As diferentes demandas ecológicas impostas pela vida epígea e hipógea podem favorecer a melhoria das funções cognitivas espaciais. Comparamos a aprendizagem e a memória espacial, em labirinto complexo do Trinomys iheringi denigratus (terrestre de Mata Atlântica), T.yonenagae (semi-fossorial das Dunas na Caatinga) e Clyomys bishopi (fossorial do Cerrado). O aprendizado e memória espacial foram avaliados 10 T.i.denigratus (250±34g), 18 T.yonenagae (125±7,8g) e seis Clyomys bishopi (338±34g), a partir do: tempo até a saída do labirinto (TFL) e o número de erros cometidos (NER), em indivíduos colocados em labirinto de seis caminhos cegos e uma saída (0,20x1,10x1,50m), durante cinco testes consecutivos (30min) por dia, durante três dias consecutivos (fase de aprendizagem). Os ratos foram novamente testados em única sessão realizada após 48, 120 e 504h (fase de memória). O desempenho foi testado ao longo dos testes utilizando uma ANOVA um-fator (p<0,05). As taxas de aprendizagem (TA) do TFL das duas espécies foram mensuradas a partir do b da equação da curva de aprendizagem, e comparadas usando-se ANOVA um-fator (p<0,05). As variáveis do último teste de cada dia com os do primeiro teste do dia seguinte foram usadas como indicativas de memória-de-médio-prazo (MMP) e comparadas por espécie (teste T, dados-pareados, p<0,05). As taxas de retenção da aprendizagem (TR) com relação aos intervalos dos testes de memória, foram usadas como índice de memória-de-longo-prazo (MLP) e foram comparadas pela ANOVA um-fator (p<0,05). As espécies não apresentaram diferença significativa entre si mas não entre os testes tanto para TFL (F=0,85; p = 0,705; F=8,86; P < 0,000) quanto para NER (F=0,56; p=0,979; F = 3,65; p = 0,000). A TA foi marginalmente significativa (F = 2,784; p = 0,077) entre as espécies, sendo que T. yonenagae e C. bishopi não apresentaram diferença entre eles e ambos diferiram do T. i. denigratus. Com relação à memória-de-médio-prazo, T. Yonenagae e T. i. denigratus apresentaram diferença significativa para TFL entre os testes 10-11 (t = -3,406; p = 0,003) (t=- 2,300; p=0,050), mas não entre os testes 5-6 (t=-0,779; p=0,447) (t = -1,061; p=0,320). Já o C.bishopi sofreu redução entre os testes 5-6 e os testes 10-11, mas sem diferença significativa. Para a variável NER, não foi detectada diferença significativa, tanto para T. yonenagae (entre os 5 testes 5 e 6: t = 314,000, P = 0,558; testes 10 e 11: t=325,000, P=0,812) quanto para T.i.denigratus (entre os testes 5-6, t=0,590, P=0,562; testes 10-11: t=-1,855 P=0,080), por outro lado, C. bishopi apresentou a tendência de redução dos valores de NER entre os testes 5-6 (t = 0,442; p = 0,676) e 10-11 (t = 3,558; p = 0,016) sendo esta significativa. Quanto à MLP, dentre cada espécie não houve diferença significativa. Assim o semi-fossorial T.yonenagae e o fossorial C.bishopi se destacam quanto a aprendizagem do que a terrestre T.idenigratus, entretanto apenas C.bishopi é mais eficiente com relação a memoria-de-médio-prazo. Caso o efeito da filogenia seja controlada, sugere-se que o hábito fossorial seja componente do regime seletivo para evolução da cognição espacial / The different ecological contests imposed by epigeal and hypogeal lifestyles can facilitate the improvement of cognition spatial. We compared the spatial learning and memory in complex maze of Trinomys iheringi denigratus (terrestrial Atlantic rainforest), T.yonenagae (semifossorial Dunes of Caatinga) and Clyomys bishopi (fossorial of Cerrado). The spatial learning and memory were assessed 10 T.i.denigratus (250 ± 34g), 18 T.yonenagae (125 ± 7.8 g) and six Clyomys bishopi (338 ± 34g), from: time to exit the maze (TFL) and the number of errors (NER) in individuals placed on the complex maze of paths six blind and an outlet (0,20 x1, 10x1, 50m) for five consecutive tests (30min) per day for three consecutive days (learning phase) . The