect cognitive abilities of many species, but it is unclear to what extent this physiological effect translates into an evolutionary relationship. 2. A reduction of competitive ability under nutritional stress has been reported as a correlated response to selection for learning ability in Drosophila melanogaster. Here we test whether the reverse holds as well, i.e. whether an evolutionary adaptation to poor food conditions leads to a decrease in learning capacities. 3. Populations of D. melanogaster were: (i) not subject to selection (control), (ii) selected for improved learning ability, (iii) selected for survival and fast development on poor food, or (iv) subject to both selection regimes. 4. There was no detectable response to selection for learning ability. 5. Selection on poor food led to higher survival, faster development and smaller adult size as a direct response, and to reduced learning ability as a correlated response. This study supports the hypothesis that adaptation to poor nutrition is likely to trade off with the evolution of improved learning ability.

Interregional compensatory mechanisms of motor functioning in progressing preclinical neurodegeneration.

Understanding brain reserve in preclinical stages of neurodegenerative disorders allows determination of which brain regions contribute to normal functioning despite accelerated neuronal loss. Besides the recruitment of additional regions, a reorganisation and shift of relevance between normally engaged regions are a suggested key mechanism. Thus, network analysis methods seem critical for investigation of changes in directed causal interactions between such candidate brain regions. To identify core compensatory regions, fifteen preclinical patients carrying the genetic mutation leading to Huntington's disease and twelve controls underwent fMRI scanning. They accomplished an auditory paced finger sequence tapping task, which challenged cognitive as well as executive aspects of motor functioning by varying speed and complexity of movements. To investigate causal interactions among brain regions a single Dynamic Causal Model (DCM) was constructed and fitted to the data from each subject. The DCM parameters were analysed using statistical methods to assess group differences in connectivity, and the relationship between connectivity patterns and predicted years to clinical onset was assessed in gene carriers. In preclinical patients, we found indications for neural reserve mechanisms predominantly driven by bilateral dorsal premotor cortex, which increasingly activated superior parietal cortices the closer individuals were to estimated clinical onset. This compensatory mechanism was restricted to complex movements characterised by high cognitive demand. Additionally, we identified task-induced connectivity changes in both groups of subjects towards pre- and caudal supplementary motor areas, which were linked to either faster or more complex task conditions. Interestingly, coupling of dorsal premotor cortex and supplementary motor area was more negative in controls compared to gene mutation carriers. Furthermore, changes in the connectivity pattern of gene carriers allowed prediction of the years to estimated disease onset in individuals. Our study characterises the connectivity pattern of core cortical regions maintaining motor function in relation to varying task demand. We identified connections of bilateral dorsal premotor cortex as critical for compensation as well as task-dependent recruitment of pre- and caudal supplementary motor area. The latter finding nicely mirrors a previously published general linear model-based analysis of the same data. Such knowledge about disease specific inter-regional effective connectivity may help identify foci for interventions based on transcranial magnetic stimulation designed to stimulate functioning and also to predict their impact on other regions in motor-associated networks.

Physiological traits affecting the distribution and wintering strategy of the bat Tadarida teniotis

