L'objectif de cette thèse était de mieux comprendre les mécanismes mnésiques liés à une stimulation nociceptive. Un premier axe de notre travail a été d'étudier l'influence de la douleur sur la mémorisation de mots grâce à une étude comportementale. Contrairement à d'autres émotions, nous avons montré qu'une douleur n'influençait pas la mémorisation du contenu d'un texte, qu'il soit lié à la douleur ou pas. Le deuxième axe, correspondant à la thématique majeure de la thèse, a été abordé à travers trois études : une étude comportementale permettant de tester la robustesse de la mémorisation nociceptive et ses spécificités; des enregistrements électro-encéphalographiques (EEG) intra-cérébraux afin d'identifier les régions cérébrales impliquées dans la mémorisation nociceptive et leurs interactions et enfin une exploration EEG de scalp chez des sujets sains permettant une vision plus globale des mécanismes mnésiques de ces stimulations. Ces études ont montré des phénomènes liés à la mémorisation non spécifiques à la stimulation nociceptive, telle que l'augmentation de la puissance alpha pendant la phase de rétention. Elles ont également mis en relief des spécificités liées à la mémorisation nociceptive en révélant l'existence d'un biais mnésique suite à une stimulation nociceptive de forte intensité, faussant l'évaluation d'une autre stimulation survenant ultérieurement. Les enregistrements EEG ont montré une augmentation de la connectivité beta entre des régions corticales de la matrice douleur et du cortex préfrontal lors de la phase de rétention. Cette connectivité pourrait refléter une trace de la mise en mémoire des informations nociceptives / The aim of this thesis was to better understand memory mechanisms of a nociceptive stimulation.A first axis of our work was to study pain influence on memorisation of words by a behavioural study. Contrary to other emotions, we demonstrated that pain didn’t influence the memory content of a text, related or not to pain.Our second axis, corresponding to the major thematic of this thesis, was addressed through three studies: a behavioural one allowing us to test robustness of nociceptive memorisation and it specificities; intracerebral electroencephalographic recordings (EEG) to identify brain regions involved in nociceptive memorisation and their interactions, and finally scalp EEG exploration in healthy subjects allowing a broader view of memorisation mechanisms of these stimulations.These studies demonstrated phenomena related to memorisation that was nonspecific to nociceptive stimulation, like alpha power enhancement during retention phase. They also highlight specificities related to nociceptive memorisation revealing memory bias existence following nociceptive stimulation of high intensity, distorting next stimulation evaluation. EEG recordings demonstrated beta connectivity enhancement between cortical regions of the pain matrix and prefrontal cortex during retention phase. This connectivity could reflect memory trace of nociceptive information

<p>From insects to mammals, the ability to constantly sense environmental stimuli is essential for the survival of most living organisms. Most animals have nocifensive behaviors towards extreme temperatures, mechanical stimuli or irritant chemicals that are considered to be noxious. Nociception is defined as the neural encoding and processing of noxious stimuli. This process starts from the activation of pain detecting peripheral sensory neurons (nociceptors) that can detect noxious mechanical, thermal or chemical stimuli. On the other hand, animals also have the ability to discriminate innocuous temperatures and to direct their locomotions to their favorable environmental temperatures and this behavior is called thermotaxis. </p><p>In this study, I used <italic>Drosophila melanogaster</italic>as a genetic model organism to study the molecular and cellular basis of nociception and thermotaxis. <italic>Drosophila</italic> larvae exhibit a stereotyped defensive behavior in response to nociceptive stimuli (termed nocifensive escape locomotion behavior, NEL). Using this behavior as a readout, we manipulated the neuronal activities of periphery sensory Type II multidendritic neurons and have identified a specific class of neurons, class IV multidendritic neurons, to function as nociceptors in <italic>Drosophila</italic> larvae. </p><p>After identifying the nociceptors, I next investigated several ion channels that are critical molecular components for larval nociception. The Degenerin Epithelial Sodium Channel (DEG/ENaC) protein called pickpocket (ppk) is required specifically for larval