Le mode de vie stressant et sédentaire associé à un environnement moderne obésogène sont les principales causes des troubles alimentaires et de l’obésité induite par le régime alimentaire. La prise de nourriture hautement savoureuse, ayant une teneur élevée en sucre et en gras, active le circuit de la récompense dans le cerveau, induisant du plaisir et des émotions positives. A l’inverse, un stress aigu évoque principalement l’inconfort ou des émotions négatives, contrecarrant le comportement de recherche de plaisir. En effet, une exposition à un stress aigu entraine une réponse alimentaire anhédonique et anorexique. En revanche, le stress chronique peut induire un comportement de surconsommation, ce qui représente un processus neuroadaptatif. Plusieurs régions cérébrales sont impliquées de façon indépendante dans le traitement du stress, de la prise alimentaire ou de la récompense. Cependant, les régions qui répondent à la fois à un stress et à la récompense alimentaire sont des candidates potentielles dans la coordination de ces réponses comportementales, avec des valeurs translationnelles se rattachant aux anomalies alimentaires induites par le stress. Des études suggèrent que le septum latéral (LS) est sensible au stress et est un centre de régulation de la prise alimentaire dans le cerveau. Cependant, le rôle du LS dans la régulation de la prise alimentaire dans des conditions normales et stressantes n’est pas clair. Dans un premier temps, nous avons examiné le rôle du LS dans la consommation de sucrose chez des rats non stressés. Nous avons démontré que l’inhibition du LS par des agonistes sélectifs des récepteurs GABAA et GABAB potentialise la prise de sucrose et les paramètres de microstructure des lapements, induisant une motivation amplifiée envers la solution de sucrose chez les rats rassasiés. Ensuite, nous avons développé un modèle de surconsommation de sucrose chez le rat, et nous avons enregistré les changements dans l’activité neuronale du LS lors du passage d’une réponse anorectique induite par un stress aigu à un phénotype de surconsommation du sucrose chez des rats stressés de manière chronique. La diminution de l’expression de l’ARNm c-fos et l’augmentation de la synthèse de GABA dans le LS ont coïncidé avec l’augmentation de consommation de sucrose observée dans ce modèle. Le stress répété a augmenté la proportion de neurones inhibés par le sucrose dans le LS. De plus, l’administration de l’agoniste du récepteur GABAB restaure la diminution de consommation de sucrose induite par un stress aigu. Nous avons également étudié la réponse neuronale en temps réel de l’aire hypothalamique antérieure (AHA) qui a des connexions robustes et réciproques avec le LS et des aires hypothalamiques impliquées dans la régulation de la prise alimentaire et du stress. Dans des conditions non stressantes, la prise de sucrose a suscité des réponses inhibitrices prédominantes dans les neurones de l’AHA. Un stress aigu a augmenté le taux de décharge de ces neurones inhibés par le sucrose, amenant à une réponse anorectique envers le sucrose. Sur la base de ces résultats, nous avons conclu que le stress active, alors que la prise de sucrose inhibe, les neurones de l’AHA et du LS. Par conséquent, le LS et l’AHA sont des régions importantes impliquées dans la régulation du stress et du comportement alimentaire. Une activité neuronale aberrante dans le LS et l’AHA peut être impliquée dans les troubles alimentaires et métaboliques. / Stressful and sedentary lifestyle accompanied by modern obesogenic environment, are the leading causes of diet-induced obesity and eating disorders. Intake of highly palatable food, with its high fat and sugar content, activates the reward pathways in the brain inducing pleasure and positive emotion. Conversely, acute stress primarily evokes discomfort or negative emotions counteracting with pleasure-seeking behaviour. In fact, acute stress exposure results in anorexic and anhedonic feeding response. In contrast, chronic stress may induce over-eating behaviour that represents a neuroadaptive process. Multiple brain regions are independently implicated in stress, feeding and reward processing. However, regions co-responsive to stress and food rewards are the candidates for coordinating behavioural responses with translational values pertaining to stress-induced feeding abnormalities. Studies suggest that the lateral septum (LS) is a stress-responsive and feeding regulating center of the brain. However, the role of LS in food intake