The ability to enter torpor at low ambient temperature, which enables insectivorous bats to survive seasonal food shortage, is often seen as a prerequisite for colonizing cold environments. Free-tailed bats (Molossidae) show a distribution with a maximum latitudinal extension that appears to be intermediate between truly tropical and temperate-zone bat families. We therefore tested the hypothesis that Tadarida teniotis, the molossid species reaching the highest latitude worldwide (46 degrees N), lacks the extreme physiological adaptations to cold that enable other sympatric bats to enter further into the temperate zone. We studied the metabolism of individuals subjected to various ambient temperatures in the laboratory by respirometry, and we monitored the body temperature of free-ranging individuals in winter and early spring in the Swiss Alps using temperature-sensitive radio-tags. For comparison, metabolic data were obtained from Nyctalus noctula, a typically hibernating vespertilionid bat of similar body size and convergent foraging tactics. The metabolic data support the hypothesis that T. teniotis cannot experience such low ambient temperatures as sympatric temperate-zone vespertilionid bats without incurring much higher energetic costs for thermogenesis. The minimum rate of metabolism in torpor was obtained at 7.5 degrees-10 degrees C in T. teniotis, as compared to 2.5 degrees-5 degrees C in N. noctula. Field data showed that T. teniotis behaves as a classic thermo-conforming hibernator in the Alps, with torpor bouts lasting up to 8 d. This contradicts the widely accepted opinion that Molossidae are nonhibernating bars. However, average body temperature (10 degrees-13 degrees C) and mean arousal frequency (3.4 d in one bat in January) appear to be markedly higher than in other temperate-zone bat species. At the northern border of its range T. teniotis selects relatively warm roosts (crevices in tall, south-exposed limestone cliffs) in winter where temperatures oscillate around 10 degrees C. By this means, T. teniotis apparently avoids the risk of prolonged exposure to energetically critical ambient temperatures in torpor (<6.5 degrees-7.5 degrees C) during cold spells. Possibly shared by other Molossidae, the physiological pattern observed in T. teniotis may clearly be linked to the intermediate latitudinal extension of this bat family.

The ability model of emotional intelligence: Searching for valid measures

Current measures of ability emotional intelligence (EI)--including the well-known Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT)--suffer from several limitations, including low discriminant validity and questionable construct and incremental validity. We show that the MSCEIT is largely predicted by personality dimensions, general intelligence, and demographics having multiple R's with the MSCEIT branches up to .66; for the general EI factor this relation was even stronger (Multiple R = .76). As concerns the factor structure of the MSCEIT, we found support for four first-order factors, which had differential relations with personality, but no support for a higher-order global EI factor. We discuss implications for employing the MSCEIT, including (a) using the single branches scores rather than the total score, (b) always controlling for personality and general intelligence to ensure unbiased parameter estimates in the EI factors, and (c) correcting for measurement error. Failure to account for these methodological aspects may severely compromise predictive validity testing. We also discuss avenues for the improvement of ability-based tests.

Natural variation in learning ability in "Drosophila melanogaster"