mechanical nociception but not for thermal nociception. Being specifically expressed in class IV multidendritic neurons (the nociceptors), pickpocket is likely to function as a first detector of mechanical stimuli and upstream of general neuronal action potential propagation. In addition, I have found that the <italic>Drosophila</italic> orthologue of mammalian TRPA1 gene, <italic>TrpA1</italic>, is required for both mechanical and thermal nociception in <italic>Drosophila</italic> larvae. I have cloned a new isoform of dTRPA1 and have found it to be specifically expressed in class IV md neurons. Unlike the known dTRPA1 isoform that is warmth activated, this new isoform is not directly activated by temperatures between 15-42 °C. Instead, it may function downstream of sensory transduction step in the nociceptors. </p><p>Interestingly, <italic>dTrpA1</italic> mutants are also defective in their thermotaxis behavior within innocuous temperature ranges. In addition to the previously reported defects in avoiding warm temperatures, I have found these flies also failed to avoid cool temperatures between 16-19.5 °C. This defect is likely to be mediated by temperature sensing neurons in the antennae. I have detected antennal expression using a GAL4 reporter of dTrpA1. Significantly, these neurons exhibit elevated calcium levels in response to cooling. dTrpA1 mutants have a premature decay of the cooling response at temperatures below 22 °C during a cooling process. I have also identified another population of cells in the antennae that can respond to temperature changes. These neurons express the olfactory co-receptor Or83b and are known to be olfactory neurons. Calcium oscillations triggered by cooling were detected in these neurons and they were terminated by warming. Severe behavioral defects in avoiding cool temperatures were found in animals lacking <italic>Or83b</italic>. Our results suggest that there are multiple pathways regulating cooling sensation in the fly antennae.</p><p>Taken together, I have shown that <italic>Drosophila</italic> serves as a great model system to study nociception and thermosensation at molecular, cellular and behavioral levels.</p> / Dissertation

Les parasomnies forment un ensemble de troubles du sommeil caractérisés par la survenue de comportements ou de phénomènes psychiques indésirables au cours du sommeil. Les parasomnies du sommeil lent profond (SLP) regroupent le somnambulisme, les terreurs nocturnes et les éveils confusionnels et surviennent au décours d’éveils brutaux en SLP. Elles s’associent souvent chez un même individu et pourraient représenter des variantes cliniques d’une même pathologie.Longtemps considérées comme des troubles bénins du sommeil, les données actuelles soulignent les conséquences des parasomnies, avec des mises en danger et un retentissement fonctionnel diurne. Nos trois premiers travaux ont permis une meilleure caractérisation du phénotype et des conséquences des parasomnies, en particulier sur le plan de la somnolence et des phénomènes douloureux chroniques. Près de la moitié des adultes parasomniaques rapportaient une plainte de somnolence diurne excessive associée à une propension marquée au sommeil sur les premières heures de la journée. Nous retrouvions une fréquence élevée de douleurs chroniques, de céphalées et de migraine. Par ailleurs nous avons décrit un phénomène fréquent d’hypo/analgésie au cours des accès parasomniaques.Le diagnostic des parasomnies du SLP repose uniquement sur des éléments cliniques, sans critères polysomnographiques objectifs. Si des travaux récents suggèrent que les parasomnies sont associées à des altérations discrètes de la microstructure du SLP, les performances diagnostiques de ces paramètres n’ont pas fait l’objet d’études spécifiques. Nous avons développé une nouvelle méthode d’analyse polysomnographique qui offre de bonnes performances de classification chez des adultes parasomniaques et des sujets témoins.Malgré cinq décennies d’études cliniques et expérimentales, la physiopathologie de ces parasomnies reste mal connue. Un modèle permet de conceptualiser les mécanismes de la maladie. Chez un patient prédisposé génétiquement, certaines conditions responsables d’une instabilité du SLP favorisent la survenue d’un éveil dissocié précipité par un stimulus éveillant. Nos travaux en cours et futurs porteront sur l’étude de ces mécanismes au moyen de techniques innovantes de génétique, d’électrophysiologie et d’imagerie fonctionnelle. / Parasomnias are sleep disorders characterized by undesirable behavioral or experiential phenomena occurring during sleep. Disorders such as