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<p>Several classes of psychotropic medications are known to produce neurological side effects. It has long been recognized that antipsychotic drugs classically block the D₂ subtype of DA receptors inducing a range of acute and subacute extrapyramidal syndromes (EPS), including parkinsonism and akathisia, as well as chronic syndromes such as tardive dyskinesia. More recently, SSRI-type drugs, which, as the name suggests, inhibit the serotonin transporter (SERT), and have been found to induce a similar profile of EPS. It is unclear how medications with such different pharmacological actions can produce similar neurological side effects. The goal of this thesis was to study the neurochemical alterations induced by antipsychotic and SSRI medications, with a specific focus on the nigrostriatal pathway, the causative location of parkinsonism.</p> <p>Environmental enrichment and exercise (EE) has been shown to have protective effects in various neurological settings. In the first experiment, we studied the changes induced by SERT inhibition compared to those induced by a non-pharmacological form of therapy, namely, environmental enrichment with exercise. The SSRI, fluoxetine (FLX) significantly reduced the levels of tyrosine hydroxylase (TH) and phosphorylated glycogen synthase kinase-3β (pGSK-3β-inactive), while increasing phosphorylated TH (pTH) in the striatum (STR). EE also reduced TH and increased pTH, but contrary to FLX, it significantly increased striatal pGSK-3β protein expression.</p> <p>Microglia, the brain’s primary immune cells, have been implicated in several neuroinflammatory conditions, including Parkinson’s disease. The purpose of the second experiment was to explore the modulatory effects of microglia on neuroleptic-induced changes in the nigrostriatal system. The typical antipsychotic, haloperidol (HAL), did not affect the overall levels of TH, though it did induce a robust increase in pTH. The microglial NADPH oxidase inhibitor, apocynin (APO), significantly attenuated this increase in pTH. HAL also induced a significant increase in striatal pGSK-3β, while apocynin, rather surprisingly, induced a stark decrease in pGSK-3β protein expression.</p> <p>The results of this thesis indicate that both pTH and pGSK-3β are intriguing markers to study in the context of dopamine neurotransmission. In addition, EE proved to be a valuable modality in which to compare the downstream effects of pharmacological treatment. It is also clear that microglia fulfill an undefined, but fascinating role as modulators of neural transmission.</p> / Master of Science in Medical Sciences (MSMS)

Mathematical models are used to estimate physiological parameters which are otherwise inaccessible to measurement. When applied to tracer kinetic data obtained in positron tomographic studies, these methods allow for the quantitative analysis of regional metabolic rates in the human brain during life. Dopamine, a neurotransmitter in the mammalian central nervous system, is synthesized by the action of aromatic amino acid decarboxylase on L-dihydroxyphenylalanine (L-dopa). A fluorinated analogue of L-dopa, 6-[18F]fluoro-L-dopa, is used as a tracer in positron tomography to study the nigrostriatal dopaminergic system. Although this tracer has been in use in man for over ten years, a definitive method of quantitative analysis has not yet emerged. The comparison of quantitative results obtained by this approach has been confounded by the diversity of mathematical modelling techniques employed. These techniques range from simple graphical analyses, which yield a single rate constant for the entire system, to complex compartmental approaches, which may not present a unique solution. The goal of this research has been to develop an approach to quantitative analysis which is both informative and mathematically justifiable. Compartmental models of increasing complexity have been evaluated by statistical methods (F-test) to determine the simplest model which adequately fits the data. This strict methodological approach indicates that a two-compartment, three-parameter model produces the best fit, in a statistical sense, to the measured data. This data has also been analyzed by a simple graphical method to yield an influx constant for the system. The influx constant has also been calculated, for comparison, from the results of the compartmental analysis. The two methods were found to be in excellent agreement; both responded predictably to physiological perturbations of the system. While the compartmental method yielded a more informative analysis of the system, the graphically determined influx constant was found to be less sensitive to measurement errors. It is recommended that these two methods be applied in parallel, such that the comparison of results may serve as an internal measure of the integrity of the analysis. / Thesis / Master of Science (MS)

