De nombreux comportements assurant la survie des insectes dépendent de l’olfaction. Comprendre comment les polluants peuvent modifier cette modalité sensorielle chez des espèces cibles (ravageurs…) et non-cibles (pollinisateurs…) et quels sont les moyens de réponse dont dispose le système olfactif est donc crucial. J’ai étudié l’impact du cadmium à doses sublétales sur l’olfaction du lépidoptère ravageur modèle Spodoptera littoralis. Sa distribution dans l’organisme, dont les antennes, a été établie puis son impact sur les capacités olfactives des chenilles et des adultes a été analysé par analyse comportementale et électrophysiologique. J’ai montré une diminution de la détection phéromonale chez les adultes mâles et du comportement attractif des chenilles vers une source de nourriture.J’ai caractérisé diverses enzymes de détoxification et protéines de choc thermique antennaires comme biomarqueurs potentiels aux polluants et révélé ainsi une diversité insoupçonnée de ces protéines dans l’antenne. Ces acteurs pourraient être impliqués dans le maintien du fonctionnement du système olfactif en participant à la clearance des xénobiotiques. Parallèlement, j’ai participé à l’étude des effets de la deltaméthrine sur l’olfaction et montré que l’application topique antennaire de doses sublétales de cet insecticide a un impact sur le système olfactif des mâles, et ce du gène au comportement.L’ensemble de nos données montrent que l’organe olfactif bien que très spécialisé, est un organe capable de développer une réponse complexe lors d’un stress xénobiotique. / Many behaviors ensuring the survival of insects depend on olfaction. Understanding how pollutants may alter this sensory modality in target (pests…) and non-targets (pollinators…) species and how the olfactory system could respond to this stress is therefore crucial. I have first studied the impact of sublethal doses of cadmium on olfaction in Spodoptera littoralis, a pest moth model. Cadmium distribution through the insect body, including antennae, has been established and its effect on the olfactory abilities of caterpillars and adults was analyzed by behavioral and electrophysiological approaches. I have showed both a decrease in pheromone detection in adult males and in the attractive behavior of caterpillars to a food source. Moreover, I have characterized various detoxification enzymes and heat shock proteins as potential antennal biomarkers for pollutant exposure and thus revealed an unsuspected diversity of these proteins in the antenna. These actors could be involved in maintaining the functioning of the olfactory system by participating in the clearance of xenobiotics. Meanwhile, I have participated in a study on the effects of deltamethrin on olfaction and showed that topical application of sublethal doses of this insecticide on antenna has an impact on the olfactory system of males, an approach from the gene to the behavior. All our data showed that although highly specialized, the olfactory organ is able to develop a complex response when challenged by a xenobiotic stress.

Le système nerveux central est isolé de l’environnement grâce à un ensemble de barrières, incluant la barrière osseuse et la barrière hémato-encéphalique. Il existe cependant des zones où ces barrières sont absentes ou affaiblies, et c’est notamment le cas au niveau des nerfs olfactifs qui ont pour origine les neurones présents dans la cavité nasale. Ces neurones participent à la détection des odeurs et leurs axones contactent directement le système nerveux central au niveau des bulbes olfactifs en traversant la lame criblée de l’éthmoïde. Cette « voie olfactive » représente ainsi un site d’entrée privilégié de certains pathogènes vers le cerveau. La muqueuse olfactive, du fait de son positionnement à l’interface entre l’environnement et le système nerveux central, constitue donc une zone particulièrement sensible sur le plan immunologique. Si cette muqueuse est connue pour produire des composants antimicrobiens, les mécanismes cellulaires et moléculaires