sleepwalking (somnambulism), sleep terrors and confusional arousal are classified under the term “Non Rapid Eye Movement (NREM) Sleep-related parasomnias” as they frequently occur during sudden arousals from slow wave sleep. They often coexist within the same individual and are considered as different phenotypes for a similar underlying pathophysiology.The widespread belief that NREM parasomnias are benign disorders is actually challenged as they can result in various adverse consequences such as violent and injurious behaviors and daytime functional impairment. Our first three studies investigated the clinical phenotype and the consequences of NREM parasomnias, especially subjective and objective daytime sleepiness and chronic pain. We found that almost an half of sleepwalkers had complaint of sleepiness with an increased objective sleep propensity in the morning. We also reported a high frequency of chronic pain, headaches and migraine in patients and described a frequent analgesia phenomenon during injurious parasomniac episodes.The diagnosis of NREM parasomnias is usually made from clinical history, without polysomnographic-based diagnostic criteria. If recent works suggested that NREM parasomnia were associated with subtle changes on the NREM microstructure, the diagnostic performances of these parameters have been poorly studied with appropriate design. We developed a new polysomnographic scoring method that offers a good classification rate of NREM parasomnia patients and controls.Despite almost five decades of clinical and laboratory investigations, the pathophysiology of NREM parasomnias remains poorly understood. One model is currently used to conceptualize the mechanisms of the disease. A predisposed patient is primed by conditions that impair slow wave sleep stability resulting in dissociated arousal precipitated by arousing stimuli. Our further works will investigate the pathophysiology of NREM parasomnia using innovative genetic, electrophysiological and functional imagery approaches.

<p>Pain is defined by the international association of pain as an "unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage". Most people have experienced one form of pain or another and although such experiences can be unsavory, pain serves the basic need for the detection of dangerous stimuli that can cause bodily harm. Because pain serves such an essential need, it is important to understand how the nervous system processes and encodes noxious or potentially tissue damaging stimuli. This neural processing is called nociception. </p><p>In this study, I use Drosophila larvae as a genetic model organism to study nociception. In response to noxious thermal and mechanical stimuli, Drosophila larvae perform a nociceptive defensive behavior (termed nocifensive) where larvae rotate in a corkscrew like fashion along the long axis causing them to move in a lateral direction. Using this behavior and genetic tools which can manipulate neuronal output, we have identified the sensory neurons which serve as larval nociceptors as class IV multidendritic sensory neurons. Further characterization of these larval nociceptors, has also shown that they are both cholinergic and peptidergic.</p><p>After the identifying the larval nociceptors, I next identified several molecular components which are required for larval mechanical nociception. I have found that the degenerin epithelial sodium channel (DEG/ENaC) called pickpocket is required for larval mechanical nociception by using genetic mutants and RNAi knockdwon. In addition, after performing a screen using RNAi to knockdown ion channel transcripts in larval nociceptors, I have identified two other DEG/ENaC channels which are required for larval mechanical nociception. DEG/ENaCs are particularly interesting because they have been identified as candidate mechanotransducers in C. elegans for the gentle touch behavior. I propose that DEG/ENaCs may serve as candidate mechanotransducers in larval mechanical nociception because they are not generally required for neuronal excitability. However, future research will be required to establish their true role in mechanical nociceptive signaling.</p><p>In addition to DEG/ENaCs, transient receptor potential (TRP) channels also play a role in nociception. painless, a channel that was first identified in a thermal nociception screen on Drosophila larvae, is required for both thermal and mechanical nociception. The last section shows that multiple isoforms of painless exist and that these different isoforms may play different roles in thermal and mechanical nociception. </p><p>Taken together, these results have begun to establish Drosophila larva as a model for studying nociception. I have identified the sensory neurons used as larval nociceptors and shown that DEG/ENaC channels play an important role in larval mechanical nociception.</p> / Dissertation

