Doctor of Philosophy / The general aim of this current work was to examine spinal cord injury (SCI), and in particular to examine the pathology of injury as it relates to changes in sensory transmission. Due to the limited possibilities for experimentation in humans, a range of animal models of SCI have been developed and are reviewed here. The weight drop SCI model is the most similar to the clinical presentation of SCI in humans and has been widely used in the rat. It was selected for the series of experiments reported in this thesis. Many of the functional deficits produced by SCI result from a cascade of biochemical events set into motion by the injury. Included amongst these is the activation of the enzyme nitric oxide synthase which produces the gaseous neuromodulator, nitric oxide (NO). NO is amongst the most widely distributed and widely utilised molecule in virtually all living organisms, and it is an important signalling molecule in the nervous system. One of the major functions performed by NO appears to relate to sensory transmission, and thus alterations in sensory transmission observed as a result of SCI may involve alterations to NO synthesis. One of the principal aims of this thesis was to examine the effect of SCI on the NO producing cells of the spinal cord and to consider what any changes in NO synthesis may suggest in regards to sensation. NO producing cells were examined using NADPH diaphorase (NADPH-d) histochemistry. As the symptoms of SCI such as motor loss and changes in sensory processing are functional changes, it was also useful to examine changes in neuronal function as a result of SCI. Widespread neuronal function was examined via immunohistochemical detection of the gene product of the immediate early gene, c-fos. It is not known how extensive the biochemical changes resulting from SCI may be, thus another of the aims of the present thesis was to examine the effects of SCI on NO synthesis not only at the level of injury, but also distant to the injury. Findings of the present thesis indicated that traumatic SCI resulted in a decrease in the number of NADPH-d positive cells from the superficial dorsal horn (SDH) of the spinal cord, while the number of these cells are increased in the ventral horn. These changes were restricted to spinal segments adjacent to the injury. Fos expression was also altered by injury and was found to decrease. The most profound changes were found to occur in lamina III, although the other laminae also demonstrated similar changes. Changes in fos expression however were notably more widespread than those for NADPH-d and were not restricted to the level of the injury, occurring at all levels of the spinal cord examined. It was interpreted that alterations in NO synthesis appear to be modulated by the local injury-induced environment while fos expression may be altered by widespread changes to the global level of activity within the central nervous system. Having observed that the number of NADPH-d positive cells of the SDH is reduced following injury, it was of interest to determine whether these cells were in fact killed, or whether they were still present but with reduced NADPH-d activity. Cell counts suggested that the NADPH-d positive cells, which were likely to represent a population of inhibitory interneurons, were not killed following injury, but rather are disrupted such that their normal biochemistry is altered. Since these cells were likely to be inhibitory and were located in laminae involved in sensory transmission, the question arose how disruption of these cells may relate to the neuropathic pain observed to develop following SCI. Thus both NADPH-d and fos expression were again examined, but this time in conjunction with the sensory function of the rats. Sensory thresholds to pain-like behaviour were determined prior to and after injury using Von Frey filaments. Rats that demonstrated a decrease in sensory threshold of at least two Von Frey filament gradations (>70%) were classed as allodynic, while those with a less than a 70% decrease in threshold were classed as non-allodynic. A subpopulation of each of the groups of rats (uninjured, non-allodynic and allodynic) underwent a somatic stimulation paradigm. It was found that stimulation resulted in an increase in the number of NO producing cells but only in the allodynic group of animals. Since this group of animals by definition would perceive this stimulation as noxious, it is likely that the noxious nature of the stimulation resulted in the increased number of NO producing cells observed. This effect occurred only in segments adjacent to the injury. When fos expression was examined in the uninjured animals it was noted that somatic stimulation resulted in a decrease