mobilisés dans le cadre d’infections par des pathogènes respiratoires restent peu décrits.Au cours de ma thèse, nous nous sommes tout d’abord focalisés sur l’interleukine 17c, connue comme puissant médiateur des réponses immunitaires innées épithéliales respiratoires et dont les récepteurs sont exprimés dans la muqueuse olfactive. Nous avons notamment pu montrer qu’elle était mobilisée in vivo dans un contexte mimant une infection virale et qu’elle favorisait le renouvellement épithélial ainsi que l’infiltration de cellules immunitaires. En voulant caractériser son action dans un contexte viral, nous avons été amenés à étudier les effets de deux virus respiratoires sur la muqueuse olfactive (le virus influenza et le virus respiratoire syncytial). Nous avons observé que les deux virus pouvaient infecter efficacement les neurones sensoriels olfactifs, mais avec une charge virale plus élevée pour influenza. A dose équivalente, le virus de la grippe provoque d'importants dégâts dans la muqueuse olfactive mais ne s’établit pas durablement dans la muqueuse, ce qui suggère que ce virus est éliminé très efficacement et rapidement. En nous focalisant sur les processus d'élimination des neurones sensoriels olfactifs infectés, nous avons identifié un nouveau mécanisme antiviral précoce basé sur l'élastase, une enzyme précédemment décrite comme sécrétée par les neutrophiles, principaux acteurs du système immunitaire inné.Dans l’ensemble, ces travaux de thèse mettent en lumière les défenses immunitaires présentes dans la cavité nasale contre les virus respiratoires et apportent de nouvelles perspectives dans le contrôle des virus infectant le système nerveux central par la voie olfactive. / The central nervous system is sheltered from the environment thanks to cranial bones and the blood brain barrier. Some parts of these barriers are weaker, especially around olfactory nerves originating from olfactory sensory neurons in the nasal cavity. These neurons detect odorants and their axons cross the cribriform plate to project directly into the brain at the level of the olfactory bulbs. The cribriform plate is a thin and perforated area of the cranial bones allowing the crossing of the olfactory nerves. This “olfactory pathway” constitutes a privileged entry site for viruses toward the central nervous system. Hence, the olfactory mucosa represents a particularly sensitive area for the immune system. While the olfactory mucosa is known to produce various anti-microbial compounds, the described molecular and cellular mechanism of immune system defenses against viruses remains sparse.The interleukin 17c (IL-17c) is known as an innate immunity response actor in the respiratory epithelium. While its receptors are expressed in the olfactory mucosa, its role in this tissue was unknown. We found that IL-17c is involved in olfactory mucosa responses to Poly(I:C) mimicking virus presence. We observed that nasal instillation of IL-17c accelerated the olfactory mucosa turn-over and induced its infiltration by immune cells. In attempt to characterize the role of IL-17c in a real viral context, we started to focus on the impact of two viruses of the respiratory tract: influenza and the respiratory syncytial virus. We observed that both viruses could effectively infect olfactory sensory neurons but with a higher virus load for influenza. Indeed, at similar doses, influenza induced important damages in the olfactory mucosa but was not present, indicating that influenza virus is very effectively and rapidly eliminated from the olfactory mucosa. By focusing on the elimination processes of infected olfactory sensory neurons, we identified a novel early anti-viral mechanism based on elastase, an enzyme previously described as secreted by neutrophils, main actors of the innate immunity system.Overall, my PhD results provide new insights on the immune defenses present in the olfactory mucosa against respiratory viruses and could bring new perspectives in the control of virus infecting the central nervous system.