Learning is the ability of an organism to adapt to the changes of its environment in response to its past experience. It is a widespread ability in the animal kingdom, but its evolutionary aspects are poorly known. Learning ability is supposedly advantageous under some conditions, when environmental conditions are not too stable - because in this case there is no need to learn to predict any event in the environment - and not changing too fast - otherwise environmental cues cannot be used because they are not reliable. Nevertheless, learning ability is also known to be costly in terms of energy needed for neuronal synthesis, memory formation, initial mistakes. During my PhD, I focused on the study of genetic variability of learning ability in natural populations. Genetic variability is the basis on which natural selection and genetic drift can act. How does learning ability vary in nature? What are the roles of additive genetic variation or maternal effects in this variation? Is it involved in evolutionary trade-offs with other fitness-related traits?¦I investigated a natural population of fruit fly, Drosophila melanogaster, as a model organism. Its learning ability is easy to measure with associative memory tests. I used two research tools: multiple inbred and isofemale lines derived from a natural population as a representative sample. My work was divided into three parts.¦First, I investigated the effects of inbreeding on aversive learning (avoidance of an odor previously associated with mechanical shock). While the inbred lines consistently showed reduced egg-to-adult viability by 28 %, the effects of inbreeding on learning performance was 18 % and varied among assays, with a trend to be most pronounced for intermediate conditioning intensity. Variation among inbred lines indicates that ample genetic variance for learning was segregating in the base population, and suggests that the inbreeding depression observed in learning performance was mostly due to dominance rather than overdominance. Across the inbred lines, learning performance was positively correlated with the egg-to-adult viability. This positive genetic correlation contradicts previous studies which observed a trade-off between learning ability and lifespan or larval competitive ability. It suggests that much of the genetic variation for learning is due to pleiotropic effects of genes affecting other functions related to survival. Together with the overall mild effects of inbreeding on learning performance, this suggests that genetic variation specifically affecting learning is either very low, or is due to alleles with mostly additive (semi-dominant) effects. It also suggests that alleles reducing learning performance are on average partially recessive, because their effect does not appear in the outbred base population. Moreover, overdominance seems unlikely as major cause of the inbreeding depression, because even if the overall mean of the inbred line is smaller than the outbred base population, some of the inbred lines show the same learning score as the outbred base population. If overdominance played an important part in inbreeding depression, then all the homozygous lines should show lower learning ability than¦outbred base population.¦In the second part of my project, I sampled the same natural population again and derived isofemale lines (F=0.25) which are less adapted to laboratory conditions and therefore are more representative of the variance of the natural population. They also showed some genetic variability for learning, and for three other fitness-related traits possibly related with learning: resistance to bacterial infection, egg-to-adult viability and developmental time. Nevertheless, the genetic variance of learning ability did not appear to be smaller than the variance of the other traits. The positive correlation previously observed between learning ability and egg- to-adult viability did not appear in isofemale lines (nor a negative correlation). It suggests that there was still genetic variability within isofemale lines and that they did not fix the highly deleterious pleiotropic alleles possibly responsible for the previous correlation.¦In order to investigate the relative amount of nuclear (additive and non-additive effects) and extra-nuclear (maternal and paternal effect) components of variance in learning ability and other fitness-related traits among the inbred lines tested in part one, I performed a diallel cross between them. The nuclear additive genetic variance was higher than other components for learning ability and survival to learning ability, but in contrast, maternal effects were more variable than other effects for developmental traits. This suggests that maternal effects, which reflects effects from mitochondrial DNA, epigenetic effects, or the amount of nutrients that are invested by the mother in the egg, are more important in the early stage of life, and less at the adult stage. There was no additive genetic correlation between learning ability and other traits, indicating that the correlation between learning ability and egg-to-adult viability observed in the first pat of my project was mostly due to recessive genes.¦Finally, my results showed that learning ability is genetically variable. The diallel experiment showed additive genetic variance was the most important component of the total variance. Moreover, every inbred or isofemale line showed some learning ability. This suggested that alleles impairing learning ability are eliminated by selection, and therefore that learning ability is under strong selection in natural populations of Drosophila. My results cannot alone explain the maintenance of the observed genetic variation. Even if I cannot eliminate the hypothesis of pleiotropy between learning ability and the other fitness-related traits I measured, there is no evidence for any trade-off between these traits and learning ability. This contradicts what has been observed between learning ability and other traits like lifespan and larval competitivity.