in fos expression, almost exclusively in lamina III. Following injury, there was no change in fos expression in lamina III observed. Instead the only change observed was an increase in fos expression in the deep dorsal horn (DDH, lamina IV and V). This occurred most profoundly in the allodynic group. These results suggested that SCI may lead to misprocessing of sensory signals such that non-noxious somatic stimuli are processed in the DDH rather than lamina III following SCI. It is proposed here that this change in laminae processing may be responsible for the perception of pain towards a non-noxious stimulus, and that the reported injury-induced loss of NO producing inhibitory interneurons in the SDH may be responsible for this alteration in sensory processing following SCI. Sensation is also processed by a number of supraspinal structures and a number of these have been implicated in the development of neuropathic pain states. The effects of SCI on neuronal activity as well as NO synthesis were examined in the periaqueductal grey region of the mid brain (PAG). SCI was shown to result in reduced neuronal activity in the PAG. This reduction in activity did not follow the somatotopy of the lateral column of the PAG (lPAG). It was suggested the reduced activity may not be solely caused by reduced spinal input as a result of SCI. Reduced neuronal activity in the PAG may indicate reduced PAG function, which includes descending modulation of spinal sensory transmission. Injury was not found to alter NADPH-d expression in the PAG. The effect of traumatic lumbar SCI on the parietal (sensorimotor) cortex of the rat was also examined, as loss of inputs following SCI have been shown to result in a profound reorganisation of the cortex. Results indicated that SCI results in a virtual cessation of neuronal activity in areas 1 and 2 of the parietal cortex, likely as a result of lost afferent drive. Theories of cortical plasticity suggest that while the primary inputs via the lumbar spinal cord may be lost following SCI, other less dominants input will remain and become more dominant. It has been proposed previously that cortical reorganisation involves a rapid reorganisation of the entire sensory system. It was interpreted that a similar process may explain the system-wide reduction in neuronal activity observed in the present series of studies.

Diss. (sammanfattning) Linköping : Linköpings universitet, 2006. / Härtill 4 uppsatser.

Thesis (Ph.D.)--Indiana University, 2009. / Title from screen (viewed on August 27, 2009). Department of Medical Neuroscience, Indiana University-Purdue University Indianapolis (IUPUI). Advisor(s): Joseph DiMicco. Includes vita. Non-Latin script record Includes bibliographical references (leaves 123-140).

Thesis (Ph. D.) -- University of Texas Southwestern Medical Center at Dallas, 2005. / Vita. Bibliography: 64-74.

L’objectif principal de cette thèse est de comprendre l’origine de la variabilité d’expression du comportement sexuel (CS). Nous avons trouvé que l’approche latérale est le CS le plus exprimé et que sa quantification peut servir comme mesure de la libido et donner une idée de la performance. Nous avons montré des effets remarquables de l’âge et de la lumière sur le CS du bélier. Nous avons également montré que les structures cérébrales impliquées dans la phase motivationnelle et consommatoire ne étaient pas les mêmes et que quel que soit le partenaire sexuel préféré, l’exposition à ce partenaire provoquait une activation des mêmes structures cérébrales ; le niveau de libido semble être déterminé par des sites spécifiques et bien précis comme l’aire préoptique, le noyau paraventriculaire et la partie médiane du Lit de la strie terminale. Le Cortex ent pourrait fonctionner comme un inhibiteur de la motivation hétérosexuelle. / The main objective of this thesis was to acquire a better understanding of the origin of the variability of the expression of sexual behavior. The nudging is most expressed sexual behavior and quantification of this behavior can be used to measure their libido and give a clue on their performance. We have discovered the remarkable effects of age et lighting of the ram's sexual behavior and that the cerebral structures involved in the motivation phase and consummatory phase are not the same and seems that, no matter which sexual partner is chosen, the fact of being exposed to this partner provokes the activation of these cerebral structures et what the expression of sexual motivation level seems to have specific and precise sites in the Preoptic Area, the Paraventricular Nucleus (PVN) and the Nucleus of the bed of the striae terminalis medial (BNSTmed). The Entorhinal cortex could function as an inhibitor of heterosexual motivation.