regulation in normal and stressful conditions is not clear. First, we have investigated the role of LS in sucrose intake in non-stressed rats. We have demonstrated that LS inhibition by selective GABAA and GABAB receptor agonists potentiates sucrose intake and licking microstructure parameters, resulting in amplified motivation towards sucrose solution in satiated rats. Further, we have developed a sucrose bingeing model in rats, and monitored the changes in LS neural activity during transformation from acute stress-induced anorectic response to sucrose-bingeing phenotype in chronically stressed rats. Decreased c-fos mRNA and increased GABA synthesis in LS coincided with the increased sucrose intake in this model. Repeated stress increased the proportion of sucrose-inhibited neurons in the LS. Supportively, administration of a GABAB receptor agonist rescued an acute stress-induced decrease in sucrose intake. We also investigated the real-time neuronal responses of the anterior hypothalamic area (AHA) which has robust reciprocal connections with LS and the hypothalamic stress- and food intake-regulating areas. During non-stressful condition, sucrose lick clusters evoked predominant inhibitory responses in AHA neurons. Acute stress increased the firing rate of these sucrose-inhibited neurons, leading to anorectic response towards sucrose. Based on these evidences, we conclude that stress activates, whereas sucrose intake inhibits LS and AHA neurons. Therefore, the LS and AHA are important brain regions involved in regulation of stress and feeding behaviour. The aberrant neuronal activity in the LS and AHA may be involved in metabolic and eating disorders.

The work addresses the unusual proposal feed for parabolic antenna with circular polariza-tion signal. This is a modified waveguide feed, waveguide polarizer with a septum. Contemporary RHCP and LHCP wave occurs in several applications of microwave commu-nication and measurement system. From this point of view the septum polarizer can be useful. The septum polarizer is a four-port waveguide device. The square waveguide at one end con-stitutes two ports because it can support two orthogonal modes. A stepped septum divides the square waveguide into two standard rectangular waveguides sharing a common broad-wall. The size of the septum as well as two versions of the waveguides excitation were analyzed and are described in this paper. Ansoft HFSS is software for design and simulation of feed. This software can visualize not only the specified model feed, but also the course of electromagnetic field in feed and over time.

BACKGROUND: His bundle pacing (HBP) is a relatively new treatment modality for patients experiencing issues with the cardiac conduction system. The treatment is thought to be an advantageous therapy compared with the standard treatment because it uses the native conduction pathway instead of introducing a non-physiological correction pathway which has been documented to increase the risk of heart failure. First carried out in humans in 2000 (Deshmukh, Casavant, Romanyshyn, & Anderson, 2000), HBP has been shown to be superior to right ventricular pacing and equivalent to cardiac resynchronization therapy. Because of the relative recency of the application of this technique in humans, there is a need for more studies to understand the long-term effectiveness and to guide training for new clinicians. 
OBJECTIVES: The objectives of this study were to (1) define the utility of three-dimensional mapping as a guiding tool for lead placement in HBP, (2) investigate the electroanatomical imaging of the atrioventricular (AV) septum, bundle of His, and other areas of the conduction system, (3) apply these observations to guide optimal pacing lead placement in the clinical setting, and (4) describe the correction of right and left bundle branch blocks by HBP. METHODS: Patients with pacemaker indication due to diseased conduction system were identified and recommended to undergo His bundle lead implantation. The lead was navigated into the heart by fluoroscopy and progressing the catheter through the axillary, subclavian, and cephalic veins. During the procedure, electroanatomical mapping was conducted by a quadripolar catheter to guide lead placement. His cloud, non-selective capture, and selective capture areas were marked and used to generate a 3D model layering the patient conduction system onto the physical anatomy. Pacemapping was then utilized to identify the most suitable area for disease correction.