¦L'apprentissage représente la capacité d'un organisme à s'adapter aux changement de son environnement au cours de sa vie, en réponse à son expérience passée. C'est une capacité très répandue dans le règne animal, y compris pour les animaux les plus petits et les plus simples, mais les aspects évolutifs de l'apprentissage sont encore mal connus. L'apprentissage est supposé avantageux dans certaines conditions, quand l'environnement n'est ni trop stable - dans ce cas, il n'y a rien à apprendre - ni trop variable - dans ce cas, les indices sur lesquels se reposer changent trop vite pour apprendre. D'un autre côté, l'apprentissage a aussi des coûts, en terme de synthèse neuronale, pour la formation de la mémoire, ou de coûts d'erreur initiale d'apprentissage. Pendant ma thèse, j'ai étudié la variabilité génétique naturelle des capacités d'apprentissage. Comment varient les capacités d'apprentissage dans la nature ? Quelle est la part de variation additive, l'impact des effets maternel ? Est-ce que l'apprentissage est impliqué dans des interactions, de type compromis évolutifs, avec d'autres traits liés à la fitness ?¦Afin de répondre à ces questions, je me suis intéressée à la mouche du vinaigre, ou drosophile, un organisme modèle. Ses capacités d'apprentissage sont facile à étudier avec un test de mémoire reposant sur l'association entre un choc mécanique et une odeur. Pour étudier ses capacités naturelles, j'ai dérivé de types de lignées d'une population naturelle: des lignées consanguines et des lignées isofemelles.¦Dans une première partie, je me suis intéressée aux effets de la consanguinité sur les capacités d'apprentissage, qui sont peu connues. Alors que les lignées consanguines ont montré une réduction de 28% de leur viabilité (proportion d'adultes émergeants d'un nombre d'oeufs donnés), leurs capacités d'apprentissage n'ont été réduites que de 18%, la plus forte diminution étant obtenue pour un conditionnement modéré. En outre, j'ai également observé que les capacités d'apprentissage était positivement corrélée à la viabilité entre les lignées. Cette corrélation est surprenante car elle est en contradiction avec les résultats obtenus par d'autres études, qui montrent l'existence de compromis évolutifs entre les capacités d'apprentissage et d'autres traits comme le vieillissement ou la compétitivité larvaire. Elle suggère que la variation génétique des capacités d'apprentissage est due aux effets pleiotropes de gènes récessifs affectant d'autres fonctions liées à la survie. Ces résultats indiquent que la variation pour les capacités d'apprentissage est réduite comparée à celle d'autres traits ou est due à des allèles principalement récessifs. L'hypothèse de superdominance semble peu vraisemblable, car certaines des lignées consanguines ont obtenu des scores d'apprentissage égaux à ceux de la population non consanguine, alors qu'en cas de superdominance, elles auraient toutes dû obtenir des scores inférieurs.¦Dans la deuxième partie de mon projet, j'ai mesuré les capacités d'apprentissage de lignées isofemelles issues de la même population initiale que les lignées consanguines. Ces lignées sont issues chacune d'un seul couple, ce qui leur donne un taux d'hétérozygosité supérieur et évite l'élimination de lignées par fixation d'allèles délétères rares. Elles sont ainsi plus représentatives de la variabilité naturelle. Leur variabilité génétique est significative pour les capacités d'apprentissage, et trois traits liés à la fois à la fitness et à l'apprentissage: la viabilité, la résistance à l'infection bactérienne et la vitesse de développement. Cependant, la variabilité des capacités d'apprentissage n'apparaît cette fois pas inférieure à celle des autres traits et aucune corrélation n'est constatée entre les capacité d'apprentissage et les autres traits. Ceci suggère que la corrélation observée auparavant était surtout due à la fixation d'allèles récessifs délétères également responsables de la dépression de consanguinité.¦Durant la troisième partie de mon projet, je me suis penchée sur la décomposition de la variance observée entre les lignées consanguines observée en partie 1. Quatre composants ont été examinés: la variance due à des effets nucléaires (additifs et non additifs), et due à des effets parentaux (maternels et paternels). J'ai réalisé un croisement diallèle de toutes les lignées. La variance additive nucléaire s'est révélée supérieure aux autres composants pour les capacités d'apprentissage et la résistance à l'infection bactérienne. Par contre, les effets maternels étaient plus importants que les autres composants pour les traits développementaux (viabilité et vitesse de développement). Ceci suggère que les effets maternels, dus à G ADN mitochondrial, à l'épistasie ou à la quantité de nutriments investis dans l'oeuf par la mère, sont plus importants dans les premiers stades de développement et que leur effet s'estompe à l'âge adulte. Il n'y a en revanche pas de corrélation statistiquement significative entre les effets additifs des capacités d'apprentissage et des autres traits, ce qui indique encore une fois que la corrélation observée entre les capacités d'apprentissage et la viabilité dans la première partie du projet était due à des effets d'allèles partiellement récessifs.¦Au, final, mes résultats montrent bien l'existence d'une variabilité génétique pour les capacités d'apprentissage, et l'expérience du diallèle montre que la variance additive de cette capacité est importante, ce qui permet une réponse à la sélection naturelle. Toutes les lignées, consanguines ou isofemelles, ont obtenu des scores d'apprentissage supérieurs à zéro. Ceci suggère que les allèles supprimant les capacités d'apprentissage sont fortement contre-sélectionnés dans la nature Néanmoins, mes résultats ne peuvent pas expliquer le maintien de cette variabilité génétique par eux-même. Même si l'hypothèse de pléiotropie entre les capacités d'apprentissage et l'un des traits liés à la fitness que j'ai mesuré ne peut être éliminée, il n'y a aucune preuve d'un compromis évolutif pouvant contribuer au maintien de la variabilité.