Chez les mammifères, le système olfactif principal est fonctionnel dans le dernier tiers du stade gestationnel. Le fœtus est donc capable de détecter avec sensibilité, discriminer, et mémoriser les odorants présents dans le liquide amniotique dans lequel il baigne. Chez le rongeur, ces odorants mémorisés in utero sont fondamentaux pour la survie du nouveau-né à la naissance en lui permettant de s’orienter vers la mamelle et de déclencher la tétée. Par la suite, ces odorants vont guider le nouveau-né dans ses choix olfactifs et alimentaires et favoriser ses apprentissages ultérieurs. Or, on sait que l’alimentation de la mère fait varier les clés olfactives des fluides biologiques (liquide amniotique, lait) et donc modifie la nature des sources olfactives rencontrées par le fœtus, puis le nouveau-né dans la période périnatale. Dans le but d’évaluer l’impact d’une exposition odorante périnatale sur le fonctionnement et la maturation du système olfactif en relation avec le développement de préférences médiées par l’olfaction et la modulation du stress au moment du sevrage, nous avons mis en place un modèle d’exposition odorante périnatale via l’alimentation maternelle dans une lignée transgénique murine exprimant le récepteur olfactif I7 couplé à une protéine fluorescente, dont l’odorant préférentiel est l’heptanal. Après validation de la présence d’heptanal dans le liquide amniotique et le lait de ces souris par GC-MS-MS, nos résultats montrent que l’exposition périnatale à l’heptanal entraine une augmentation significative du nombre de glomérules I7 présents au niveau du bulbe olfactif à PN12 par rapport aux animaux contrôles sans modification notable de l’homéostasie tissulaire ou de la transcription du gène I7 au niveau de la muqueuse olfactive. Ce changement structural important au niveau des projections axonales du bulbe olfactif s’accompagne d’un faible effet sur le comportement olfactif des souriceaux dont les capacités de discrimination ne sont que très faiblement améliorées par rapport aux souriceaux non exposés. A PN21, l’effet de l’exposition odorante sur le nombre de glomérules I7 est atténué, mais reste significatif. A ce stade, les souriceaux odorisés montrent une attraction olfactive pour l’heptanal par rapport au groupe contrôle non exposé, bien que l’effet sur un choix entre aliment odorisé ou pas soit plus contrasté. D’un point de vue moléculaire, ces effets sont associés à une diminution de l’expression du récepteur I7, et de gènes de la signalisation neuronale pouvant traduire une modification de la dynamique cellulaire. Et comme le montrent les résultats obtenus en électro-olfactogramme à cet âge, la sensibilité de la muqueuse olfactive vis-à-vis de l’heptanal est diminuée alors qu’elle ne l’est pas pour d’autres composés odorants. Ces travaux montrent que l’exposition périnatale à un odorant s’accompagne d’effets précoces sur le système olfactif qui impactent son organisation et d’effets sur les choix olfactifs qui se renforcent au cours du développement. Enfin, l’effet d’une exposition périnatale à l’heptanal sur la réponse à des conditions stressantes après séparation maternelle au moment du sevrage a été évaluée en enregistrant des souriceaux CD1 élevés dans les mêmes conditions d’odorisation que les souriceaux mI7-GFP adoptés, en open-field odorisé ou non. Nous avons montré que la réaction de stress des souriceaux à PN21, exposés en périnatal à l’heptanal, dans l’open field, est atténuée lorsque l’heptanal est présent dans l’environnement, comparé à la réaction des souriceaux non exposés qui affichent un comportement d’anxiété. Dans l’ensemble, cette étude a donc permis de mettre en évidence les conséquences en terme d’effets comportementaux (préférences médiées par l’olfaction et diminution du stress), structuraux et moléculaires, d’une exposition odorante périnatale chez le jeune, à l’aide d’une lignée transgénique pour laquelle nous disposions de peu de données. / In mammals, the main olfactory system displays all the structural and functional characteristics at the last third of the gestational stage. Thus, the fetus is able to detect, to discriminate, but also to memorize the odorants present in the amniotic fluid in which it bathes. In the rodent, these odors memorized in utero are fundamental for the survival of the newborn at birth by allowing it to trend itself towards food sources. Afterwards, odorants are guiding the newborn to olfactory and food