Autism is a severe developmental disorder characterized by impairments in reciprocal social interaction and communication, coupled with repetitive stereotypic activities. Evidence from twin and family studies strongly suggest that genetic factors play a significant role in the etiology of autism. The factors involved in the development of autism are also thought to underlie related pervasive developmental disorders (PDD). The affected sib-pair method was used to screen nine autosomal candidate loci in 18 families, each of which have two or more children with autism or a related PDD. Candidate loci were selected on the basis that: (1) the locus is near genetic disorders or chromosomal abnormalities found to co-occur with autism; and/or (2) the gene encodes a protein which has been speculated to play a role in the pathophysiology of autism. Genotypes of the affected children and their parents were determined for the following microsatellite markers which are tightly linked to the candidate genes/regions: 13S118, DRD2, TH, HRAS-1, 22S343, D15S11, GABRB3, 16S291, and DBH. No significant concordance between affected siblings was observed for any of the loci tested. During the study, however, many of the families were found to be uninformative at the dopamine beta hydroxylase (DBH) microsatellite locus. A comparsion of DBH allele frequencies observed in the parents to published British values revealed a significant difference between the two groups (L2=13.16, df=5, p<0.05). Given this finding, and the knowledge that serum DBH activity is largely under the control of DNA sequences in or close to the DBH gene, serum DBH activities were measured in the parents and in an adult control group. Mean serum DBH activity was found to be significantly lower in parents with two autistic/PDD children compared to an adult control group (Student's t=-1.71, df=60, p<0.05). DBH alleles are defined by a polymorphic dinucleotide repeat and the presence or absence of a 19 bp sequence. Upon further analysis the frequency of alleles in which the 19 bp sequence is deleted was found to be significantly increased in the mothers with two autistic/PDD children, compared to both published frequencies (L2=11.99, df=1, p<0.001) and to a Canadian control group (L2=6.96, df=1, p<0.01). Subsequent investigation revealed that deletion of the 19 bp sequence is associated with lower mean serum DBH enzyme activity (nondeletion homozygotes 44.5±28.6 iu/L; heterozygotes 30.4±16.0 iu/L; and deletion homozygotes 20.5±15.3 iu/L; F=5.45, df=59, p<0.01). Based on these findings it is proposed that lowered maternal serum DBH activity provides a uterine environment which, in conjunction with genotypic susceptiblity of a fetus, results in autism or a related PDD. / Thesis / Master of Science (MS)

Cette thèse démontre que les récepteurs nucléaires Nur77 et Nor-1 ainsi que les neuropeptides dynorphine (DYN) et enképhaline (ENK) sont des facteurs déterminants de la régulation du système dopaminergique. Notre premier manuscrit démontre d’une part que Nur77 et Nor-1 sont très clairement impliqués dans la régulation de l’homéostasie du système dopaminergique et qu’ils y jouent des rôles distincts, voire opposés, dans les conditions basales et dans les réponses comportementales et biochimiques aux psychostimulants. La délétion génétique de Nur77 augmente la proportion des récepteurs D2 en haute affinité (D2high), supprime les stéréotypies et perturbe la persistance de la préférence de place induites par l’administration répétée de psychostimulants. À l’inverse, la délétion de Nor-1 diminue la proportion des récepteurs D2high, atténue les comportements moteurs en réponse à l’amphétamine et supprime la sensibilisation comportementale. La délétion de Nor-1 module également l’expression de la DYN et de l’ENK favorisant ainsi une diminution de la réponse comportementale alors que celle de Nur77 induit l’effet inverse. Ainsi, Nor-1 et Nur77 jouent des rôles opposés, la délétion de Nor-1 tempère les comportements moteurs, celle de Nur77 les exacerbe. Notre second manuscrit démontre d’autre part que la DYN et l’ENK sont toutes deux nécessaires et ont des rôles opposés dans la manifestation des comportements de base médiés par la dopamine. Par contre, dans les conditions d’une exposition répétée aux psychostimulants, la DYN et l’ENK agissent de concert en potentialisant l’exacerbation de l’activité locomotrice et sont donc toutes deux indispensables à la sensibilisation comportementale. Nos travaux révèlent également l’existence d’interactions entre les neurotransmissions enképhalinergique et dynorphinergique et donc entre les deux voies de sortie indirecte et directe des ganglions de la base. Aussi, les neuropeptides DYN et ENK sont modulés différentiellement par la délétion de Nur77 et de Nor-1 et inversement leur délétion régule de manière différente l’expression de ces facteurs de transcription. Ceci suggère l’existence d’une relation de régulation réciproque entre les récepteurs nucléaires et ces neuropeptides. Nur77 et Nor-1 sont donc des régulateurs clés de la transmission dopaminergique et des réponses comportementales aux psychostimulants et ce, principalement via la modulation des récepteurs dopaminergiques et des neuropeptides striataux. / This present study demonstrates that the nuclear receptors Nur77 and Nor-1 and the neuropeptides dynorphin (DYN) and enkephalin (ENK) are crucial in dopaminergic system regulation. On one hand, our first manuscript shows that Nur77 and Nor-1 are deeply involved in the homeostatic regulation of the dopaminergic system and play distinct, mostly opposite roles, in basal dopaminergic neurotransmission and in psychostimulants-induced behavioral and biochemical effects. In particular, Nur77 deletion exacerbates the behavioral effects of both acute and chronic amphetamine (AMPH) administrations while Nor-1 deletion has the opposite effect. In fact, Nur77 deletion favors the upregulation of the proportion of D2 receptors in high affinity state (D2high) and suppress AMPH-induced stereotyped behavior. On the contrary, Nor-1 deletion downregulates the D2high receptors proportion, attenuates