Accidentologic aspects of helicopter rescue missions involving winching of a physician

Introduction: Medical helicopter services provide several advantages,like the ability to perform air searches for lost victims, a rapid method ofshuttling rescue personnel and equipment to the victim, and the deliveryof early on-site advance medical care. When landing is not possible, therescuers can also be directly winched to the victim. As outdoor activitiesare increasing, few data are available about the type of accidentsleading to a rescue operation involving the use of the winch. We soughtto study the epidemiology and accidentology of such rescues.Methods: We retrospectively reviewed the medical reports of a singlehelicopter-based emergency medical service. Data from 1 January 2003to 31 December 2008 were analyzed. Cases with emergency callindicating that the victim was deceased were excluded. Data includedthe age and gender of the patients, the type of patients activitypreceeding the injury, the mecanism of injury, and the type of lesions(main diagnosis).Results: 9879 rescue missions were conducted between 1 January2003 and 31 December 2008. The 921 (9.3%) missions involvingwinching of the emergency physician were analysed. The male:femaleratio of the patients was 2:1. There were 56 (6%) patients aged 15 orunder. Most of the patients, while injured, were practising winter sportsor mountain-related activities in the summer (table 1). Falls accountedfor the great majority of the trauma events (700 patients or 76%),followed by illnesses (81 patients or 9 %). Of the 921 missions in whichthe physician was winched in the field, 28 (3%) were avalanche rescuesand 13 (1%) were glacier crevasse rescues. Trauma to the upper andlower extremities accounted for 429 (47%) of all injuries, followed by175 (19%) head injuries and 108 (12%) spinal lesions. Hypothermia,frostbite and altitude illnesses were diagnosed in 11 (1%) cases.In 128(14%) cases two different diagnoses were made, and in 69 (7%) threeor more diagnoses.Conclusions: In our helicopter emergency base, between 2003 and2008, 921 rescue missions (9.3%) involved winching of the emergencydoctor. Patients rescued using the winch usually practice outdoorsports, and are predominantly male. The mechanism of the injury isusually a fall, and extremities and head injuries account for more than50% of the main diagnosis made on the field.

Chronic low-frequency rTMS of primary motor cortex diminishes exercise training-induced gains in maximal voluntary force in humans.

Although there is consensus that the central nervous system mediates the increases in maximal voluntary force (maximal voluntary contraction, MVC) produced by resistance exercise, the involvement of the primary motor cortex (M1) in these processes remains controversial. We hypothesized that 1-Hz repetitive transcranial magnetic stimulation (rTMS) of M1 during resistance training would diminish strength gains. Forty subjects were divided equally into five groups. Subjects voluntarily (Vol) abducted the first dorsal interosseus (FDI) (5 bouts x 10 repetitions, 10 sessions, 4 wk) at 70-80% MVC. Another group also exercised but in the 1-min-long interbout rest intervals they received rTMS [Vol+rTMS, 1 Hz, FDI motor area, 300 pulses/session, 120% of the resting motor threshold (rMT)]. The third group also exercised and received sham rTMS (Vol+Sham). The fourth group received only rTMS (rTMS_only). The 37.5% and 33.3% gains in MVC in Vol and Vol+Sham groups, respectively, were greater (P = 0.001) than the 18.9% gain in Vol+rTMS, 1.9% in rTMS_only, and 2.6% in unexercised control subjects who received no stimulation. Acutely, within sessions 5 and 10, single-pulse TMS revealed that motor-evoked potential size and recruitment curve slopes were reduced in Vol+rTMS and rTMS_only groups and accumulated to chronic reductions by session 10. There were no changes in rMT, maximum compound action potential amplitude (M(max)), and peripherally evoked twitch forces in the trained FDI and the untrained abductor digiti minimi. Although contributions from spinal sources cannot be excluded, the data suggest that M1 may play a role in mediating neural adaptations to strength training.