rats were tested in one session held after 48, 120 and 504Hours (memory phase). The performance was analyzed over the tests using a one-way ANOVA (p <0.05). Learning rates (TA) of the TFL of both species were measured from the b of the equation of the learning curve, and compared using one-way ANOVA (p <.05). The variables for each of the last test day with the first test the following day were used as indicators of memory to medium-term (MMP) and compared by species (t-test, paired-data, p <0.05) . Retention rates of learning (TR) with respect to the intervals of memory tests, were used as an index of memory-to-long-term (MLP) and were compared by one-way ANOVA (p <0.05). The species did not differ significantly from each other but not between tests for both TFL (F = 0.85, p = 0.705 F = 8.86, P <0.000) and for NER (F = 0.56, p = 0.979 , F = 3.65, p = 0.000). The TA was marginally significant (F = 2.784, p = 0.077) between species, and T. yonenagae and C. bishopi showed no difference between them and both were different from T. i. denigratus. With respect to memory-to-medium term, T. yonenagae and T. i. denigratus showed significant difference between the tests 11 and 10 for TFL (t = -3.406, p = 0.003) (t = -2.300, p = 0.050), but not between tests 5 and 6 (t = -0.779, p = 0.447 ) (t = -1.061, p = 0.320). Already C.bishopi showed decreased between tests 5-6 and tests 10-11, but without significant difference. For variable NER, no significant differences were detected for both T. yonenagae (between tests 5 and 6: t = 314.000, P = 0.558, Tests 10 and 11: t = 325,000 P = 0.812) and for T.i.denigratus (between tests 5.6, t = 0.590, P = 0.562; Tests 10-11: 7 t = -1.855 p = 0.080), on the other hand C. bishopi showed a trend to decreased NER between tests 5-6 (t = 0.442, p = 0.676) and 10-11 (t = 3.558, p = 0.016) which is significant. As for MLP, among each species there was no significant difference. Thus the semi-fossorial T.yonenagae and fossorial C.bishopi stand out as the learning of the terrestrial T.i.denigratus, however only C.bishopi is more efficient with respect to memory-to-medium term, if the effect of phylogeny is controlled, we suggested that the fossoriality could comprising the part of selective regime for evolution of the spatial cognition

As diferentes demandas ecológicas impostas pela vida epígea e hipógea podem favorecer a melhoria das funções cognitivas espaciais. Comparamos a aprendizagem e a memória espacial, em labirinto complexo do Trinomys iheringi denigratus (terrestre de Mata Atlântica), T.yonenagae (semi-fossorial das Dunas na Caatinga) e Clyomys bishopi (fossorial do Cerrado). O aprendizado e memória espacial foram avaliados 10 T.i.denigratus (250±34g), 18 T.yonenagae (125±7,8g) e seis Clyomys bishopi (338±34g), a partir do: tempo até a saída do labirinto (TFL) e o número de erros cometidos (NER), em indivíduos colocados em labirinto de seis caminhos cegos e uma saída (0,20x1,10x1,50m), durante cinco testes consecutivos (30min) por dia, durante três dias consecutivos (fase de aprendizagem). Os ratos foram novamente testados em única sessão realizada após 48, 120 e 504h (fase de memória). O desempenho foi testado ao longo dos testes utilizando uma ANOVA um-fator (p<0,05). As taxas de aprendizagem (TA) do TFL das duas espécies foram mensuradas a partir do b da equação da curva de aprendizagem, e comparadas usando-se ANOVA um-fator (p<0,05). As variáveis do último teste de cada dia com os do primeiro teste do dia seguinte foram usadas como indicativas de memória-de-médio-prazo (MMP) e comparadas por espécie (teste T, dados-pareados, p<0,05). As taxas de retenção da aprendizagem (TR) com relação aos intervalos dos testes de memória, foram usadas como índice de memória-de-longo-prazo (MLP) e foram comparadas pela ANOVA um-fator (p<0,05). As espécies não apresentaram diferença significativa entre si mas não entre