choices and are promoting subsequent learning. It is known that the mother's diet varies the olfactory keys of the biological fluids (amniotic fluid, milk) and thus modifies the nature of the olfactory sources encountered by the fetus and then the newborn in the perinatal period. The neuroanatomic and functional consequences of this impregnation are the subject of recent studies. The objective of this thesis was to characterize the effects of perinatal odor exposure on the maturation and functioning of the olfactory system in relation to the development of olfactory preferences and to a stressing challenge at weaning. For that, we set up a model of perinatal odor exposure through maternal feeding in the mI7-GFP murine transgenic strain expressing the olfactory receptor I7 coupled with the Green Fluorescent Protein (GFP). We evaluated the neuroanatomic, molecular and behavioral consequences on the pups before weaning, and their evolution over time by focusing our efforts on the postnatal stages 3 (PND3), PND12-14 and PND21. Due to the fragility of the transgenic strain, we worked on mI7-GFP mice pups crossfostered by CD1 mice mothers raised under the same conditions after having validated the presence of heptanal in the amniotic fluid of mI7-GFP mice and the milk of CD1 mice by GC-MSMS. We characterized the effects of perinatal odor exposure on the maturation and functioning of the olfactory system in relation to the olfactory preference until weaning (mI7-GFP mice pups under CD1 adoptive mothers) and on the stress reaction to maternal separation at weaning (CD1 mice pups under biological mother). Our results show that perinatal exposure to heptanal leads to a significant increase in the number of I7 glomeruli in the olfactory bulb (OB) associated to a slight modification of the tissue homeostasis in the olfactory mucosa (OM) and to subtle differencies in heptanal sensitivity and preferences, that are amplified at PND21. From a molecular point of view, these effects are associated to a down-regulation of the expression of the I7 receptor and genes of neuronal signaling and an odorantspecific decrease in EOG response which may highlight a modification of the cellular dynamics. Finally, the effect of perinatal exposure to heptanal on the response to stressing conditions after maternal separation was assessed by recording CD1 mice pups grown under the same conditions than fostered mi7 mice on odorized and non odorized open-field. We showed that the reaction of odorized mice in the open field at PND21 is attenuated when the odorant is present in the environment, compared to non odorized mice that display anxiety-like behavior. Overall, this study demonstrates the consequences of a perinatal odorant exposure in the young, in terms of behavior (olfactory preference and anxiety), structural and molecular plasticity of the olfactory system, on a transgenic strain for which we had little available data.

Le frelon Vespa velutina, est une espèce invasive introduite en France il y a une dizaine d’années. Cet Hyménoptère social chasse de nombreux insectes, et plus particulièrement des abeilles, exerçant une forte pression de prédation sur l’entomofaune. Son établissement en Europe est donc susceptible d’avoir un impact néfaste sur les activités humaines et sur la biodiversité locale. L’olfaction joue un rôle central dans la biologie du frelon, que ce soit pour la communication intraspécifique (phéromones) ou la recherche de nourriture. Pour limiter l’impact de V. velutina, une stratégie prometteuse serait d’interférer avec son comportement olfactif. Nous avons donc cherché à acquérir une meilleure connaissance du système olfactif des frelons ainsi que des signaux chimiques impliqués dans leur comportement de prédation. Nous avons tout d’abord décrit et comparé l’organisation du système olfactif des différentes castes d’une colonie de frelons. Le premier centre olfactif du cerveau, le lobe antennaire, est constitué d’unités morphologiques et fonctionelles, les glomérules. Nous avons démontré l’existence de glomérules hypertrophiées (macroglomérules), potentiellement spécialisées dans la détection des phéromones sexuelles, chez les mâles. Nous avons également observé des similarités neuroanatomiques frappantes dans l’organisation du lobe antennaire chez des Hyménoptères de familles différentes (fourmis, abeilles, frelons), permettant de reconstruire une partie de l’histoire évolutive de cette