Made available in DSpace on 2016-06-02T19:22:11Z (GMT). No. of bitstreams: 1 5903.pdf: 2922633 bytes, checksum: dfd272eca77563615a9e3fe15f5907c9 (MD5) Previous issue date: 2014-04-10 / Universidade Federal de Minas Gerais / The Locus coeruleus (LC) has been suggested as a CO2 chemoreceptor site in mammals. Most of the studies involving the role of LC in hypercapnic ventilatory response have been performed in males. Since, ovarian steroids modulate the activity of LC neurons and females have a different respiratory response to CO2 of males, we evaluated the activity of LC noradrenergic neurons during normocapnia and hypercapnia in diestrus, ovariectomized (OVX; 0,2 mL/rat of corn oil, s.c., for 3 days) and estradiol-treated ovariectomized (OVX+E2; 10 μg/0,2 mL/rat, s.c., for 3 days) female rats and in intact, orchidectomized (ORX; 0,2 mL/rat of corn oil, s.c., for 7 days), testosterone-treated orchidectomized (ORX+T; 0,25 mg/0,2 mL/rat, s.c., for 7 days) and estradiol-treated orchidectomized (ORX+E2; 10 μg/0,2 mL/rat, s.c., for 3 days) male rats by using double-label immunohistochemistry to c-Fos/TH. Additionally, we assessed the role of noradrenergic LC neurons in OVX and OVX+E2 females on respiratory response to hypercapnia by using 6-hydroxydopamine. Hypercapnia (7% CO2) increased the double-staining (c-Fos/TH-ir) in LC neurons in all groups when compared to air exposure. In the OVX+E2 group there was attenuation in the c-Fos expression in normocapnia and hypercapnia. Hypercapnia increased ventilation in OVX and OVX+E2 groups, which resulted from increases of respiratory frequency (fR) and tidal volume (VT) in sham and 6-OHDA-lesioned groups. The hypercapnic ventilatory response was significantly decreased in 6-OHDA-lesioned rats compared with sham group (29.4% in OVX group and 28.7% in OVX+E2 group) due to a reduced VT in OVX+E2 group and in OVX group due to a decrease in VT and fR. A reduction in TH+ neurons (~61% in OVX and OVX+E2 group) was observed seven days after the microinjections of 6-OHDA in the LC. LC chemical lesion and estradiol did not affect body temperature (Tb). However, hypercapnia caused reduction in Tb of sham (OVX 10 and OVX+E2) and lesioned groups. Thus, we can conclude that noradrenergic neurons in the LC of female and male rats are activated by CO2. However, in OVX+E2 group, estradiol reduced the immunoreactivity compared to OVX group during normocapnia and hypercapnia. Additionally, LC noradrenergic neurons play role in hypercapnic ventilatory response in females but do not affect temperature regulation during normocapnic and hypercapnic conditions. / O Locus coeruleus (LC) é uma área quimiossensível ao CO2 em mamíferos. A maioria dos estudos envolvendo a participação do LC na resposta ventilatória a hipercapnia é realizada em machos. Visto que esteróides ovarianos modulam a atividade de neurônios do LC e fêmeas apresentam uma resposta respiratória ao CO2 diferente de machos, nós avaliamos a atividade dos neurônios noradrenérgicos do LC durante normocapnia e hipercapnia em ratas ciclando em diestro, ovariectomizadas (OVX; 0,2 mL/rata de óleo de milho, s.c., por 3 dias) e ovariectomizadas tratadas com estradiol (OVX+E2; 10 μg/0,2 mL/rata, s.c., por 3 dias) e em ratos intactos, orquidectomizados (ORX; 0,2 mL/rato de óleo de milho, s.c., por 7 dias), orquidectomizados tratados com testosterona (ORX+T; 0,25 mg/0,2 mL/rato, s.c., por 7 dias) e tratados com estradiol (ORX+E2; 10 μg/0,2 mL/rato, s.c., por 3 dias) usando dupla-marcação imunoistoquímica para c-Fos/TH. Adicionalmente, nós avaliamos a participação dos neurônios noradrenérgicos do LC em fêmeas OVX e OVX+E2 na resposta respiratória a hipercapnia usando a neurotoxina 6-hidroxidopamina. A hipercapnia (7% CO2) aumentou a dupla marcação (c-Fos/TH-ir) nos neurônios do LC em todos os grupos comparados a normocapnia. No grupo OVX+E2 houve uma atenuação da expressão de c-Fos no LC em normocapnia e hipercapnia. A hipercapnia causou aumento na ventilação nos grupos OVX