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Le système cholinergique joue un rôle important dans de nombreuses fonctions cognitives telles que l'attention et l'apprentissage perceptuel. La stimulation pharmacologique du système cholinergique par le donépézil, un inhibiteur de l’acétylcholinestérase, est un moyen efficace pour améliorer les fonctions cognitives et le traitement cortical via les récepteurs muscariniques et nicotiniques. En effet, le donépézil permet l'accumulation d'acétylcholine dans la fente synaptique. Toutefois, l’effet de la stimulation pharmacologique du système cholinergique sur le traitement visuel complexe et l’apprentissage perceptuel n’est pas encore bien défini. L'objectif de cette thèse est d'étudier, d'une part, l'effet de la combinaison d’un entrainement visuel répétitif avec une stimulation cholinergique sur les capacités visuelles chez le rat et l’humain et, d'autre part, l’effet de la stimulation pharmacologique du système cholinergique sur la restauration des capacités visuelles dans un modèle de déficit visuel chez les rats. Nos résultats ont montré qu’un entrainement visuel/cholinergique entraînait : 1) une potentialisation à long terme de la réponse visuelle corticale chez le rat, 2) une récupération plus rapide des capacités visuelles chez la rat suite un écrasement du nerf optique 3) une amélioration de la performance dans une tâche perceptivo-cognitive de haut niveau plus rapide et conservée dans le temps chez les jeunes sujets sains. Le patron d’électroencéphalographie chez le sujet humain pratiquant une tâche d’attention visuelle n’est cependant pas modifié par l’administration d’une dose unique de donépézil. Ensembles, ces résultats soulignent le bénéfice considérable de la combinaison d’une stimulation du système cholinergique lors de l’entrainement visuel répétitif afin d'obtenir des améliorations de la perception visuelle. Cela présente une avenue très intéressante pour la réhabilitation chez les humains. / The cholinergic system plays an important role in many cognitive functions such as attention and perceptual learning. Pharmacological stimulation of the cholinergic system via donepezil, an acetylcholinesterase inhibitor, is an efficient tool for enhancing cognitive functions and cortical processing via muscarinic and nicotinic receptors. In fact, donepezil allows the build-up of acetylcholine in the synaptic cleft. However, whether pharmacological manipulation of the cholinergic system has an effect on complex visual processing and perceptual learning remains unclear. The goal of this thesis is to investigate on the one hand the effect of combining repetitive visual training with cholinergic enhancement on visual capacities in rats and humans and on the other hand the effect of the pharmacological stimulation of the cholinergic system on visual restoration in a model of visual deficit in rats. Our results showed that cholinergic potentiation induces 1) a long-term potentiation of visual cortical response following repetitive visual stimulation, 2) a faster recovery of brightness discrimination in rats with an optic nerve crush, 3) a faster progression of and a sustained performance in a highly demanding perceptual-cognitive task for healthy young humans. However, the EEG pattern for subjects performing a visual attention task is not modified by a single administration of donepezil. Together these results underline the substantial benefice of combining cholinergic enhancement with visual training in order to obtain visual perception improvements, which presents an interesting avenue for visual rehabilitation paradigm in humans.

<p>The duodenal epithelium secretes bicarbonate ions and this is regarded as the primary defence mechanism against the acid discharged from the stomach. For an efficient protection, the duodenum must also function as a sensory organ identifying luminal factors. Enteroendocrine cells are well-established intestinal “taste” cells that express signaling peptides such as orexins and guanylins. Luminal factors affect the release of these peptides, which may modulate the activity of nearby epithelial and neural cells.</p><p>The present thesis considers the effects of orexins and guanylins on duodenal bicarbonate secretion. The duodenal secretory response to the peptides was examined in anaesthetised rats <i>in situ</i> and the effects of orexin-A on intracellular calcium signaling by human as well as rat duodenal enterocytes were studied <i>in vitro</i>.</p><p>Orexin-A, guanylin and uroguanylin were all stimulants of bicarbonate secretion. The stimulatory effect of orexin-A was inhibited by the OX₁-receptor selective antagonist SB-334867. The muscarinic antagonist atropine on the other hand, did not affect the orexin-A-induced secretion, excluding involvement of muscarinic receptors. Orexin-A induced calcium signaling in isolated duodenocytes suggesting a direct effect at these cells. Interestingly, orexin-induced secretion and calcium signaling as well as mucosal orexin-receptor mRNA and OX₁-receptor protein levels were all substantially downregulated in overnight fasted rats compared with animals with continuous access to food. Further, secretion induced by Orexin-A was shown to be dependent on an extended period of glucose priming.</p><p>The uroguanylin-induced bicarbonate secretion was reduced by atropine suggesting involvement of muscarinic receptors. The melatonin receptor antagonist luzindole attenuated the secretory response to intra-arterially administered guanylins but had no effect on secretion when the guanylins were given luminally. </p><p>In conclusion, the results suggest that orexin-A as well as guanylins may participate in the regulation of duodenal bicarbonate secretion. Further, the duodenal orexin system is dependent on the feeding status of the animals.</p>