structure, au sein de cet ordre. En particulier, nous avons démontré l’homologie d’un groupe de glomérules impliqué dans le traitement des hydrocarbures cuticulaires, signaux de reconnaissance intraspécifique, chez les frelons et les fourmis. Ce système a pu représenter une préadaptation pour l’apparition de comportements sociaux dans ces familles. De plus, nos résultats ont montré que le nombre de glomérules dans ce système varie fortement chez différentes espèces de frelons, probablement en relation avec les différents niveaux de sympatrie dans lesquels vivent ces espèces. Le lobe antennaire des frelons présente ainsi des adaptations concernant aussi bien le nombre de glomérules que leurs volumes respectifs. Enfin, nous avons effectué des essais comportementaux pour déterminer quels composés odorants sont impliqués dans l’attraction de V. velutina envers les ruches d’abeilles domestiques. Nos résultats suggèrent que les ouvrières de frelon sont sélectivement attirées par des odorants indiquant la présence de ruches, dont des phéromones d’abeille. Ces résultats permettent d’envisager le développement de stratégies de piégeage utilisant des appâts olfactifs spécifiques. / The hornet Vespa velutina is an invasive species introduced from China to France about 10 years ago. This social hymenoptera preys on numerous insects species, but predominantly from honeybee colonies, hence exerting a stong predation pressure on insect fauna. Its etablishment to Europe can have strong detrimental effects on human activities and local biodiversity. Olfaction plays a central role in the biology and behavior of hornets, for both intraspecific communication or food search. To limit the impact of V. Velutina, a promising strategy would be to interfere with its olfactory behaviors. We thus aimed to acquire a better knowledge on the olfactory system of hornets and on the chemical signals involved in their predatory behavior. We first described and compared the organization of the olfactory system of the different castes of hornets. The first olfactory processing center, the antennal lobe, consists of morphological and functional units, the glomeruli. We have demonstrated the existence of enlarged glomeruli (macroglomeruli), potentially specialized in the detection of sex pheromones in males. We also observed striking neuroanatomical similarities in the antennal lobe organization of different Hymenoptera families (ants, bees, hornets) allowing to retrace part of the evolutionary history of this structure within that insect order. In particular, we demonstrated the homology of a glomerular cluster involved in the processing of cuticular hydrocarbons (intraspecific recognition signals) among hornets and ants. This systsem could be a preadaptation for the emergence of social behaviors in these families. In addition, our results showed that the number of glomeruli within this system varies across hornet species, probably due to the different sympatry levels these species experience. The hornet antennal lobe presents adaptations both in the number and the volume of glomeruli. Finally, we performed behavioral tests to identify odor compounds involved in the attraction of V. Velutina towards bee hives. Our results suggest that workers are selectively attracted to olfactory cues indicating the presence of hives, including some honeybee pheromones. These results allow considering the development of trapping strategies using specific baits.

La compréhension des mécanismes cérébraux régulant la prise alimentaire est devenue cruciale face à la pandémie mondiale d’obésité. L’ingestion d’aliments est sous le contrôle d’un large réseau de structures cérébrales qui régulent la balance énergétique en régulant l’apport de nourriture et la dépense énergétique. Etant donné l’importance de l’olfaction dans l’appréciation des aliments, il est primordial d’identifier des mécanismes précis liant olfaction et nutrition.Nous avons choisi d’étudier l’activité dans le Bulbe Olfactif principal (BO), la première structure cérébrale qui permet la représentation spatiotemporelle des odeurs. De façon intéressante, des récepteurs aux hormones anorexigènes et orexigènes sont exprimés à la fois dans l’hypothalamus et le BO. Toutefois, l’impact de la leptine (et de l’obésité) sur l’activité du BO in vivo demeure inconnu.Pour évaluer l’action de la leptine et de l’obésité sur la plasticité olfactive, nous avons choisi le modèle murin ob/ob. Nous