os testes tanto para TFL (F=0,85; p = 0,705; F=8,86; P < 0,000) quanto para NER (F=0,56; p=0,979; F = 3,65; p = 0,000). A TA foi marginalmente significativa (F = 2,784; p = 0,077) entre as espécies, sendo que T. yonenagae e C. bishopi não apresentaram diferença entre eles e ambos diferiram do T. i. denigratus. Com relação à memória-de-médio-prazo, T. Yonenagae e T. i. denigratus apresentaram diferença significativa para TFL entre os testes 10-11 (t = -3,406; p = 0,003) (t=- 2,300; p=0,050), mas não entre os testes 5-6 (t=-0,779; p=0,447) (t = -1,061; p=0,320). Já o C.bishopi sofreu redução entre os testes 5-6 e os testes 10-11, mas sem diferença significativa. Para a variável NER, não foi detectada diferença significativa, tanto para T. yonenagae (entre os 5 testes 5 e 6: t = 314,000, P = 0,558; testes 10 e 11: t=325,000, P=0,812) quanto para T.i.denigratus (entre os testes 5-6, t=0,590, P=0,562; testes 10-11: t=-1,855 P=0,080), por outro lado, C. bishopi apresentou a tendência de redução dos valores de NER entre os testes 5-6 (t = 0,442; p = 0,676) e 10-11 (t = 3,558; p = 0,016) sendo esta significativa. Quanto à MLP, dentre cada espécie não houve diferença significativa. Assim o semi-fossorial T.yonenagae e o fossorial C.bishopi se destacam quanto a aprendizagem do que a terrestre T.idenigratus, entretanto apenas C.bishopi é mais eficiente com relação a memoria-de-médio-prazo. Caso o efeito da filogenia seja controlada, sugere-se que o hábito fossorial seja componente do regime seletivo para evolução da cognição espacial / The different ecological contests imposed by epigeal and hypogeal lifestyles can facilitate the improvement of cognition spatial. We compared the spatial learning and memory in complex maze of Trinomys iheringi denigratus (terrestrial Atlantic rainforest), T.yonenagae (semifossorial Dunes of Caatinga) and Clyomys bishopi (fossorial of Cerrado). The spatial learning and memory were assessed 10 T.i.denigratus (250 ± 34g), 18 T.yonenagae (125 ± 7.8 g) and six Clyomys bishopi (338 ± 34g), from: time to exit the maze (TFL) and the number of errors (NER) in individuals placed on the complex maze of paths six blind and an outlet (0,20 x1, 10x1, 50m) for five consecutive tests (30min) per day for three consecutive days (learning phase) . The rats were tested in one session held after 48, 120 and 504Hours (memory phase). The performance was analyzed over the tests using a one-way ANOVA (p <0.05). Learning rates (TA) of the TFL of both species were measured from the b of the equation of the learning curve, and compared using one-way ANOVA (p <.05). The variables for each of the last test day with the first test the following day were used as indicators of memory to medium-term (MMP) and compared by species (t-test, paired-data, p <0.05) . Retention rates of learning (TR) with respect to the intervals of memory tests, were used as an index of memory-to-long-term (MLP) and were compared by one-way ANOVA (p <0.05). The species did not differ significantly from each other but not between tests for both TFL (F = 0.85, p = 0.705 F = 8.86, P <0.000) and for NER (F = 0.56, p = 0.979 , F = 3.65, p = 0.000). The TA was marginally significant (F = 2.784, p = 0.077) between species, and T. yonenagae and C. bishopi showed no difference between them and both were different from T. i. denigratus. With respect to memory-to-medium term, T. yonenagae and T. i. denigratus showed significant difference between the tests 11 and 10 for TFL (t = -3.406, p = 0.003) (t = -2.300, p = 0.050), but not between tests 5 and 6 (t = -0.779, p = 0.447 ) (t = -1.061, p = 0.320). Already C.bishopi showed decreased between tests 5-6 and tests 10-11, but without significant difference. For variable NER, no significant differences were detected for both T. yonenagae (between tests 5 and 6: t = 314.000, P = 0.558, Tests 10 and 11: t = 325,000 P = 0.812) and