e OVX+E2, o qual resultou do aumento da frequência respiratória (fR) e volume corrente (VT) nos grupos controle e lesados. A resposta ventilatória a hipercapnia foi significativamente atenuada no grupo lesado comparado ao grupo controle (29,4% no grupo OVX e 28,7% no grupo OVX+E2) devido à queda no VT no grupo OVX+E2 e no grupo OVX foi devido a queda no VT e na fR. Observamos uma redução de neurônios noradrenérgicos (~61% nos grupos OVX e OVX+E2) sete dias após microinjeções de 6-OHDA no LC. A lesão química do LC e o 8 estradiol não afetaram a Tc. Entretanto, a hipercapnia promoveu redução na temperatura dos grupos sham (OVX e OVX+E2) e lesado. Assim, nós podemos concluir que os neurônios noradrenérgicos do LC de fêmeas e machos são ativados por CO2. Entretanto, no grupo OVX+E2, o estradiol reduziu a imunorreatividade comparado ao grupo OVX durante normocapnia e hipercapnia. Adicionalmente, os neurônios noradrenérgicos do LC de fêmeas participam da resposta ventilatória a hipercapnia, mas não participam da regulação da temperatura durante condições normocápnicas e hipercápnicas.

Submitted by Viviane Lima da Cunha (viviane@biblioteca.ufpb.br) on 2016-01-26T13:19:09Z No. of bitstreams: 1 arquivototal.pdf: 2866873 bytes, checksum: d719d963c473f40750c279e2b5305270 (MD5) / Made available in DSpace on 2016-01-26T13:19:09Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 2866873 bytes, checksum: d719d963c473f40750c279e2b5305270 (MD5) Previous issue date: 2015-04-24 / Episodic-like memory is a subtype of declarative memory that refers recall an integration of where and when a certain event (what) happened. The hippocampus –subregions function in pattern separation process are key to mediating of episodic memory recall. Glutamatergic neurotransmission, particularly AMPA and NMDA receptors, have been characterized as essential in neuroplastic processes. Ketamine is a non-competitive NMDA antagonist available at clinical practice with effect on cognitive performance and plasticity. This study’s goal was to evaluate the acute action of ketamine on behavioral and neurochemical aspects of episodic-like memory through immediate-early gene expression (IEG), c-Fos. The experimental procedure was done at a circular arena, and consists of two training sessions and a test of five minutes each. In the first training, the animal was placed in a circular open field to explore four similar objects (A), after a 1 hour, the rats start a second sample with four other objects (B), two of those appear in different spatial locations relative for the first sample. In the test, four objects are shown, two recent-familiar (B) and two old-familiar (A), two displaced (A2, B2) and two stationary (A1 and B1). Forty-six 3-month-old male Wistar rats were separated in five groups. The home cage group (n=6; without apparatus exposure) was used to measure IEG basal expression. The other four groups, with 10 rats each, went through the behavioral test. One of them received saline 0.9% and the other two received 8 mg/kg or 15 mg/kg ketamine ip immediately after the second sample, while the control group received no treatment. All objects and spatial location in this protocol were randomized among groups. The analyses were blinded for groups and the behavioral measures were distance, speed and time of exploration in all sessions. The exploration ratio and discrimination ratio of the four objects in the test session were calculated. Wilcoxon test showed statistically significant differences between these pairs of objects in the control group: A1> A2, B2> B1 and A1> B1. The data indicate that these rats could integrate the three elements of episodic-like memory. The saline group demonstrated the same exploration pattern of control group for comparisons between A1>A2 and B2>B1, but statistical differences were not found between A1and B1. The Welch’s analysis showed a difference of c-Fos expression in all hippocampal sub-regions. The control group had the highest c-Fos expression in the