avons d’abord décrit la répartition spatiale de l’activité dans le BO en réponse à une odeur alimentaire et à une odeur neutre chez ces souris en les comparant à des souris témoins grâce une technique de neuroimagerie fonctionnelle, l’Imagerie par Résonance Magnétique renforcée au Manganèse (MEMRI). Par le développement d’une méthode de comparaison statistique indépendant de l’utilisateur, le SPM (Statistical Parametric Mapping), nous avons mis en évidence une augmentation de l’activité spontanée et de l’activité induite par odeur alimentaire dans le BO des ob/ob. Cependant, l’activité induite par une odeur neutre n’était pas plus élevée. L’injection de leptine a pour résultat d’augmenter le signal MEMRI dans les couches profondes du BO et ne restaure que partiellement l’activité des ob/ob. En quantifiant la neurogenèse dans le BO par injections de BrdU, nous avons mis en évidence une survie accrue des cellules granulaires et périglomerulaires chez les ob/ob.Pour évaluer la dynamique temporelle de l’activité du BO, nous avons enregistré par électrophysiologie les variations de l’activité oscillatoire du potentiel de champ local dans les couches profondes du BO pendant l’apprentissage d’une tâche de discrimination olfactive, le Go/NoGo. L’apparition d’une oscillation lente dite bêta (15-40 Hz) pendant cet apprentissage est un marqueur fonctionnel de l’état du réseau olfactif. Elle est dépendante des retours centrifuges provenant du cortex olfactif, majoritairement du cortex piriforme. Si nous n’avons pas observé de différence importante dans la discrimination olfactive, nous avons en revanche mis en évidence un problème motivationnel chez les animaux ob/ob, qui n’effectuaient la tâche que si la récompense hydrique contenait du sucre. Nos enregistrements montrent une forte augmentation des oscillations bêta chez les souris obèses après apprentissage comparé aux souris témoins. / Olfaction makes possible both the detection and the processing of odors related to food location and palatability. Interestingly, receptors to anorexigen and orexigen hormones and neuropeptides found in the hypothalamus are also expressed in the main olfactory bulb (MOB), suggesting that feeding state has an impact on odor representation. However, neuronal mechanisms linking olfaction, food intake and metabolic disorders are still unclear. In this PhD thesis, we wanted to further understand mechanisms of the olfactory-feeding crosstalk and tested the effects of obesity on olfactory activity in the MOB. Leptin, a peptidergic hormone produced by adipocytes, is a major regulator of the energy balance and inhibits food intake. Ob/ob mice are deficient in leptin from birth and are widely used as a murine model of obesity. We used a functional neuroimaging technique, Manganese Enhanced Magnetic Resonance Imaging (MEMRI), in association with statistical parametric mapping (SPM) to monitor food odor-evoked spatial activity in the MOB of these mice. Using MEMRI, we found that odor-evoked signal is different, both in terms of intensity and localization between lean and ob/ob mice for the spontaneous activity and in response to food odor. However, this is not the case for a neutral odor. Moreover, leptin impacts both spontaneous activity and food odor-evoked signal intensity in both groups. Interestingly leptin strongly activates deep layers (mitral cell layer and mainly granule cell layer) of the MOB. To pinpoint what cellular/molecular mechanisms can be responsible for these changes in the spatial distribution of activity, we analyzed the effects of the lack of leptin on the composition and activity of the MOB cellular network.We quantified bulbar adult neurogenesis and found that 21 days after BrdU injections, a cell birth marker, ob/ob mice showed an increased number of both new periglomerular and granular cells as compared to control, suggesting that leptin regulates new neuron elimination. We also tested whether an inflammation could be occurring in the MOB. Using RTPCR of different neuronal and glial markers we did not observe strong signs of inflammation. Then we probed changes in local network activity in the deep layers of the MOB by recording local field potentials during a Go/NoGo odor discrimination task. We observed that the power of beta oscillations, the functional marker of the olfactory network between the MOB and the olfactory cortex, is way higher in the MOB of ob/ob mice compared to control mice.