for T.i.denigratus (between tests 5.6, t = 0.590, P = 0.562; Tests 10-11: 7 t = -1.855 p = 0.080), on the other hand C. bishopi showed a trend to decreased NER between tests 5-6 (t = 0.442, p = 0.676) and 10-11 (t = 3.558, p = 0.016) which is significant. As for MLP, among each species there was no significant difference. Thus the semi-fossorial T.yonenagae and fossorial C.bishopi stand out as the learning of the terrestrial T.i.denigratus, however only C.bishopi is more efficient with respect to memory-to-medium term, if the effect of phylogeny is controlled, we suggested that the fossoriality could comprising the part of selective regime for evolution of the spatial cognition

Despite very extensive studies related to molecular processes underlying memory formation, still little known about the potential differences in the brain biochemistry between &ldquo / good&rdquo / and &ldquo / poor&rdquo / learners belonging to a random population of young animals. In the present study, an attempt was taken to correlate the individual variation in short- and long-term spatial memory in three different lines of young, healthy rats: inbred Wistar (W), outcrossed Wistar/Spraque Dawley (W/S) and pigmented Long-Evans rats, with hippocampal levels of selected enzymes known as &ldquo / memory molecules&rdquo / including neuronal (n), endothelial (e) and inducible (i) NOS, CaMKII&alpha / , PKA and ChAT. Additionally, in order to indirectly estimate the activity of CaMKII&alpha / and PKA, hippocampal levels of their phosphorylated forms (pCaMKII&alpha / and pPKA) were assessed. Rats were classified as &ldquo / good&rdquo / and &ldquo / poor&rdquo / learners on the basis of their performance in a partially baited 12-arm radial maze. The hippocampal protein levels were measured using Western Blot technique. In addition to individual variation in animals&rsquo / learning capacity, strain-depended differences have also been observed. Deficient performance recorded in inbred W rats compared to outcrossed W/S rats, and &ldquo / poor&rdquo / learners from both rat groups had predominantly related to the higher frequency of reference memory errors. The results of biochemical assays showed strain-depended differences in the NOS expression. The overall NOS levels were significantly higher in outcrossed W/S rats compared to inbred W rats. In both rat lines, the rate of learning positively correlated with hippocampal levels of nNOS and negatively correlated with iNOS levels. Hippocampal eNOS levels correlated negatively with animals&rsquo / performance but only in the W rats. These results suggested that all 3 NOS isoforms are implemented in the learning process playing, however, different roles in neural signaling. Experiments carried out on Long-Evans rats did not reveal a significant difference in the basal hippocampal levels of the CaMKII&alpha / , however, the level of the pCaMKII&alpha / , was significantly higher in &ldquo / good&rdquo / learners. Also, hippocampal levels of both PKA and pPKA, as well as that of ChAT were significantly higher in &ldquo / good&rdquo / as compared to &ldquo / poor&rdquo / learners. Taken together, the latter findings indicate that low hippocampal expression of PKA and ChAT as well as low CaMKII&alpha / or PKA activation may cause learning deficits in random population of young rats, and thus, these enzymes can be considered target molecules when looking for cognitive enhancers to treat memory deficits in young subjects.

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

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

Thesis (Ph. D.)--Miami University, Dept. of Psychology, 2008. / Title from second page of PDF document. Includes bibliographical references (p. 60-67).

Thesis (M.A.)--Miami University, Dept. of Psychology, 2006. / Title from first page of PDF document. Includes bibliographical references (p. 18-22).