locomotor activity in response to chronic AMPH administration and consequently suppresses the development of behavioral sensitization. Nor-1 deletion modulates DYN and ENK expression in a way that promotes decreased behavioral responses to psychostimulants and that is opposite to the effects of Nur77 deletion on these very same neuropeptides. Also, Nur77 deletion suppresses the persistance of cocaine-induced place preference wherese Nor-1 deletion has no effect. Thus, Nor-1 and Nur77 mostly play opposite roles, Nor-1 deletion dampens ambulatory activity whereas Nur77 deletion exacerbates it. On the other hand, our second manuscript shows that DYN and ENK are both necessary and play opposite roles in dopamine-mediated basal behaviors. However, during chronic psychostimulants exposure, DYN and ENK both contribute to the exacerbation of locomotor activity and they are consequently both essential for the expression of behavioral sensitization. Besides, our results highlight a cross-talk between ENK and DYN neurotransmissions and thus between the indirect and direct output pathways of the basal ganglia. Interestingly, we also show that the striatal DYN and ENK deletions could differentially modulate Nur77 et Nor-1 expression. This suggests that the nuclear receptors and the neuropeptides ENK and DYN share an intimate reciprocal regulation relationship. Collectively, our results strongly establish that Nur77 and Nor-1 are key regulators of the dopaminergic neurotransmission and of behavioral responses to psychostimulants and this, mostly via the modulation of dopaminergic receptors and striatal neuropeptides.

Chronic nicotine use has been linked to increased sensitivity to nondrug rewards as well as improvement in mood among individuals with depression, and these effects have been hypothesized to be mediated through alternations in striatal dopamine activity. Similarly, chronic nicotine use is hypothesized to influence the mechanisms by which healthy and depressed individuals learn about rewards in their environment. However, the specific behavioral and neural mechanisms by which nicotine influences the learning process is poorly understood. Here, we use a probabilistic learning task, functional magnetic resonance imaging and neurocomputational analyses, to show that chronic smoking is associated with higher reward sensitivity, along with lower learning rate and striatal prediction error signal. Further, we show that these effects do not differ between individuals with and without major depressive disorder (MDD). In addition, a negative correlation between reward sensitivity and striatal prediction error signal was found among smokers, consistent with the suggestion that enhanced tonic dopamine associated with increased reward sensitivity leads to an attenuation of phasic dopamine activity necessary for updating of reward value during learning. / Master of Science

La compréhension des fonctions du cerveau a toujours fasciné les scientifiques travaillant dans différents domaines de recherche et reste un sujet de recherche très vaste et complexe dont la maîtrise requière non seulement une étude approfondie des neurosciences mais aussi des outils facilitant cette étude. La conception de ces outils, tout comme le reste du matériel nécessaire aux études scientifiques, a connu de grands progrès suite aux avances technologiques des différents domaines d'ingénierie. Cependant, certaines molécules, notamment les neurotransmetteurs, qui sont impliquées dans le bon fonctionnement du cerveau et dont le dysfonctionnement est souvent associé aux pathologies neuropsychologiques restent très difficiles à discerner avec précision parmi d'autres molécules avec des propriétés physicochimiques semblables et surtout à cause de leur trop faible concentration dans les liquides physiologiques. Ce problème est encore plus en plus critique pour des applications in situ qui nécessitent une réponse rapide avec un minimum de matériel. Plusieurs méthodes de séparation et de détection moléculaire utilisées dans les autres domaines de recherche, malgré leur succès dans la détection de la plus part des neurotransmetteurs, ne conviennent pas au développement d'un outil de détection compact et réutilisable. Parmi ces méthodes, les plus représentatives sont basées sur des techniques telles que : 1. l'imagerie tomographique, la chromatographie en phase liquide à haute performance et les méthodes analytiques, qui utilisent la dérivatisation et dont la technologie actuelle ne permet pas la miniaturisation. 2. l'électrochimie, dont la sensibilité et la sélectivité sont limitées et dont surtout l'application se limite aux molécules actives aux réactions redox. 3. La colorimétrie, utilisant principalement des marqueurs non-cyclables. Pour des analyses ex situ qui ne nécessitent pas une réponse immédiate, ces techniques peuvent convenir pour réaliser la détection d'un neurotransmetteur donné. Cependant, pour comprendre le fonctionnement du système nerveux au niveau cellulaire, les recherches en neurosciences et en pathologie neuronale bénéficieraient d'un système autonome permettant de faire des mesures continues in situ. Même si ces méthodes fonctionnent au niveau cellulaire, le défi réside dans le fait elles sont difficilement miniaturisables avec les technologies actuelles. Cette thèse de doctorat comporte deux volets de recherche et ses contributions ont été présentées dans cinq conférences internationales et trois articles de journaux publiés ou soumis. L'objectif du premier volet de recherche est de développer