dentate gyrus when compared to the other groups, suggesting the role of this sub-region for integration of episodic-like memory. The two sub-anesthetic doses of ketamine induced a deficit for this type of memory. The highest dose demonstrated a possible hypolocomotion effect, characterized by decreasing of total distance traveled and speed, compared to the other groups at the test session. In short, the deficit of episodic-like memory was characterized both as amnesic effect of ketamine and as decrease of c-Fos in the dentate gyrus of those groups, suggesting a possible role of this field in episodic-like memory formation. / A memória similar à episódica é um subtipo de memória declarativa que se refere à recordação, de forma integrada, de onde e quando um determinado evento (o quê) aconteceu. A funcionalidade das sub-regiões do hipocampo dorsal no processo de separação de padrões apresenta-se como mediadora chave da recordação episódica. A neurotransmissão glutamatérgica, em especial dos receptores AMPA e NMDA, caracteriza-se como essencial em processos neuroplásticos. A Cetamina é um dos poucos antagonistas não competitivos NMDA disponíveis na prática clínica com efeitos no desempenho cognitivo e na plasticidade. O objetivo do presente estudo foi avaliar a ação aguda da Cetamina no comportamento da memória do tipo episódica e a funcionalidade das sub-regiões hipocampais (CA1, CA3 (ab e c) e GD), através da expressão do gene imediato (IEG), c-Fos. O procedimento experimental, realizado em uma arena circular, consistiu em duas sessões de treino e uma de teste com duração de cinco minutos cada. No primeiro treino, o animal é colocado em um campo aberto circular para explorar quatro objetos iguais (A), após o intervalo de 1 hora, o rato inicia o segundo treino com outros quatro objetos (B), destes dois aparecem em disposições espaciais não alocadas na primeira sessão. Na etapa do teste são apresentados quatro objetos, sendo dois recentes (B) e dois antigos (A), dois deslocados (A2 e B2) e dois estacionários (A1 e B1). Neste estudo, 46 ratos Wistar machos adultos foram divididos em cinco grupos. O grupo home cage foi escolhido como controle para a avaliação basal dos IEGs nas sub-regiões do hipocampo dorsal. Quatro grupos, contendo 10 animais cada, realizaram o procedimento comportamental, sendo um grupo controle e três grupos que passaram por intervenção farmacológica: um grupo que recebeu Salina 0.9% (i.p.) e os outros dois receberam a Cetamina (i.p.), nas doses de 8mg/kg e 15 mg/kg, imediatamente após o segundo treino. As análises do estudo foram duplo-cego e os objetos e suas localizações espaciais foram randomizadas entre os grupos. As medidas comportamentais utilizadas foram a “distância total percorrida”, a “velocidade” e o “tempo de exploração” para todas as sessões. Na sessão de teste também foram calculadas a “taxa de exploração” e a “taxa de discriminação” dos objetos. No teste de Wilcoxon o grupo controle apresentou o desempenho padrão estatisticamente significativo: A1>A2, B2>B1 e A1>B1. Integrando os três elementos da memória episódica, seguido pelo grupo salina que apresentou o mesmo perfil de exploração entre os objetos antigos e recentes, A1>A2, B2>B1. A análise do Welch mostrou diferenças neuroquímicas em todas as sub-regiões do hipocampo, destacando um aumento de c-Fos no giro denteado (GD) dos animais controles quando comparado aos outros grupos, sugerindo o papel desta sub-região para a integração da memória tipo episódica. As duas doses sub-anestésicas da Cetamina induziram um déficit para este tipo de memória. A dose mais elevada demonstrou um possível efeito hipolocomotor, caracterizado pela redução na distância total percorrida e na velocidade, em comparação com os outros grupos, na sessão de teste. Em suma, o déficit de memória tipo episódica foi caracterizado tanto pelo efeito amnésico de Cetamina quanto pela redução de c-Fos no GD desses grupos, sugerindo um possível papel deste campo na formação desse tipo de memória.

Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2016-04-25T23:08:58Z No. of bitstreams: 1 KarenCrisantoDeOliveira_DISSERT.pdf: 1361957 bytes, checksum: b209b79db41ee94dbb8c96a8da57599b (MD5) / Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2016-04-27T23:45:33Z (GMT) No. of bitstreams: 1 KarenCrisantoDeOliveira_DISSERT.pdf: 1361957 bytes, checksum: b209b79db41ee94dbb8c96a8da57599b (MD5) / Made available in DSpace on 2016-04-27T23:45:33Z (GMT). No. of bitstreams: 1 KarenCrisantoDeOliveira_DISSERT.pdf: 1361957 bytes, checksum: b209b79db41ee94dbb8c96a8da57599b (MD5) Previous issue date: 2015-05-08 / Estudos com tra?ador neuronal em rato tem demonstrado que os n?cleos anterior do hipot?lamo, divis?o dorsomedial do n?cleo ventromedial do hipot?lamo e pr?-mamilar dorsal s?o altamente conectados. Quando o rato ? exposto ao predador ou seu odor estes n?cleos apresentam alta express?o de Fos e a les?o deles reduz o comportamento defensivo contra predador. A este conjunto de n?cleos foi dado o nome de Sistema Hipotal?mico de Defesa. No entanto, pouco se sabe sobre a resposta deste sistema ao odor de diferentes predadores ou seu papel em camundongos. Neste trabalho, expusemos camundongos Swiss aos odores de dois predadores (gato e cobra) para verificar a express?o de Fos no Sistema Hipotal?mico de Defesa, assim como os comportamentos defensivos exibidos. A an?lise mostrou que a exposi??o do camundongo ao odor de gato provocou um aumento na express?o da prote?na Fos comparado ao controle, enquanto que o odor de cobra n?o teve o mesmo efeito, o que foi corroborado pelos dados comportamentais. Nossos resultados indicam que esse distinto circuito em camundongo parece agir diferencialmente aos est?mulos odor?feros de diferentes predadores, provocando rea??es comportamentais distintas, sendo que o odor de cobra parece n?o ser percebido como um est?mulo amea?ador pelos camundongos Swiss. / Studies using neuronal tract-tracer in rat have shown that the anterior hypothalamic nucleus, dorsomedial division of the ventromedial nucleus of the hypothalamus and dorsal premammillary nucleus are highly connected. When the rat is exposed to predator or its odor these nuclei have shown a expression of Fos and their lesion reduces defensive behavior against predator. This set of nuclei was named the Hypothalamic Defense System. However, little is known about the response of this system to the odor of different predators or its role in mice. In this work, we exposed Swiss mice to two different predators odor (cat and snake) to verify the Fos expression in the Hypothalamic Defense System, as well as the defensive behaviors displayed. The analysis showed that the mice exposure to cat odor had an increased expression of Fos protein compared to control, while those exposed to snake odor showed no rise in Fos expression, which was corroborated by the behavioral data. Our results indicate that this distinct circuit in mice seems to act differentially to odorous stimuli of different predators, causing distinct behavioral responses of mice and that the odor of snake seems not to be perceived by Swiss mice as a threatening stimulus.