Dissociation between components of spatial memory in rats after recovery from the effects of retrohippocampal lesions

A series of 4 experiments examined the performance of rats with retrohippocampal lesions on a spatial water-maze task. The animals were trained to find and escape onto a hidden platform after swimming in a large pool of opaque water. The platform was invisible and could not be located using olfactory cues. Successful escape performance required the rats to develop strategies of approaching the correct location with reference solely to distal extramaze cues. The lesions encompassed the entire rostro-caudal extent of the lateral and medial entorhinal cortex, and included parts of the pre- and para-subiculum, angular bundle and subiculum. Groups ECR 1 and 2 sustained only partial damage of the subiculum, while Group ECR+S sustained extensive damage. These groups were compared with sham-lesion and unoperated control groups. In Expt 1A, a profound deficit in spatial localisation was found in groups ECR 1 and ECR+S, the rats receiving all training postoperatively. In Expt 1B, these two groups showed hyperactivity in an open-field. In Expt 2, extensive preoperative training caused a transitory saving in performance of the spatial task by group ECR 2, but comparisons with the groups of Expt 1A revealed no sustained improvement, except on one measure of performance in a post-training transfer test. All rats were then given (Expt 3) training on a cueing procedure using a visible platform. The spatial deficit disappeared but, on returning to the normal hidden platform procedure, it reappeared. Nevertheless, a final transfer test, during which the platform was removed from the apparatus, revealed a dissociation between two independent measures of performance: the rats with ECR lesions failed to search for the hidden platform but repeatedly crossed its correct location accurately during traverses of the entire pool. This partial recovery of performance was not (Expt 4) associated with any ability to discriminate between two locations in the pool. The apparently selective recovery of aspects of spatial memory is discussed in relation to O'Keefe and Nadel's (1978) spatial mapping theory of hippocampal function. We propose a modification of the theory in terms of a dissociation between procedural and declarative subcomponents of spatial memory. The declarative component is a flexible access system in which information is stored in a form independent of action. It is permanently lost after the lesion. The procedural component is "unmasked" by the retrohippocampal lesion giving rise to the partial recovery of spatial localisation performance.

Weed or wheel! FMRI, behavioural, and toxicological investigations of how cannabis smoking affects skills necessary for driving.

Marijuana is the most widely used illicit drug, however its effects on cognitive functions underling safe driving remain mostly unexplored. Our goal was to evaluate the impact of cannabis on the driving ability of occasional smokers, by investigating changes in the brain network involved in a tracking task. The subject characteristics, the percentage of Δ(9)-Tetrahydrocannabinol in the joint, and the inhaled dose were in accordance with real-life conditions. Thirty-one male volunteers were enrolled in this study that includes clinical and toxicological aspects together with functional magnetic resonance imaging of the brain and measurements of psychomotor skills. The fMRI paradigm was based on a visuo-motor tracking task, alternating active tracking blocks with passive tracking viewing and rest condition. We show that cannabis smoking, even at low Δ(9)-Tetrahydrocannabinol blood concentrations, decreases psychomotor skills and alters the activity of the brain networks involved in cognition. The relative decrease of Blood Oxygen Level Dependent response (BOLD) after cannabis smoking in the anterior insula, dorsomedial thalamus, and striatum compared to placebo smoking suggests an alteration of the network involved in saliency detection. In addition, the decrease of BOLD response in the right superior parietal cortex and in the dorsolateral prefrontal cortex indicates the involvement of the Control Executive network known to operate once the saliencies are identified. Furthermore, cannabis increases activity in the rostral anterior cingulate cortex and ventromedial prefrontal cortices, suggesting an increase in self-oriented mental activity. Subjects are more attracted by intrapersonal stimuli ("self") and fail to attend to task performance, leading to an insufficient allocation of task-oriented resources and to sub-optimal performance. These effects correlate with the subjective feeling of confusion rather than with the blood level of Δ(9)-Tetrahydrocannabinol. These findings bolster the zero-tolerance policy adopted in several countries that prohibits the presence of any amount of drugs in blood while driving.

