Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.

Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2008.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2008.

Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2008.

Orientador: Elenice Aparecida de Moraes Ferrari / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-23T21:27:10Z (GMT). No. of bitstreams: 1 Sperandeo_MariaLuizaAntunes_D.pdf: 3058745 bytes, checksum: 13c43e27d3d229473548efb9ae77c620 (MD5) Previous issue date: 2013 / Resumo: O estudo do condicionamento clássico aversivo contribuiu para caracterizar as fases da formação da memória (aquisição, consolidação, reconsolidação, persistência e extinção) e os mecanismos de plasticidade neuronal subjacentes. Entre estes, a ativação de receptores glutamatérgicos NMDA, de transcrição gênica e síntese proteica parecem fundamentais. O fator neurotrófico derivado de cérebro (BDNF) e o gene de expressão imediata (IEG) zenk são ativados no hipocampo de mamíferos durante a reconsolidação e a extinção. Este estudo investigou os efeitos da inibição da síntese proteica e do bloqueio dos receptores NMDA no hipocampo de pombos na reconsolidação e extinção da memória de medo contextual. No Experimento 1, pombos foram condicionados, testados ao contexto (reativação), submetidos à infusão intra-hipocampo de salina (SAL-PR), de anisomicina (ANI-PR) ou de MK-801 (MK-PR) após o teste (pós-reativação; PR), e retestados 2 dias depois (Rt 2d). No Experimento 2, três grupos tiveram um segundo reteste, 9 dias após a infusão (Rt 9d), enquanto que outros três grupos não passaram pelo teste (sem reativação- SR). O treino (20 min) teve três pareamentos som-choque. No teste e no Rt 2d houve exposição ao contexto do condicionamento por 5 min e no reteste Rt 9d, por 30 min. Nos dois experimentos, todos os grupos apresentaram alta ocorrência de congelamento (CONG) nas sessões de treino e de teste, mas no Rt 2d os grupos ANI-PR e MK-PR mostraram uma redução significativa de CONG (p < 0,05). Os grupos SR exibiram alta ocorrência de CONG tanto no Rt 2d, quanto no início do Rt 9d (p > 0,05). No Rt 9d o grupo MK-PR não teve recuperação espontânea de CONG, sugerindo prejuízo irreversível provocado pelo MK-801 na memória de medo contextual. Os grupos, SAL-PR, SAL-SR, ANI-PR, ANI-SR e MK-SR mostraram diminuição gradual de CONG durante a sessão de Rt 9d, evidenciando a extinção. Análises com Western blotting após o Rt 9d indicaram que o conteúdo de BDNF-maduro no hipocampo dos pombos SAL-PR foi significativamente maior em comparação aos demais grupos (p < 0,05), mas não foram observadas diferenças entre os grupos para o Zenk (p > 0,05). Isso sugere a participação do BDNF hipocampal na reconsolidação e na extinção da memória de medo contextual em pombos. Assim, a inibição da síntese proteica e o bloqueio dos receptores NMDA no hipocampo de pombos, após o teste ao contexto, prejudicaram a reconsolidação da memória de medo condicionado ao contexto. Além disso, os prejuízos observados foram dependentes da reativação da memória durante o teste / Abstract: The study of classical aversive conditioning has contributed to the characterization of different phases in memory formation (acquisition, consolidation, reconsolidation, extinction and persistence) and the underlying mechanisms of neuronal plasticity. Among these, the activation of NMDA glutamate receptors, gene transcription and protein synthesis are pointed as essentials. The brain-derived neurotrophic factor (BDNF) and immediate expression gene (IEG) zenk are activated in the hippocampus of mammals during reconsolidation and extinction. This study investigated the effects of protein synthesis inhibition and blockade of NMDA receptors in the hippocampus of pigeons on reconsolidation and extinction of contextual fear memory. In Experiment 1, pigeons were conditioned, tested in the context (reactivation), received intra-hippocampus infusion of saline (SAL-PR), anisomycin (ANI-PR) or MK-801 (MK-PR) after the test (post-reactivation, PR), and had a retest two days later (Rt 2d). Experiment 2, had a retest 9 days after intra-hippocampus infusion (Rt 9d) for three PR groups, and other three groups that were not tested 24h after training served as control for reactivation (no reactivation-NR). Three tone-shock pairings were presented during training (20 min). Pigeons were exposed to the context during 5 min in the test and Rt 2d sessions and during 30 min in Rt 9d. In both experiments, the occurrence of freezing (FRZ) was high in training and testing sessions for all the groups, but ANI-PR and MK-PR pigeons showed a significant decrease in FRZ during the Rt 2d (p < 0.05). The NR groups exhibited high occurrence of FRZ both in the Rt 2d and in the beginning of Rt 9d (p > 0.05). MK-PR pigeons had no spontaneous recovery of FRZ, suggesting irreversible impairment caused by MK-801 in contextual fear memory. The groups, SAL-PR, SAL-NR, ANI-PR, ANI-NR and MK-NR showed a gradual decrease in FRZ during the Rt 9d session, evidencing extinction. Western Blotting analysis indicated that the content of mature BDNF in the hippocampus of SAL-PR group after Rt 9d session was higher than that seen for the other groups (p < 0.05), but no between-group differences for Zenk were observed (p > 0.05). This suggests the involvement of hippocampal BDNF in reconsolidation and extinction of contextual fear memory in pigeons. The present data show that inhibition of protein synthesis and blockade of NMDA receptors in the hippocampus of pigeons, after the testing session to context, impaired reconsolidation of contextual fear conditioning memory and affected the process of extinction. Furthermore, the impairments were dependent on the reactivation of fear memory during the test / Doutorado / Fisiologia / Doutor em Biologia Funcional e Molecular