This research involves an examination of the olfactory ability of individuals with Frontotemporal Dementia, Alzheimer's disease, and geriatric individuals with cognitive complaints owing to Major Depressive Disorder or Generalized Anxiety Disorder. The purpose of this study was to determine if olfactory differences were useful in differentiating between demented and non-demented individuals. Due to the pathway of the olfactory tract, it can be expected that there would be equal olfactory deficits in those diagnosed with Frontotemporal Dementia and Alzheimer's disease, and that these deficits would be worse than those found in geriatric individuals with Major Depressive Disorder or Generalized Anxiety Disorder. Five hypotheses were investigated. The first utilized an ANCOVA and found that the olfaction of the demented group was worse than that of the non-demented, psychiatric group. The second utilized a series of Discriminant Function Analyses and F-tests and determined that olfaction best classified demented and non-demented individuals. The third implemented a Mixed Model ANOVA to assess for lateralized smell deficits within the demented group and between the demented and non-demented groups and found no main effects of lateralization or interaction effects. The fourth hypothesis investigated the relationship between smell and commonly used neuropsychological tests in a Frontotemporal Dementia sample, and found that there was no difference between the relationship of tests measuring the frontal and temporal lobes to those measuring other cerebral areas. The fifth hypothesis replicated Hypothesis 4 in an Alzheimer's disease sample and found that there was a significant difference between the relationship of tests measuring the frontal and temporal lobes to those measuring other cerebral areas. Primarily, this study demonstrated that dementia patients present with significantly more olfactory deficits than a psychiatric sample with subjective cognitive complaints. Additionally, olfaction correctly distinguished the Dementia Group from the Psychiatric Group with 81.6% accuracy, 90.2% sensitivity and 67.6% specificity. Alone, these classification statistics are quite impressive, appearing equivalent, or possibly superior to the classification statistics of commonly used neuropsychological tests of memory, executive functioning, and visuospatial ability. This study concluded that adding an olfactory measure to an assessment battery provides clinically relevant data, and enhances the diagnostic accuracy of the battery. However, though this study found the Alberta Smell Test was a valuable addition to a test battery, the absence of lateralized findings demonstrated the unirhinal format, by which the Alberta Smell Test is administered, does not provide diagnostically relevant information above and beyond the information a clinician will gain from birhinal assessment.

The earliest stage of Alzheimer’s disease (AD) pathology begins in one of the main components of the olfactory pathway, the entorhinal cortex, making deficits in smell a potential prospective biomarker for the early detection of AD. This study contributes to the field with a reproduction and extension of work by Wilson, Arnold, Schneider, Boyle, Buchman, and Bennett (2009). A sample of 1089 individuals (M=78.4 years), more than double the data available in 2009, completed annual assessments of olfactory functioning, and cognitive functioning for up to 18 years with brain donation at death. Mixed effects models conditioned on demographics estimated between and within-person effects in olfactory functioning and episodic memory (EM). After successful reproduction of Wilson et al. (2009), addition of AD pathology (ADP) demonstrated that both ADP and olfaction were significantly related to EM at baseline. Higher ADP at autopsy was significantly related to faster declines in olfaction, as well as more rapid declines in EM. Higher olfactory scores were associated with higher EM scores and a model for EM with olfaction as time-varying covariate indicated that at a given occasion, individuals with higher olfactory scores also have higher EM scores. These results align with the hypotheses that difficulty in identifying odors predicts development of cognitive impairment; increased levels of AD pathology are related to both decreased EM at baseline and faster declines, as well as faster rates of decline in olfaction; and olfaction and cognition are travelling together over time. / Graduate / 2018-06-01 / 0766 / 0633 / jknight@uvic.ca

Resources are often unevenly distributed through the environment, resulting in a challenging task for insects to locate food, mates and oviposition sites. Consequently, there is an ongoing need to unravel how insects rely on behavioural and sensory traits while searching for resources in heterogeneous environments. In the first part of this thesis, I addressed this issue by studying how neighbouring resources can affect the likelihood of insects finding their preferred host resources. These effects of neighbouring resources are commonly referred to as associational effects, and are expected to result from limitations in the sensory physiology of insects. Such limitations constrain the insect’s ability to correctly evaluate resource quality at the different steps involved in insect search behaviour. Furthermore, I determined whether the physiological state of an insect, and sensory experiences made during larval stages, can affect host search behaviour in heterogeneous environments. By comparing the behaviour of Drosophila melanogaster in environments with single and multiple resources, I found that the presence of neighbouring recourses increased the selection rates for attractive resources, while it decreased the selection