The neural basis for writing from dictation in the temporoparietal cortex.

Cortical electrical stimulation mapping was used to study neural substrates of the function of writing in the temporoparietal cortex. We identified the sites involved in oral language (sentence reading and naming) and writing from dictation, in order to spare these areas during removal of brain tumours in 30 patients (23 in the left, and 7 in the right hemisphere). Electrostimulation of the cortex impaired writing ability in 62 restricted cortical areas (.25 cm2). These were found in left temporoparietal lobes and were mostly located along the superior temporal gyrus (Brodmann's areas 22 and 42). Stimulation of right temporoparietal lobes in right-handed patients produced no writing impairments. However there was a high variability of location between individuals. Stimulation resulted in combined symptoms (affecting oral language and writing) in fourteen patients, whereas in eight other patients, stimulation-induced pure agraphia symptoms with no oral language disturbance in twelve of the identified areas. Each detected area affected writing in a different way. We detected the various different stages of the auditory-to-motor pathway of writing from dictation: either through comprehension of the dictated sentences (word deafness areas), lexico-semantic retrieval, or phonologic processing. In group analysis, barycentres of all different types of writing interferences reveal a hierarchical functional organization along the superior temporal gyrus from initial word recognition to lexico-semantic and phonologic processes along the ventral and the dorsal comprehension pathways, supporting the previously described auditory-to-motor process. The left posterior Sylvian region supports different aspects of writing function that are extremely specialized and localized, sometimes being segregated in a way that could account for the occurrence of pure agraphia that has long-been described in cases of damage to this region.

Low-frequency transcranial magnetic stimulation over left dorsal premotor cortex improves the dynamic control of visuospatially cued actions.

Left rostral dorsal premotor cortex (rPMd) and supramarginal gyrus (SMG) have been implicated in the dynamic control of actions. In 12 right-handed healthy individuals, we applied 30 min of low-frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) over left rPMd to investigate the involvement of left rPMd and SMG in the rapid adjustment of actions guided by visuospatial cues. After rTMS, subjects underwent functional magnetic resonance imaging while making spatially congruent button presses with the right or left index finger in response to a left- or right-sided target. Subjects were asked to covertly prepare motor responses as indicated by a directional cue presented 1 s before the target. On 20% of trials, the cue was invalid, requiring subjects to readjust their motor plan according to the target location. Compared with sham rTMS, real rTMS increased the number of correct responses in invalidly cued trials. After real rTMS, task-related activity of the stimulated left rPMd showed increased task-related coupling with activity in ipsilateral SMG and the adjacent anterior intraparietal area (AIP). Individuals who showed a stronger increase in left-hemispheric premotor-parietal connectivity also made fewer errors on invalidly cued trials after rTMS. The results suggest that rTMS over left rPMd improved the ability to dynamically adjust visuospatial response mapping by strengthening left-hemispheric connectivity between rPMd and the SMG-AIP region. These results support the notion that left rPMd and SMG-AIP contribute toward dynamic control of actions and demonstrate that low-frequency rTMS can enhance functional coupling between task-relevant brain regions and improve some aspects of motor performance.