Results: HBP mapping data were available in 24 patients. Several different responses to pacemapping were observed in the area of the AV septum including selective HBP (S-HBP), non-selective HBP (NS-HBP) (with upper, lower, and common variants), and right bundle branch (RBB) capture. Capture areas were superimposed onto the 3D model in real time and used to guide lead implantation for purposes of correcting various forms of conduction disease. The use of electroanatomical mapping (EAM) reduced the need for fluoroscopic guidance compared with the non-EAM-assisted procedure. Four common patterns were observed while mapping: (1) pattern 1, selective capture surrounded by upper and lower non-selective regions of capture; (2) pattern 2, selective capture surrounded by a common non-selective region of capture; (3) pattern 3, two separate non-selective capture areas with no selective capture; (4) pattern 4, common non-selective capture area with no selective capture. There was no correlation between capture threshold voltage and location of non-selective capture. Also, no correlation was found between capture threshold voltage and presence of common non-selective versus upper and lower non-selective capture areas. Patients with left bundle branch block (LBBB) and RBBB had similar His capture anatomy and were correctable by NS-HBP. CONCLUSIONS: HBP guided by electroanatomical mapping should be considered as a standard approach during pacemaker implantation. Because the underlying conduction anatomy is variable among patients, the use of EAM can direct lead positioning at a more physiologic location. In addition, EAM-guided implantation can reduce the need for fluoroscopy.

Doctor of Phylosophy (PhD) / Schizophrenia is a severe, chronic and disabling mental disorder with a worldwide prevalence of approximately 1 %. It is a lifelong illness characterized by psychotic symptoms which typically first appear in late adolescence/early adulthood. The symptoms of schizophrenia are usually categorized as positive (hallucinations and delusions), negative (blunted affect and poverty of speech) and cognitive (memory, attention and executive function impairments). Schizophrenia is thought to arise from an interaction between several susceptibility genes and environmental factors, one of them being the use of cannabis, the most widely used illicit drug in the world. Human population studies show that cannabis use is associated with schizophrenia, and it is now well recognised that cannabis use increases the risk of developing schizophrenia by approximately twofold. The reasons for the association between cannabis and schizophrenia remain controversial and different theories have been proposed to explain the nature of this relationship. According to the self-medication hypothesis of schizophrenia, patients with psychotic disorders use cannabis to alleviate aversive symptoms of the disorder or the side effects associated with antipsychotic medications. Other theories posit that cannabis is a component cause contributing to the development of schizophrenia. Supporting this, an increasing body of evidence shows that cannabis use increases the incidence and severity of psychotic symptoms and that cannabis use most frequently precedes the onset of schizophrenia. As a large majority of cannabis users do not develop schizophrenia, a gene-environment interaction appears necessary for the development of the disorder. That is, cannabis use may unmask latent schizophrenia in individuals that have a genetic predisposition to the disorder. Family studies provide strong evidence of a genetic contribution to the aetiology of schizophrenia. Several candidate genes are likely involved in the disorder, but this thesis will specifically focus on the neuregulin 1 (NRG1) gene. NRG1 was first proposed as a schizophrenia susceptibility gene in 2002 and linkage studies have since replicated this association in diverse populations around the world. In addition, changes in expression of Nrg1 isoforms and its receptor ErbB4 have been reported in the brain of schizophrenia