La partie céphalique de notre corps est le siège de douleurs qui, comme la migraine, peuvent être très invalidantes. Le sous noyau caudal du trijumeau (Sp5C) assure le transfert des messages nociceptifs provenant de la face et des méninges vers les centres supérieurs. Ce transfert est modulé par des projections descendantes provenant de centres supraspinaux dont l'hypothalamus. Comment sont organisés les contrôles descendants hypothalamiques sur le Sp5C ? En utilisant le traceur retrograde, Fluorogold (FG), nous avons analysé les projections hypothalamiques sur le Sp5C. Elles proviennent du noyau paraventricular (PVN), de l'aire hypothalamique laterale (LH), de l'aire hypothalamique perifornicale (PFX), du noyau A11 et de l'aire retrochiasmatique (RCA). La zone ophtalmique V1 du Sp5C reçoit la plus forte densité de projections. Ces projections sont systématiquement bilatérales. Par double marquage immunohistochimique traceur/phénotype, nous avons précisé les phénotypes neurochimiques des neurones projetant du A11, LH et PFX vers le Sp5C. Dans le noyau A11, 60% environ de ces neurones sont dopaminergiques (DA) et 10% environ contiennent l'alpha-calcitonin gene related peptide (CGRP). De plus, 15% de ces neurones dans LH et 30% de ceux-ci dans PFX sont oréxinergiques. L'expression de Fos est augmentée dans le noyau A11 après stimulation nociceptive tonique inflammatoire (formol facial sous-cutané), indiquant que ce noyau contribue au traitement de l'information douloureuse. Cependant, ni les neurones DA ni les neurones FG expriment Fos. Par une approche comportementale et électrophysiologique, nous avons précisé le rôle des contrôles hypothalamiques dans la modulation de la nociception trigéminale. La lésion par acide kaïnique ou 6-OHDA d'un noyau A11 abaisse les réponses nociceptives comportementales (test au formol) chez le rat vigil. Pour tester l'hypothèse d'un contrôle hypothalamique orexinergique, nous avons enregistré les réponses électrophysiologiques de neurones trigéminaux à la stimulation électrique de leur champ récepteur. L'injection intracisternale (0.6 nmol dans 5μl) d'orexine A réduit (environ 50%) les réponses à l'activation sélectivement des fibres afférentes de type C sans modifier leur windup. Au total, plusieurs de nos résultats méritent d'être soulignés. (1) Les voies hypothalamiques descendantes semblent contrôler préférentiellement les inputs méningés. (2) Un dysfonctionnement prolongé du noyau A11 provoque un état d'hypoalgésie, suggérant que l'activation des afférences DA provoque un état d'hyperalgie. Or, les résultats d'injections locales de DA ou de manipulations aigues du noyau A11 suggèrent un contrôle DA inhibiteur sur l'information nociceptive. Le dysfonctionnement DA pourrait favoriser une plasticité dans le Sp5C. (3) Enfin, l'inhibition sélective des réponses C par l'orexine A, suggère l'existence d'un contrôle présynaptique inhibiteur du message nociceptif trigéminal. / Pain syndroms located in the head, such as migraine, can be particularly invalidating. Sensory inflow generated bynociceptors in the face and meninges activate neurons in the medullary dorsal horn (MDH), within the trigeminal system.There, a network of descending projections from cerebral structures enhance or inhibit the transfer of nociceptive informationto higher centers. However, the functional anatomy of such descending controls of nociceptive information are still ill-defined.Here, we investigated the descending hypothalamic projections to the MDH. Using the retrograde tracer, Fluorogold (FG), we analyzed the organization of hypothalamic projections to MDH. They originate from the paraventricular nucleus (PVN), lateral hypothalamic area (LH), perifornical hypothalamic area (PFX), A11 nucleus and retrochiasmatic area (RCA). Within MDH, the V1 area, where primary afferent fibers of the ophthalmic branch of the trigeminal nerve terminate, receives the strongest hypothalamic projections. Hypothalamic projections to MDH are bilateral. Using double-immunolabelling, we determined the molecular phenotype of A11 nucleus, LH and PFX projecting neurons to MDH. In A11 nucleus, about 60% of projecting neurons to MDH are dopaminergic (DA) and about 10% contain the alphacalcitonin gene related peptide (CGRP). Fifteen percent of LH projecting neurons to MDH and 30% of PFX ones contain orexin. Pain (facial formalin test) elevates Fos