Genome-wide transcriptional responses to shade: Linking shade avoidance and auxin

Plants have the ability to use the composition of incident light as a cue to adapt development and growth to their environment. Arabidopsis thaliana as well as many crops are best adapted to sunny habitats. When subjected to shade, these plants exhibit a variety of physiological responses collectively called shade avoidance syndrome (SAS). It includes increased growth of hypocotyl and petioles, decreased growth rate of cotyledons and reduced branching and crop yield. These responses are mainly mediated by phytochrome photoreceptors, which exist either in an active, far-red light (FR) absorbing or an inactive, red light (R) absorbing isoform. In direct sunlight, the R to FR light (R/FR) ratio is high and converts the phytochromes into their physiologically active state. The phytochromes interact with downstream transcription factors such as PHYTOCHROME INTERACTING FACTOR (PIF), which are subsequently degraded. Light filtered through a canopy is strongly depleted in R, which result in a low R/FR ratio and renders the phytochromes inactive. Protein levels of downstream transcription factors are stabilized, which initiates the expression of shade-induced genes such as HFR1, PIL1 or ATHB-2. In my thesis, I investigated transcriptional responses mediated by the SAS in whole Arabidopsis seedlings. Using microarray and chromatin immunoprecipitation data, we identified genome-wide PIF4 and PIF5 dependent shade regulated gene as well as putative direct target genes of PIF5. This revealed evidence for a direct regulatory link between phytochrome signaling and the growth promoting phytohormone auxin (IAA) at the level of biosynthesis, transport and signaling. Subsequently, it was shown, that free-IAA levels are upregulated in response to shade. It is assumed that shade-induced auxin production takes predominantly place in cotyledons of seedlings. This implies, that IAA is subsequently transported basipetally to the hypocotyl and enhances elongation growth. The importance of auxin transport for growth responses has been established by chemical and genetic approaches. To gain a better understanding of spatio-temporal transcriptional regulation of shade-induce auxin, I generated in a second project, an organ specific high throughput data focusing on cotyledon and hypocotyl of young Arabidopsis seedlings. Interestingly, both organs show an opposite growth regulation by shade. I first investigated the spatio-transcriptional regulation of auxin re- sponsive gene, in order to determine how broad gene expression pattern can be explained by the hypothesized movement of auxin from cotyledons to hypocotyls in shade. The analysis suggests, that several genes are indeed regulated according to our prediction and others are regulated in a more complex manner. In addition, analysis of gene families of auxin biosynthetic and transport components, lead to the identification of essential family members for shade-induced growth re- sponses, which were subsequently experimentally confirmed. Finally, the analysis of expression pattern identified several candidate genes, which possibly explain aspects of the opposite growth response of the different organs.

Aspects opératoires et péri-opératoires de la stimulation cérébrale profonde [Operative and perioperative aspects of deep brain stimulation].

La stimulation cérébrale profonde (SCP) nécessite l'implantation chirurgicale d'un système comprenant électrodes cérébrales et boîtier(s) de stimulation. Les noyaux cérébraux visés par la méthodologie stéréotaxique d'implantation doivent être visualisés au mieux par une imagerie à haute résolution. La procédure chirurgicale d'implantation des électrodes se fait si possible en anesthésie locale pour faire des mesures électro-physiologiques et tester en peropératoire l'effet de la stimulation, afin d'optimiser la position de l'électrode définitive. Dans un deuxième temps, le ou les générateur(s) d'impulsions sont implantés en anesthésie générale. La SCP pour les mouvements anormaux a une très bonne efficacité et un risque de complications graves faible quoique non nul. Les complications liées au matériel sont les plus fréquentes. Deep brain stimulation (DBS) requires the surgical implantation of a system including brain electrodes and impulsion generator(s). The nuclei targeted by the stereotaxic implantation methodology have to be visualized at best by high resolution imaging. The surgical procedure for implanting the electrodes is performed if possible under local anaesthesia to make electro-physiological measurements and to test intra-operatively the effect of the stimulation, in order to optimize the position of the definitive electrode. In a second step, the impulsion generator(s) are implanted under general anaesthesia. DBS for movement disorders has a very good efficacy and a low albeit non-zero risk of serious complications. Complications related to the material are the most common.