patients. NRG1 polymorphism has also been associated with cognitive and behavioural differences in schizophrenia patients compared to healthy individuals. Collectively, NRG1 is now recognized as one of the most promising genes that confer an increased risk of developing schizophrenia. The creation of knockout mice lacking a specific gene offers an exciting new approach in the study of mental disorders. While several mutant mice for Nrg1 and ErbB4 receptor have been developed, this thesis focussed on mice that are heterozygous for the transmembrane domain of the Nrg1 gene (named Nrg1 HET mice). These mice exhibit a schizophrenia-like phenotype including hyperactivity that can be used as a reflection of positive symptoms of schizophrenia. Furthermore, they display impairments in social recognition memory and prepulse inhibition (PPI), a model of attentional deficits observed in schizophrenia patients. In addition, the brains of Nrg1 HET contain fewer functional NMDA receptors and more 5-HT2A receptors than wild type-like (WT) animals which is consistent with the neurotransmitters imbalance observed in schizophrenic patients. The phenotype of Nrg1 HET mice is age-dependent, another aspect that mirror the late adolescent/early adulthood onset of schizophrenia symptoms. The present thesis aimed at developing an animal model of genetic vulnerability to cannabinoid-precipitated schizophrenia by utilising Nrg1 HET mice to observe if these animals show an altered behavioural and neuronal response to cannabinoid exposure. We hypothesise that Nrg1 deficiency will alter the neurobehavioural responses of animals to cannabinoids. The experiments detailed within the first research chapter (Chapter 2) aimed at examining the behavioural effects of an acute exposure to the main psychoactive constituent of cannabis, Δ9-tetrahydrocannabinol (THC), in Nrg1 HET mice using a range of behavioural tests of locomotion, exploration, anxiety and sensorimotor gating. Relative to WT control mice, Nrg1 HET mice were more sensitive to both the locomotor suppressant action of THC, as measured in the open field test, and to the anxiogenic effects of THC in the light-dark test, although the effects in this procedure may be confounded by the drug-free hyperactive phenotype of Nrg1 HET mice. Importantly, Nrg1 HET mice expressed a greater THC-induced enhancement in PPI than WT mice. Taken together, the data presented in Chapter 2 show that a deficiency in a schizophrenia susceptibility gene Nrg1 enhanced the behavioural impact of THC. After having established a link between Nrg1 deficiency and increased sensitivity to the behavioural effects of cannabinoids in Chapter 2, Chapter 3 assessed the neuronal activity underlying the effects of an acute THC exposure on Nrg1 HET mice by using c-Fos immunohistochemistry. In the ventral part of the lateral septum (LSV), THC selectively increased c-Fos expression in Nrg1 HET mice with no corresponding effect being observed in WT mice. In addition, a non-significant trend for THC to promote a greater increase in c-Fos expression in Nrg1 HET mice than WT mice was observed in the central nucleus of the amygdala, the bed nucleus of the stria terminalis and the paraventricular nucleus of the hypothalamus. Consistent with Nrg1 HET mice exhibiting a schizophrenia-related phenotype, these mice expressed greater drug-free levels of c-Fos in the shell of the nucleus accumbens and the LSV. Interestingly, the effects of genotype on c-Fos expression, drug-free or following THC exposure, were only observed when animals experienced behavioural testing prior to perfusion. This suggests that an interaction with stress was necessary for the promotion of these effects. As the risk of developing psychosis in vulnerable individuals increases with the frequency of cannabis use, Chapter 4 assessed the effects of repeated exposure to cannabinoids on Nrg1 HET mice. As THC was not available at the time, the synthetic analogue of THC, CP 55,940, was used in this experiment. Behavioural testing showed that tolerance to CP 55,940-induced