Esta dissertação de mestrado tem por objetivo apresentar, analisar e discutir a experiência de ensino de Francês Língua Estrangeira para estudantes da Escola Politécnica da USP, por meio do Programa CFI (Curso de Francês para Iniciantes). Tal formação, iniciada em 2001, foi concebida pelo Centro de Línguas da Faculdade de Filosofia, Letras e Ciências Humanas da Universidade de São Paulo a pedido da Comissão de Relações Internacionais da Escola Politécnica, e tinha por finalidade preparar os alunos que fossem fazer dois anos de curso em faculdades de engenharia francesas (Ecoles Polytechniques, Ecoles Centrales, Ponts et Chaussés, etc), no âmbito do Programa Duplo Diploma em Engenharia promovida pela Poli-USP. Nosso estudo corresponde ao período em que se decidiu discutir a progressão e o equilíbrio entre as duas modalidades de ensino trabalhadas - o Francês, Língua Estrangeira (FLE) geral e o Francês com Objetivos Específicos (FOS) - na formação dos estudantes, que passara de 2 para 3 anos, incluindo um módulo específico (Módulo France) e cujo número de inscritos havia chegado a quinhentos por semestre letivo. Nesse período, coube à equipe pedagógica a concepção geral do curso e a preparação do material didático de cada um dos seis módulos de ensino oferecidos, o que trouxe resultados bastante positivos, como mostram os questionários respondidos por alunos do Duplo Diploma que participaram de tal formação. / The objective of this undergraduate thesis is to present, analyze and discuss the experience of teaching French as a foreign language for students at the Polytechnic School at University of São Paulo through the FCB Program (French Course for Beginners). This course, started in 2001, was designed by the Language Center at the College of Philosophy, Languages and Human Sciences of the University of São Paulo by request of the International Relations Commission of the Polytechnic School to prepare students who had been selected for the Dual Diploma Program in Engineering sponsored by Poli-USP, that is, a program in which students would spend two years of their undergraduate program at a French College of Engineering (Ecoles Polytechniques, Ecoles Centrales, Ponts et Chaussés, etc). Our study corresponds to the period in which we decided to reevaluate the progress and the balance between the two approaches used during the course general French as a Foreign Language (FFL) and French with Specific Objectives (FSO) a course which had increased from 2 to 3 years and which included a specific module (France module) and whose number of enrolled participants had reached 500 per semester. During this period, the pedagogical team (coordinators and teachers) were responsible for the general conception of the new course and for the textbooks of each one of the 6 teaching modules offered. The results obtained were extremely satisfactory as shown in the questionnaires answered by the Dual Diploma students who took this course.

The brain and spinal cord make up the central nervous system (CNS), and as an immune-privileged site, it requires special immune surveillance and regulation. The complement system is a component of innate immunity produced locally in the CNS, since size restrictions from the blood brain barrier prevent complement proteins from easily passing through from the rest of the body. The complement pathway contributes to inflammatory cell recruitment, cell lysis, and opsonization, and thus requires regulation to avoid inappropriate activation. Despite its important role in innate immunity, very little is known about complement production, regulation, and function in the CNS of healthy or diseased individuals. For this dissertation, the central goal was to investigate and characterize the regulation of complement factor H (CFH), a regulator of the alternative pathway of complement activation. CFH polymorphisms have been associated with a number of diseases including atypical hemolytic syndrome, age-related macular degeneration, and Alzheimer's disease, but the regulation of CFH is not well understood, especially in the CNS. To investigate the role of CFH in the CNS, mRNA and protein production in glial cells was first established. The murine CFH (mCFH) promoter was cloned and the transcription start site was identified in astrocytes, microglia, and liver tissue. The mCFH promoter was truncated and different regions were investigated for enhancer or silencer activity. Database mining identified potential transcription factor binding sites, and mutagenesis studies and binding assays identified transcription factor binding candidates. Specifically, the activating protein-1 (AP-1) transcription factors c-Jun and c-Fos bound to a region of the mCFH promoter between – 416 base pairs (bp) and – 175 bp in an electrophoretic mobility supershift assay. Cytokine stimulation increased mCFH mRNA and protein production, as well as the mRNA production of c-Jun and c-Fos and the protein production of c-Jun. These results suggest a relationship between cell cycle and complement regulation, and the investigation of how these transcription factors and CFH affect disease will be a valuable area of research for CNS immune regulation.