Schizophrenia is a serious neuropsychiatric disease with a lifetime prevalence of 1% and it disrupts almost all mental functions. It manifests with many symptoms, which can be roughly classified into three main classes - positive, negative and cognitive dysfunctions. The psychosis, which can be often seen in schizophrenia, is a very serious problem that along with all other symptoms influences the patients' clinical status as well as quality of their life. As no direct causes or causal treatments for schizophrenia are known, scientist often focus on animal models of schizophrenia as tools for investigating mechanisms that can take a part in real disease and for seeking novel antipsychotics. This thesis aims at investigating two-week subchronic treatment with dizocilpine (MK-801), a non-competitive antagonist of NMDA receptors, in Wistar and Long-Evans rats aged 30 (PND 30) and 60 days (PND 60) at the onset of the treatment. Subsequently, long-term neurobehavioral consequences of this experimental psychosis were studied by testing rats at three behavioral tasks: the Elevated-plus maze (EPM), the Morris water maze (MWM) and active place avoidance on a rotating arena (Carousel). The Western blot method was used to determine post-mortem changes in expression of the NR1, NR2A and NR2B subunits of the...

Active allothetic avoidance task (AAPA) could be a useful tool to study cognitive deficit of schizofrenia. In this task two different reference frames are created. The subject should distinguish which oriental frame is relevant for navigation and is proper for the solution of the task. This ability is called cognitive coordination. It is proved that the process of cognitive coordination is impaired in schizophrenic individuals, which comes to light in a Stroop test. Schizophrenia-like behavior can be modelled on the rats by a non-competitive NMDA receptor antagonist dizocipline (MK-801). The aim of these thesis was to study the existence of alternative strategies and the influence of different habituation on the performance of rats within AAPA. Furthermore, we have been studying the influence of MK-801 at a dose of 0.15mg / kg on the cognitive coordination in this task. We have found that the rats are able to learn AAPA task after pre-training without distal orientation cues, using relatively efficient alternative strategies. In these alternative strategies the idiothetic navigation is applied. The performance of rats in AAPA task is influenced by different conditions during habituation. We have proved that MK-801 at this dosage has no effect on cognitive performance of the rats in AAPA task, but...

Non-competitive antagonists of NMDA receptors can induce psychomimetic effects - they can cause schizophrenia-like behavior in healthy volunteers. MK-801 is such an agent. It is often used to model schizophrenia-like behavior in experimental animals. On the other hand, non-competitive antagonists of NMDA receptors show antidepressant effects both in patients suffering from depression and in animal models. Currently, cognitive deficit is considered to be a crucial symptom of the schizophrenia. Cognitive coordination is a process distinguishing irrelevant and relevant stimuli. A disruption of this process could play a pivotal role in cognitive deficit in schizophrenia. Active Allothetic Place Avoidance task (AAPA) could be a useful tool to study this phenomenon. In this task an animal has to distinguish between two spatial (reference) frames, whereas one of them is irrelevant and the other is relevant. The aims of my diploma thesis were: to study 1) behavioral strategies of laboratory rats in AAPA task and 2) effect of MK-801 on behavioral strategies and cognitive efficiency of rats in this task. The rats demonstrated two different strategies in the AAPA task. The first strategy was an active avoidance of an aversive sector; the second one was "freezing" with minimal active movement on the arena. Application...

Schizophrenia is a severe neuropsychiatric disorder characterized by positive, negative and cognitive symptoms with poor functional outcomes, placing an enormous burden on the individual, caregivers and society. Although deficits in cognition are an integral part of the disease and the best predictor of functional outcomes, there is as yet no established treatment addressing them. Avoidance of a hidden place on a continuously rotating arena (Carousel) requires cognitive control and is a rodent model of cognitive coordination of information from dissociated spatial frames, which is impaired in acute pharmacological and neurodevelopmental model of schizophrenia. Cognitive training on the Carousel during adolescence alleviates adult cognitive deficit in a neurodevelopmental model of schizophrenia and improves neural coordination (oscilations in the beta and gamma band), which is thought to be necessary for cognition. We examined if cognitive training during adolescence eliminates the deficit in neuronal coordination observed in adult rats after acute systemic NMDA receptor antagonist MK-801 (0.15 mg/kg). During adolescence, rats were either trained in spatial avoidance on Carousel or merely handled. As adults, rats received two 5-min exploration sessions in the same (A/A) or in two distinct...