hypothermia and locomotor suppression developed more rapidly in Nrg1 HET mice compared to WT mice. On the contrary, tolerance to the anxiogenic-like effect of CP 55,940 in the light-dark test was observed in WT mice, however no such tolerance occurred to this effect in Nrg1 HET mice. Similarly, no tolerance developed to CP 55,940-induced thigmotaxis in Nrg1 HET mice as measured in the open field. For PPI, on the first day of exposure opposite effects were observed, with CP 55,940 treatment facilitating PPI in Nrg1 HET mice and decreasing it in WT mice. However, the differential effect of CP 55,940 on PPI was not maintained with repeated testing as both genotypes became tolerant to the effects of the cannabinoid on sensorimotor gating. In addition, a selective increase in Fos B/ΔFos B expression, a marker of longer-term neuronal changes, was observed in the LSV of Nrg1 HET mice following chronic CP 55,940 exposure, with no corresponding effect seen in WT mice. These results collectively demonstrate that the neuregulin system is involved in the neuroadaptive response to repeated cannabinoid exposure. One of the main schizophrenia endophenotypes observed in human studies are cognitive impairments of higher executive functions. Thus Chapter 5 aimed to develop a procedure to allow evaluation of cannabis-induced working memory deficits in mice. Few studies have investigated the effects of chronic cannabinoid exposure on memory performance and whether tolerance occurs to cannabinoidinduced memory impairment. Here we studied the effects of repeated exposure to THC on spatial memory and the expression of the immediate early gene zif268 in mice. One group of animals were not pre-treated with THC while another group was given 13 daily injections of THC prior to memory training and testing in the Morris water maze. Both groups were administered THC throughout the memory training and testing phases of the experiment. THC decreased spatial memory and reversal learning, even in animals that received the THC pre-treatment and were tolerant to the locomotor suppressant effects of the drug. Zif268 immunoreactivity was reduced in the CA3 of the hippocampus and in the prefrontal cortex only in non pre-treated animals, indicating that while tolerance to the effects of cannabinoids on neuronal activity arose, cannabinoid-promoted memory impairment in these animals persisted even after 24 days of exposure. Taken together these data demonstrate that the spatial memory impairing effects of THC are resistant to tolerance following extended administration of the drug. Such a model could be applied to Nrg1 HET mice in future studies to observe if cannabinoid-induced working memory impairments and the development of tolerance to this effect are altered relative to WT mice. In conclusion, this thesis provides the first evidence that partial deletion of the schizophrenia susceptibility gene Nrg1 modulates the neurobehavioural actions of acutely and chronically administered cannabinoids. Nrg1 HET mice appear more sensitive to the acute neurobehavioural effects of cannabinoids. Notably, acutely administered THC facilitated attentional function by increasing PPI in Nrg1 HET mice. However, with repeated cannabinoid administration this acute benefit was lost. The Nrg1 HET mice displayed a long-lasting anxiogenic profile that was resistant to tolerance. Conversely, Nrg1 HET mice developed tolerance to the locomotor suppressant and hypothermic effects of cannabinoids more rapidly than WT mice, indicating a distorted neuroadaptive response in these animals. Another major finding of this thesis is that the lateral septum appears to be an important brain region dysregulated by cannabinoids in Nrg1 HET mice. Cumulatively, this research highlights the fact that neuregulin 1 and cannabinoid systems appear to interact in the central nervous system. This may ultimately enhance our understanding of how gene-environment interactions are responsible for cannabis-induced development of schizophrenia.

Mémoire de Sage-femme : Médecine : Nantes : 2007. / Bibliogr.