rates for less attractive resources. These effects are referred to as associational susceptibility and associational resistance respectively. Furthermore, by studying oviposition behaviour, I found that during these small-scale behavioural decisions, associational effects are mainly governed by gustatory mediated selection and less by olfactory mediated selection. The oviposition assay eliminated potential misinterpretations of resource quality along the different steps of search behaviour, hence the results suggested that associational effects rely on distinctive selection behaviour between resource types rather than on sensory constraints. In the second part of this thesis I determined whether natal experiences can be used by insects as sensory shortcuts to find host resources, and whether this leads to better larval performance on those selected host resources. For this purpose, I studied the interactions between the larval parasitoid Asecodes lucens and the oligophagous leaf beetle Galerucella sagittariae. The results showed that the relationship between oviposition preference and larval performance, of both insect species, depends on an interactive effect between the insects’ natal origin and the quality of the different host resources. Moreover, I found that the natal origin was a better predictor for the adult host preference, rather than for larval performance. This suggests that, aside from the actual quality of the host resources, locating any suitable host might be even more limiting for the female’s fitness. / <p>At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Accepted. Paper 3: Submitted.</p>

<p>Olfaction is one of the most primitive of our senses, and the olfactory receptors that mediate this very important chemical sense comprise the largest family of genes in the mammalian genome. It is therefore surprising that we understand so little of how olfactory receptors work. In particular we have a poor idea of what odorous chemicals are detected by most of the olfactory receptors in the genome, and for those receptors which we have paired with ligands, we know relatively little about how the structure of these ligands can either activate or inhibit the activation of these receptors. Furthermore the large repertoire of olfactory receptors, which belong to the G protein coupled receptor (GPCR) superfamily, can serve as a model to contribute to our broader understanding of GPCR- ligand binding, especially since GPCRs are important pharmaceutical targets.</p><p>In this dissertation, I explore the relationship between olfactory receptors and their ligands, both by manipulating the ligands presented to the olfactory receptors, as well as by altering the structure of the receptor itself by mutagenesis. Here we report the probable requirement of a hydrated germinal-diol form of octanal for activation of the rodent OR-I7 receptor by ligand manipulation, and the successful in vitro modeling and manipulation of ketamine binding to MOR136-1. We also report the results of a large-scale screen of 1190 human and mouse olfactory receptors for receptors activated by volatile general anesthetics, which has lead to the identification of 32 olfactory receptor-volatile general anesthetic pairs.</p> / Dissertation

Traditional studies of simple perceptual choice tasks in vertebrates identified behavioural characteristics of deliberate decision-making that guided the development of general mathematical models, and the search for neurophysiological correlates. Current experimental and modelling efforts aim to uncover biophysical and circuit level mechanisms of decision-making processes. However, genetic manipulability constraints and lack of high-throughput assays make further progress in vertebrate studies a steep endeavour. In this thesis I studied decision-making in Drosophila melanogaster in trained two-alternative forced-choice olfactory tasks with varying stimulus contrast, using a high-resolution single fly behavioural assay. Analysing accuracy and reaction time as a function of task difficulty (i.e., stimulus contrast) showed that flies display behavioural characteristics of evidence accumulation processes, a signature of vertebrate decision-making: reaction times increased and perceptual accuracy declined as stimulus contrast decreased. Mutants for the gene encoding the transcription factor FoxP took longer than wild-type flies to form decisions of similar or reduced accuracy, especially in difficult tasks. Using the putative FoxP promoter to ascertain FoxP expression identified subsets of mushroom body intrinsic Kenyon cells, in &alpha;&beta; core and &gamma; neurons, as potential sites of FoxP action. Disrupting FoxP expression or decreasing neuronal excitability specifically in &alpha;&beta; core neurons mimicked the phenotype observed in FoxP mutants. FoxP expression therefore affects the development or function of &alpha;&beta; core neurons in the progression of a decision process towards commitment. To identify molecular processes involved in evidence integration regulated by FoxP I further screened 2nd and 3rd chromosome deficiency lines in a sensitised FoxP mutant background, uncovering genomic regions of interest for further study. Finally, analysing naive performance in tasks of increasing difficulty showed that naive discriminations are faster and less accurate than trained ones, pointing to the existence of two decision-making systems. FoxP mutants appear to engage the slower, more accurate decision making system and the mushroom body seems to be involved in naive discriminations. The molecular and neuronal players involved in olfactory decision making in Drosophila melanogaster uncovered in this thesis will allow researching decision making systems to an unprecedented level of detail.