expression in A11 nucleus, suggesting that it contributes to pain processing. However, it is worth noting that Fos-immunoreactive neurons are neither DA nor projecting neurons. We combined behavioral and electrophysiological techniques to get further insights into the role of hypothalamic projections on trigeminal pain. Lesion of A11 nuclei, by locally injecting kainic acid or 6-OHDA, reduces spontaneous pain behavior (facial formalin test). To examine whether orexin descending hypothalamic projections control trigeminal pain, we examined the effect of intracisternally applied orexin A on electrophysiological responses of trigeminal neurons to electrical stimulation of their receptive field. Orexin A (0.6 nmol in 5μl) selectively reduces (about 50%) C-fiber-evoked responses but not the windup phenomenon. Several of these results are worth to note. (1) Descending hypothalamic projections predominantly control VI area of MDH, where primary afferent fibers innervating the meninges terminate. (2) The effect of long-lasting dysfunction of A11nucleus suggests that activation of descending DA projections produce a state of hyperalgesia. This is at odds with theconclusion of previous reports on the effects of local administration of DA or acute manipulations of A11 nuclei, suggestingthat descending DA projections rather inhibit nociceptive transmission. Long-lasting dysfunction of descending A11 DAprojections might enable plasticity changes in DH neuronal network. (3) That orexin A selectively inhibits C-fiber-evokedresponses suggests that orexin A selectively controls the transfer of nociceptive information via a presynaptic mechanism.

No description available.

Insect grooming has various functions, including defense against parasites and pathogens, cleaning of dust particles, and maintenance of sensory receptors. The hierarchy of grooming behavior suggests that cleaning one body part is more crucial than the other, the priority order more specifically being eyes, antennae, abdomen, then wings, followed by the thorax. Histamine is an extensively studied neurotransmitter found in the central nervous system of many animals. In Drosophila, histamine is found in both the peripheral and central nervous systems and is necessary for visual and mechanosensory behaviors. Histamine-gated chloride channel 1 (HisCl1) and Ora transientless (Ort) are two characterized histamine receptors, both of which are vital for visual signaling in the fly. / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2019. / FAU Electronic Theses and Dissertations Collection

Abdominal pain is a common symptom of inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). Although the extent differs, visceral inflammation is thought to play a significant role in nociception in these disorders. This thesis describes studies examining mechanisms of inflammation-induced changes in nociceptive signaling from the colon using human colonic biopsy and animal models of the conditions. Citrobacter rodentium infection in mice produced profound colitis at day 10 post-infection which resolved by day 30. Perforated current clamp recordings showed that inflammation induced hyperexcitability of colonic DRG neurons that persisted at day 30 post-infection. Similarly, multi-unit afferent nerve recordings revealed enhanced firing of colonic afferents following colon distension at this time. In voltage clamp studies, suppression of IA K+ currents in post-infected C. rodentium neurons was observed. Combining water-avoidance stress (WAS) and C. rodentium infection exaggerated these effects. Interactions between proteases and stress mediators underlie these actions. In vivo studies revealed WAS combined with C. rodentium post-infection induced visceral hyperalgesia and allodynia. A separate series of studies examined the possible role of cysteine proteases in post-infectious IBS. The cysteine protease cathepsin-s (Cat-S) induced neuronal excitability and, provoked visceral hypersensitivity in mice. Human IBS supernatants increased neuronal excitability, but this was reversed in neurons pre-treated with the cysteine protease inhibitor E-64. Together these data suggest that Cat-S is a secreted neuromodulator in human IBS supernatants and could be important in nociceptive signaling in IBS. In studies examining whether similar mechanisms operate in a traditional inflammatory condition, IBD, human ulcerative colitis (UC) supernatants showed elevated TNF-α levels. Exogenous TNF-α and UC-supernatants increased colonic nociceptor excitability, which was attenuated in neurons from TNFR knock-out animals. TNF-α and UC-supernatants both increased TTX-R Nav1.8 and suppressed IA and IK K+ currents. Together these results suggest that inflammation significantly increases and sustains peripheral nociceptive signaling in IBD and IBS. These effects involve changes in the properties of nociceptive DRG neurons through actions of specific secreted factors which modulate specific voltage-gated ion channels. Chronic stress exaggerates these changes through synergistic actions of stress hormones and local mediators, suggesting an interplay between central and peripheral mechanisms. / Thesis (Ph.D, Physiology) -- Queen's University, 2011-07-28 10:17:58.863