The lateral septum is heavily implicated in anxiety regulation, with lesions or pharmacological inhibition of this region suppressing rats' defensive responses in various rat models of anxiety. My first objective was to explore the functional relationship between the lateral septum and its major afferent structure, the ventral hippocampus. Although these structures are extensively connected, it was not clear if they work in concert to regulate anxiety-like behaviours. This idea was tested using a pharmacological disconnection technique, whereby communication between these two structures was disabled by infusing the GABAA agonist muscimol into one side of the lateral septum and the contralateral side of the ventral hippocampus. Increases in open-arm exploration were evident when muscimol was co-infused into one side of the lateral septum and the contralateral ventral hippocampus. By contrast, open arm exploration was not altered when muscimol was co-infused into one side of the lateral septum and the ipsilateral ventral hippocampus. These results support the contention that the ventral hippocampus and the lateral septum regulate rats' open arm exploration in a serial fashion, and that this involves ipsilateral projections from the former to the latter site. My second objective was to further characterize the neuropharmacological aspects of lateral septal regulation of behavioural defence. The lateral septum contains high levels of NPY Y1 and Y2 receptor binding sites in the brain, yet little is known about their contribution in anxiety regulation at this site. Therefore, the second aim of my thesis was to characterize the contribution of NPY and its Y1 and Y2 receptor subtypes in the lateral septal regulation of anxiety in the elevated plus maze, novelty-induced suppression of feeding, and shock-probe burying tests. I determined that distinct NPY receptors differentially contribute to NPY-mediated anxiolysis in a test specific manner, with the Y1 receptor mediating NPY-induced anxiolysis in the novelty-induced suppression of feeding test, and the Y2 receptor mediating NPY13-36-induced anxiolysis in the plus-maze test. Taken together, the results from these studies reinforce the view that the regulation of anxiety involves a variety of different, yet overlapping neural processes. / Thesis (Ph.D, Neuroscience Studies) -- Queen's University, 2012-09-25 18:02:11.172

Doctor of Phylosophy (PhD) / Schizophrenia is a severe, chronic and disabling mental disorder with a worldwide prevalence of approximately 1 %. It is a lifelong illness characterized by psychotic symptoms which typically first appear in late adolescence/early adulthood. The symptoms of schizophrenia are usually categorized as positive (hallucinations and delusions), negative (blunted affect and poverty of speech) and cognitive (memory, attention and executive function impairments). Schizophrenia is thought to arise from an interaction between several susceptibility genes and environmental factors, one of them being the use of cannabis, the most widely used illicit drug in the world. Human population studies show that cannabis use is associated with schizophrenia, and it is now well recognised that cannabis use increases the risk of developing schizophrenia by approximately twofold. The reasons for the association between cannabis and schizophrenia remain controversial and different theories have been proposed to explain the nature of this relationship. According to the self-medication hypothesis of schizophrenia, patients with psychotic disorders use cannabis to alleviate aversive symptoms of the disorder or the side effects associated with antipsychotic medications. Other theories posit that cannabis is a component cause contributing to the development of schizophrenia. Supporting this, an increasing body of evidence shows that cannabis use increases the incidence and severity of psychotic symptoms and that cannabis use most frequently precedes the onset of schizophrenia. As a large majority of cannabis users do not develop schizophrenia, a gene-environment interaction appears necessary for the development of the disorder. That is, cannabis use may unmask latent schizophrenia in individuals that have a genetic predisposition to the disorder. Family studies provide strong evidence of a genetic contribution to the aetiology of schizophrenia. Several candidate genes are likely involved in the disorder, but this thesis will specifically focus on the neuregulin 1 (NRG1) gene. NRG1 was first proposed as a schizophrenia susceptibility gene in 2002 and linkage studies have since replicated this association in diverse populations around the world. In addition, changes in expression of Nrg1 isoforms and its receptor ErbB4 have been reported in the brain of schizophrenia patients. NRG1 polymorphism has also been