The duodenal epithelium secretes bicarbonate ions and this is regarded as the primary defence mechanism against the acid discharged from the stomach. For an efficient protection, the duodenum must also function as a sensory organ identifying luminal factors. Enteroendocrine cells are well-established intestinal “taste” cells that express signaling peptides such as orexins and guanylins. Luminal factors affect the release of these peptides, which may modulate the activity of nearby epithelial and neural cells. The present thesis considers the effects of orexins and guanylins on duodenal bicarbonate secretion. The duodenal secretory response to the peptides was examined in anaesthetised rats in situ and the effects of orexin-A on intracellular calcium signaling by human as well as rat duodenal enterocytes were studied in vitro. Orexin-A, guanylin and uroguanylin were all stimulants of bicarbonate secretion. The stimulatory effect of orexin-A was inhibited by the OX1-receptor selective antagonist SB-334867. The muscarinic antagonist atropine on the other hand, did not affect the orexin-A-induced secretion, excluding involvement of muscarinic receptors. Orexin-A induced calcium signaling in isolated duodenocytes suggesting a direct effect at these cells. Interestingly, orexin-induced secretion and calcium signaling as well as mucosal orexin-receptor mRNA and OX1-receptor protein levels were all substantially downregulated in overnight fasted rats compared with animals with continuous access to food. Further, secretion induced by Orexin-A was shown to be dependent on an extended period of glucose priming. The uroguanylin-induced bicarbonate secretion was reduced by atropine suggesting involvement of muscarinic receptors. The melatonin receptor antagonist luzindole attenuated the secretory response to intra-arterially administered guanylins but had no effect on secretion when the guanylins were given luminally. In conclusion, the results suggest that orexin-A as well as guanylins may participate in the regulation of duodenal bicarbonate secretion. Further, the duodenal orexin system is dependent on the feeding status of the animals.

Le système cholinergique est impliqué dans les phénomènes d’attention, de mémoire et d’apprentissage et les récepteurs cholinergiques régulent de multiples fonctions du système nerveux central. Néanmoins, leur rôle au niveau de la modulation des propriétés du cortex visuel reste à être établi. L’un des objectifs de cette thèse était d’étudier le rôle des récepteurs muscariniques impliqués dans le fonctionnement normal du cortex visuel. Nous avons pu déterminer que les récepteurs muscariniques sont impliqués dans l’établissement de nombreuses propriétés visuelles telles la taille des champs récepteurs, la sensibilité au contraste, la sélectivité à la fréquence spatiale et la finesse de la connectivité corticale. L’autre objectif était d’identifier les récepteurs cholinergiques impliqués dans la potentiation des capacités visuelles. Nous avons amélioré le traitement cognitif de l’information visuelle par stimulation électrique du télencéphale basal (noyau où sont localisés les corps cellulaires cholinergiques) et par la stimulation cholinergique par le donépézil, un inhibiteur de l’acétylcholinestérase. La combinaison répétée d’une stimulation visuelle et cholinergique (qu’elle soit électrique ou pharmacologique) améliore similairement l’activité corticale visuelle. Toutefois, les récepteurs impliqués ne sont pas les mêmes. Suite à la stimulation pharmacologique, ce sont principalement les récepteurs muscariniques qui influencent l’acuité visuelle de manière tardive et cette modulation est plus précoce lors de la stimulation électrique. Ces résultats démontrent que le couplage répétitif d’une stimulation cholinergique et d’une stimulation visuelle est en mesure d’améliorer l’activité corticale visuelle. Le fait de connaître les récepteurs cholinergiques impliqués permettra dans un futur proche de les cibler directement pour améliorer la fonction corticale. / The cholinergic system is involved in attention, learning and memory and cholinergic receptors regulate multiple functions of the central nervous system. Nevertheless, their role in modulating the properties of the visual cortex remains to be established. One of the objectives of this thesis was to study the role of muscarinic receptors involved in the normal function of the visual cortex. We have been able to determine that the muscarinic receptors are involved in the establishment of many visual properties such as the size of the receptor fields, contrast sensitivity, spatial frequency selectivity and accuracy of the cortical connectivity. The other objective was to identify the cholinergic receptors involved in the potentiation of visual abilities. We improved the cognitive processing of visual information by electrical stimulation of the basal forebrain (the nucleus where the cholinergic cell bodies are located) and by cholinergic stimulation using donepezil, an acetylcholinesterase inhibitor. The repeated combination of visual and cholinergic stimulations (whether electrical or pharmacological) similarly enhances visual cortical activity. However, the receptors involved are not the same. Following the pharmacological stimulation, it is mainly the muscarinic receptors that influence visual acuity with a delay in the receptors expression and this modulation is earlier for the electrical stimulation. These results demonstrate that repetitive coupling of cholinergic stimulation and visual stimulation can enhance visual cortical activity. Knowing the cholinergic receptors involved will allow in a near future to target them directly to improve cortical function.