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Glutaric acidemia type I (GA-I) is an inborn error of metabolism (EIM), characterized biochemically by major accumulation of glutaric acid (GA) and pathologically by a characteristic striatal degeneration. The clinical manifestations are mainly neurological and develop during childhood (up to 5 years old). Among these changes, there are the seizures and cognitive deficits, which may be precipitated by infectious processes. From this, the first hypothesis to be tested in this study was to investigate whether lipopolysaccharide E. coli 055 B5 serotype (LPS; 2 mg/Kg; i.p.), an inflammatory agent, could facilitate seizures induced by GA in young rats (21 days of life). For this, firstly it was determined the acute dose of intrastriatal GA (1.3 μmol/striatum) that cause behavioral and electroencephalographic (EEG) seizures in young rats. Moreover, it was shown that LPS administration 3 hours before GA intrastriatal injection did not change the seizures, but when LPS was administered 6 hours before the GA, it reduced the latency and increased the duration of behavioral and EEG seizures induced by GA in young rats. It also was observed that LPS injection caused an initial drop in rectal temperature of young rats (up to 2 hours), followed by a rise in temperature that started at 3 hours and remained high until 6 hours after LPS injection. Furthermore, it was shown that LPS injection 3 and 6 hours before intrastriatal injection of GA caused an increase in striatal levels of IL-1β in young rats, and this increase was statistically higher in 6 than in 3 hours. In addition, it was observed that the increase in IL-1β striatal levels, caused by LPS administration, positively correlated with total time of seizures. Finally, it was observed that previous use of IL-1β antibody prevented the latency reduction and the increased duration of seizures caused by LPS administration 6 h before intrastriatal injection of GA in young rats. Thus, these findings suggest that the signaling of IL-1β present in inflammation produced by LPS contributes significantly to neuronal hyperexcitability, and thus to reduce latency and increase the duration of seizures induced by GA. Therefore, pharmacological treatments that block the specific functions or overproduction of IL-1β in GA-I, may represent an unconventional strategy to treat this condition. However, clinical studies should be conducted to evaluate the effectiveness of treatment in glutaricoacidemic patients with convulsions. Since patients with GA-I have other important neurological changes addition to the seizures, as cognitive impairments, the second hypothesis to be tested in this study was to determine whether chronic treatment with GA (5 μmol/g; s.c.; twice per day; from the 5th to the 28th day of life) could cause spatial memory impairment in young rats, and verify whether the inflammation produced by LPS (2 mg/Kg; i.p.; one per day; from the 25th to the 28th day of life) could facilitate the cognitive deficit induced by GA. In addition, it also was evaluated the possible impact of these treatments on functional and structural changes in the hippocampus of these animals. Initially it was shown that chronic treatment with GA, as well as the treatments with LPS and GA-LPS, caused a deficit in spatial learning of young rats. However, it was demonstrated that the treatment with GA-LPS produced a greater impairment in spatial memory compared to other treatments. In addition, it was observed that none of the treatments affected weight or locomotor activity/exploratory of animals. It also was shown that chronic treatment with GA, as well as treatments with LPS and GA-LPS, increased the hippocampal levels of IL-1β and TNF-α in young rats. Furthermore, it was demonstrated that treatments with GA, LPS and GA-LPS caused a reduction in total hippocampal volume of young rats. Finally it was observed that treatments with GA, LPS and GA-LPS caused a reduction of α1 subunit activity of Na+,K+-ATPase enzyme. On the other hand, it was shown that treatments with GA and LPS caused an increase in activity of α2/3 subunits of the enzyme. Thus, only treatment with GA-LPS showed a reduction in total activity of Na+,K+-ATPase in the hippocampus of young rats. These data indicate that the impairment in spatial learning observed