associated with cognitive and behavioural differences in schizophrenia patients compared to healthy individuals. Collectively, NRG1 is now recognized as one of the most promising genes that confer an increased risk of developing schizophrenia. The creation of knockout mice lacking a specific gene offers an exciting new approach in the study of mental disorders. While several mutant mice for Nrg1 and ErbB4 receptor have been developed, this thesis focussed on mice that are heterozygous for the transmembrane domain of the Nrg1 gene (named Nrg1 HET mice). These mice exhibit a schizophrenia-like phenotype including hyperactivity that can be used as a reflection of positive symptoms of schizophrenia. Furthermore, they display impairments in social recognition memory and prepulse inhibition (PPI), a model of attentional deficits observed in schizophrenia patients. In addition, the brains of Nrg1 HET contain fewer functional NMDA receptors and more 5-HT2A receptors than wild type-like (WT) animals which is consistent with the neurotransmitters imbalance observed in schizophrenic patients. The phenotype of Nrg1 HET mice is age-dependent, another aspect that mirror the late adolescent/early adulthood onset of schizophrenia symptoms. The present thesis aimed at developing an animal model of genetic vulnerability to cannabinoid-precipitated schizophrenia by utilising Nrg1 HET mice to observe if these animals show an altered behavioural and neuronal response to cannabinoid exposure. We hypothesise that Nrg1 deficiency will alter the neurobehavioural responses of animals to cannabinoids. The experiments detailed within the first research chapter (Chapter 2) aimed at examining the behavioural effects of an acute exposure to the main psychoactive constituent of cannabis, Δ9-tetrahydrocannabinol (THC), in Nrg1 HET mice using a range of behavioural tests of locomotion, exploration, anxiety and sensorimotor gating. Relative to WT control mice, Nrg1 HET mice were more sensitive to both the locomotor suppressant action of THC, as measured in the open field test, and to the anxiogenic effects of THC in the light-dark test, although the effects in this procedure may be confounded by the drug-free hyperactive phenotype of Nrg1 HET mice. Importantly, Nrg1 HET mice expressed a greater THC-induced enhancement in PPI than WT mice. Taken together, the data presented in Chapter 2 show that a deficiency in a schizophrenia susceptibility gene Nrg1 enhanced the behavioural impact of THC. After having established a link between Nrg1 deficiency and increased sensitivity to the behavioural effects of cannabinoids in Chapter 2, Chapter 3 assessed the neuronal activity underlying the effects of an acute THC exposure on Nrg1 HET mice by using c-Fos immunohistochemistry. In the ventral part of the lateral septum (LSV), THC selectively increased c-Fos expression in Nrg1 HET mice with no corresponding effect being observed in WT mice. In addition, a non-significant trend for THC to promote a greater increase in c-Fos expression in Nrg1 HET mice than WT mice was observed in the central nucleus of the amygdala, the bed nucleus of the stria terminalis and the paraventricular nucleus of the hypothalamus. Consistent with Nrg1 HET mice exhibiting a schizophrenia-related phenotype, these mice expressed greater drug-free levels of c-Fos in the shell of the nucleus accumbens and the LSV. Interestingly, the effects of genotype on c-Fos expression, drug-free or following THC exposure, were only observed when animals experienced behavioural testing prior to perfusion. This suggests that an interaction with stress was necessary for the promotion of these effects. As the risk of developing psychosis in vulnerable individuals increases with the frequency of cannabis use, Chapter 4 assessed the effects of repeated exposure to cannabinoids on Nrg1 HET mice. As THC was not available at the time, the synthetic analogue of THC, CP 55,940, was used in this experiment. Behavioural testing showed that tolerance to CP 55,940-induced hypothermia and locomotor suppression developed more rapidly in Nrg1 HET mice compared to WT mice. On the contrary, tolerance to the anxiogenic-like effect of CP 55,940 in the light-dark test was observed in WT mice, however no such tolerance occurred to this effect in Nrg1 HET mice. Similarly, no tolerance developed to CP 55,940-induced thigmotaxis in Nrg1 HET mice as measured in the open field. For PPI, on the first day of exposure opposite effects were observed, with CP 55,940 treatment facilitating PPI in Nrg1 HET mice and decreasing it in WT mice. However, the differential effect of CP 55,940 on PPI was not maintained with repeated testing as both genotypes became tolerant to the effects of the cannabinoid on sensorimotor gating. In addition, a selective increase in Fos B/ΔFos B expression, a marker