Plusieurs variables biologiques, psychologiques, ainsi que des différences culturelles, ont été mises en cause afin d'expliquer la différence de perception de la douleur existante entre les hommes et les femmes. Il est connu que les hormones sexuelles gonadiques influencent la réponse nociceptive chez l’animal et chez l’humain. Le cerveau a aussi la capacité de synthétiser ses propres "hormones sexuelles", les neurostéroïdes. Les objectifs étaient: 1) évaluer les facteurs influençant de perception de la douleur chez les hommes et les femmes, 2) mettre en relation les niveaux d’hormones gonadiques et adrénergiques avec les symptômes cliniques et la perception de la douleur chez des sujets fibromyalgiques et sains, et 3) évaluer l'implication des hormones gonadiques et de leurs métabolites 3?5?-réduits dans la transmission de la douleur et l'efficacité des mécanismes de contrôle descendants de la douleur (MCDD) chez les mâles et les femelles. Résultats: 1) Des analyses statistiques ont permis de conclure que bien que plusieurs facteurs psychologiques soient différents entre les hommes et les femmes, et qu'ils influencent aussi la douleur, il semble y avoir des différences physiologiques intrinsèques qui font que les hommes sont moins sensibles et plus tolérants à la douleur que les femmes. 2) Nous avons évalué l'implication des hormones gonadiques et adrénergiques chez des sujets sains et des sujets fibromyalgiques. Un déséquilibre des androgènes corrèle avec l'importance des symptômes cliniques et de la sensibilité/tolérance à la douleur expérimentale dans cette pathologie. 3) Les hormones gonadiques ont une implication à la fois sur les mécanismes de transmission et de modulation de la douleur. Leurs métabolites 3?5?-réduits, quant à eux, affectent uniquement la transmission nociceptive, mais de façon sexe-dépendante. Lors d'un paradigme de retrait de progestérone mimant la phase lutéale du cycle menstruel, la capacité d'activation des MCDD est particulièrement diminuée et cet effet semble être dû à la présence de métabolites 3?5?-réduits. Ce projet a mis en évidence la complexité de la modulation de la douleur chez les hommes et les femmes. En effet, plusieurs facteurs physiologiques et psychologiques ont été identifiés et sont impliqués dans un réseau d'interactions complexes qui déterminent la réponse douloureuse physiologique et pathologique sexe-spécifique. [symboles non conformes]

Orientador: Clélia Akiko Hiruma-Lima / Resumo: A dor é um dos principais indicadores de enfermidade. Ela é uma sensação desagradável, complexa e extremamente subjetiva, relacionada a algum estímulo lesivo ou potencialmente lesivo ao organismo. Quando esses estímulos danificam tecidos do organismo a resposta inflamatória é iniciada. Essa resposta é necessária para a resolução de diversos danos e essencial para a defesa do organismo. A inflamação é uma resposta vascular realizada por mediadores inflamatórios. Se houver falha neste processo pode haver a perda da função tecidual. A abordagem mais comum para reduzir a dor e a inflamação é através do uso de medicamentos anti-inflamatórios não esteroidais (AINEs). Entretanto, o uso destes fármacos sem as devidas orientações, ou por longos períodos, pode levar ao aparecimento de sérias reações adversas como as úlceras pépticas. Uma alternativa para o tratamento da dor e inflamação é o uso de espécies vegetais com propriedades medicinais. Nesse contexto, a espécie Arrabidaea brachypoda é uma espécie medicinal comumente utilizada nas regiões sudeste e nordeste brasileira para o tratamento de cálculo renal e dores nas articulações. Considerando a utilização popular da planta, o objetivo do projeto foi avaliar a ação antinociceptiva e anti-inflamatória do extrato diclorometano das raízes de A. brachypoda (DEAB) em modelos experimentais in vivo e seus mecanimos de ação. Neste trabalho avaliamos a toxicidade aguda do DEAB e também o efeito desse extrato sobre a performance motora dos a... (Resumo completo, clicar acesso eletrônico abaixo) / Mestre