une méthode de détection de neurotransmetteurs basée sur la détection du déplacement bathochrome de la bande plasmon de nanoparticules d'or ultrastables fonctionnalisées avec un aptamère spécifique à la molécule cible. L'objectif du deuxième volet de recherche est de concevoir un système compact basé sur la spectroscopie visible pour la détection du déplacement bathochrome de la bande plasmon des nanoparticules d'or utilisées comme biocapteurs de la molécule cible. Les deux volets ont alors pour objectifs spécifiques de : 1. Échantillonner un volume prédéterminé d'une solution inconnue, la mélanger avec un volume adéquat de nanoparticules d'or fonctionnalisées et détecter de façon autonome la concentration de dopamine dans la solution inconnue 2. Réutiliser les nanoparticules d'or ultrastables fonctionnalisées pour des utilisations futures. À ce jour, mis à part mes travaux de recherche, aucune méthode de détection de neurotransmetteurs ou autre molécule, atome ou ion n'utilise des nanoparticules d'or ou autre nano-objets plasmoniques réutilisables. La contribution majeure de ce projet, réalisé dans le premier volet de recherche, est la mise au point d'une méthode de détection moléculaire basée sur des nanoparticules d'or ultrastables et réutilisables qui ne s'agrègent pas dans conditions non supportables par d'autres types de nanoparticules d'or. Pour concrétiser l'objectif de détection de la dopamine in situ, le système optofluidique a été développé dans le deuxième volet de recherche et, en plus d'avoir une résolution spectrale comparable à un spectrophotomètre commercial, son module fluidique permet un échantillonnage automatique dans un volume 11 × 9 × 6 cm³. / Understanding the functions of the brain has always fascinated scientists working in different domains and it remains a very broad and complex subject of research requiring not only a depth study of neuroscience but also adequate tools to facilitate this study. The design of these tools, as well as the rest of the scientific equipment, has known great advances due to technological advances in the various fields of engineering. However, some molecules, such as neurotransmitters, which are involved in the adequate brain functions and whose dysfunction is often associated with neuropsychological pathologies remain very difficult to detect with precision among other molecules with similar physicochemical properties due to their very low concentration in physiological fluids. This problem is even more critical for in situ applications which require a quick response with limited equipment. Despite their success in the detection of most neurotransmitters, most molecular separation and detection methods used in other research fields, are not suitable for the development of compact and reusable detection systems. Among these methods, the most representative are based on techniques such as: 1. Tomographic imaging, high-performance liquid chromatography, and derivatization-based analytical methods that are not suitable for miniaturization with current technology. 2. Electrochemistry whose sensitivity and selectivity are limited and whose application is mainly limited to redox-active molecules. 3. Colorimetry based on non-reusable markers. For ex situ analyzes which do not require an immediate response, at least one of these techniques is suitable for the detection of a given neurotransmitter. However, to understand how the nervous system works at the cellular level, research in neuroscience and neuronal pathology may benefit from an autonomous system able to make continuous measurements in situ. Although these methods actually work at the cellular level, the challenge lies in the fact that they are difficult to miniaturize with current technologies. This project has two parts and its contributions have been presented in five international conferences and three published or submitted journal articles. The aim of the first part of the project was to develop a neurotransmitter detection method based on the measurement of the bathochromic shift of aptamer modified ultrastable gold nanoparticles' plasmon band as a response to the concentration of the target molecule. The aim of the second part is to design a compact system based on visible spectroscopy for the detection of the possible bathochromic shift of the plasmon band of the gold nanoparticles used as a probe for the target molecule. The specific objectives of this project include: 1. Sample a predetermined volume of an unknown solution, mix it with an adequate volume of functionalized gold nanoparticles and automatically detect the dopamine concentration in the unknown solution. 2. Reuse functionalized ultrastable gold nanoparticles for future uses. So far, apart from this project, there is any detection method for neurotransmitters or any other molecule, atom, or ion based on reusable gold nanoparticles or any other reusable plasmonic nano-objects. The major contribution, realized in the first part of this project, is the development of a new molecular detection method based on ultrastable and recyclable gold nanoparticles which do not aggregate under the most difficult conditions for other types of gold nanoparticles. Furthermore, to achieve the objective of detecting dopamine in situ, the optofluidic system developed in the second part of this project, not only has a spectral resolution comparable to the commercial laboratory spectrophotometer but also contain a fluidic module to allow automatic sampling and the whole system have a volume of only 11 × 9 × 6 cm³.