of longer-term neuronal changes, was observed in the LSV of Nrg1 HET mice following chronic CP 55,940 exposure, with no corresponding effect seen in WT mice. These results collectively demonstrate that the neuregulin system is involved in the neuroadaptive response to repeated cannabinoid exposure. One of the main schizophrenia endophenotypes observed in human studies are cognitive impairments of higher executive functions. Thus Chapter 5 aimed to develop a procedure to allow evaluation of cannabis-induced working memory deficits in mice. Few studies have investigated the effects of chronic cannabinoid exposure on memory performance and whether tolerance occurs to cannabinoidinduced memory impairment. Here we studied the effects of repeated exposure to THC on spatial memory and the expression of the immediate early gene zif268 in mice. One group of animals were not pre-treated with THC while another group was given 13 daily injections of THC prior to memory training and testing in the Morris water maze. Both groups were administered THC throughout the memory training and testing phases of the experiment. THC decreased spatial memory and reversal learning, even in animals that received the THC pre-treatment and were tolerant to the locomotor suppressant effects of the drug. Zif268 immunoreactivity was reduced in the CA3 of the hippocampus and in the prefrontal cortex only in non pre-treated animals, indicating that while tolerance to the effects of cannabinoids on neuronal activity arose, cannabinoid-promoted memory impairment in these animals persisted even after 24 days of exposure. Taken together these data demonstrate that the spatial memory impairing effects of THC are resistant to tolerance following extended administration of the drug. Such a model could be applied to Nrg1 HET mice in future studies to observe if cannabinoid-induced working memory impairments and the development of tolerance to this effect are altered relative to WT mice. In conclusion, this thesis provides the first evidence that partial deletion of the schizophrenia susceptibility gene Nrg1 modulates the neurobehavioural actions of acutely and chronically administered cannabinoids. Nrg1 HET mice appear more sensitive to the acute neurobehavioural effects of cannabinoids. Notably, acutely administered THC facilitated attentional function by increasing PPI in Nrg1 HET mice. However, with repeated cannabinoid administration this acute benefit was lost. The Nrg1 HET mice displayed a long-lasting anxiogenic profile that was resistant to tolerance. Conversely, Nrg1 HET mice developed tolerance to the locomotor suppressant and hypothermic effects of cannabinoids more rapidly than WT mice, indicating a distorted neuroadaptive response in these animals. Another major finding of this thesis is that the lateral septum appears to be an important brain region dysregulated by cannabinoids in Nrg1 HET mice. Cumulatively, this research highlights the fact that neuregulin 1 and cannabinoid systems appear to interact in the central nervous system. This may ultimately enhance our understanding of how gene-environment interactions are responsible for cannabis-induced development of schizophrenia.

Thesis (M.S.)--Duquesne University, 2008. / Title from document title page. Abstract included in electronic submission form. Includes bibliographical references (p. 63-76) and index.

Thesis (Ph.D.)--Duquesne University, 2009. / Title from document title page. Abstract included in electronic submission form. Includes bibliographical references (p. 123-151) and index.

L’utilisation du cannabis peut précipiter la schizophrénie, en particulier chez les individus qui présentent une vulnérabilité génétique aux désordres mentaux. Des recherches humaines et animales indiquent que la neuréguline 1 (Nrg1) est un gène de susceptibilité à la schizophrénie. L’objectif de cette thèse est d’examiner si une modification du gène Nrg1 chez des souris mutante module les effets neuronaux et comportementaux des cannabinoïdes après traitement aiguë et chronique. De plus cette thèse examine les effets d'un pré-traitement au delta9-tétrahydrocannabinol, le principal composant psychotropique du cannabis, sur un modèle de flexibilité cognitive chez la souris. / Cannabis use may precipitate schizophrenia, especially in individuals who have a genetic vulnerability to the disorder. Human and animal researches indicate that neuregulin 1 (Nrg1) is a susceptibility gene for schizophrenia. This thesis aim at investigating if partial deletion of Nrg1 in mutant mice modulate the neuronal and behavioural effects cannabinoids after acute or chronic treatment. In addition, this thesis examine the effects of a pre-treatment with delta9-tetrahydrocannabinol, the main psychoactive constituent of cannabis, in a model of cognitive flexibility in the mice.