in rats treated with GA, LPS and GA-LPS was due to increased levels of inflammatory cytokines, the reduction in hippocampal volume and the inhibition of α1 subunit activity of Na+,K+-ATPase enzyme. However, the worsening in spatial memory observed in rats treated with GA-LPS was due to inhibition of total activity of Na+,K+-ATPase, which was specific α2/3 isoforms, since only this group showed no compensatory response the activity of these subunits. Therefore, this second part of the study showed that chronic treatment with GA caused a deficit in spatial learning in young rats, and that the presence of an inflammatory process increased the impairment in spatial memory induced by GA alone. Thus, understanding the mechanisms involved in seizures and cognitive deficits observed in patients with GA-I in the presence of an inflammatory process is important for the development of new therapies to treat this condition, as well as other diseases associated with the presence of inflammatory mediators. / A acidemia glutárica tipo I (GA-I) é um erro inato do metabolismo (EIM) caracterizada bioquimicamente pelo acúmulo principal de ácido glutárico (GA) e patologicamente por uma característica degeneração estriatal. As manifestações clínicas são predominantemente neurológicas, e desenvolvem-se principalmente na infância (até os 5 anos de idade). Entre estas alterações, destacam-se as convulsões e os déficits cognitivos, os quais podem ser precipitados por processos infecciosos. A partir disso, a primeira hipótese a ser testada neste estudo foi investigar se o lipopolissacarídeo sorotipo E. coli 055 B5 (LPS; 2 mg/Kg; i.p.), um agente inflamatório, facilitaria as convulsões induzidas pelo GA em ratos jovens. Para isso, primeiramente determinou-se a dose intraestriatal aguda de GA (1.3 μmol/estriado) que causa convulsões comportamentais e eletroencefalográficas (EEG) em ratos jovens (21 dias). Em seguida foi verificado que a administração de LPS 3 horas antes da injeção intraestriatal de GA não alterou as convulsões, mas quando o LPS foi administrado 6 horas antes do GA, ele reduziu a latência e aumentou a duração das convulsões comportamentais e EEG induzidas pelo GA em ratos jovens. Observou-se também que injeção de LPS causou uma queda inicial na temperatura retal dos ratos jovens (até 2 horas), seguida de uma elevação na temperatura que iniciou em 3 horas e permaneceu alta até 6 horas após a injeção de LPS. Além disso, foi verificado que injeção de LPS 3 e 6 horas antes da injeção intraestriatal de GA causou um aumento nos níveis estriatais de IL-1β nos ratos jovens, sendo esse aumento estatisticamente maior em 6 do que em 3 horas. Também foi observado que o aumento nos níveis estriatais de IL-1β, causado pela administração de LPS, correlacionou-se positivamente com o tempo total de convulsões. Por fim, verificou-se que uso prévio do anticorpo da IL-1β preveniu a redução da latência e o aumento da duração das convulsões causadas pela administração de LPS 6 horas antes da injeção intraestriatal de GA nos ratos jovens. Assim, estes achados sugerem que a sinalização da IL-1β presente no processo inflamatório produzido pelo LPS contribui decisivamente para a hiperexcitabilidade neuronal e, consequentemente, para a redução da latência e o aumento da duração das convulsões induzidas pelo GA. Dessa maneira, tratamentos farmacológicos específicos que bloqueiam a superprodução ou as funções da IL-1β na GA-I, podem representar uma estratégia não convencional para o tratamento dessa patologia. Entretanto, estudos clínicos devem ser realizados a fim de avaliar a eficácia desse tratamento nos pacientes glutaricoacidêmicos que apresentam convulsões. Desde que os pacientes com GA-I apresentam outras alterações neurológicas importantes além das convulsões, como prejuízos cognitivos, a segunda hipótese a ser testada neste estudo foi verificar se o tratamento crônico com GA (5 μmol/g; s.c.; duas vezes por dia; do 5° ao 28° dia de vida) causaria déficit de memória espacial em ratos jovens, bem como se a inflamação produzida pelo LPS (2 mg/Kg; i.p.; uma vez por dia; do 25° ao 28° dia de vida) facilitaria o déficit cognitivo induzido pelo GA. Além disso, também foi objetivo avaliar o impacto desses tratamentos sobre possíveis alterações funcionais e estruturais no hipocampo desses animais. Inicialmente verificou-se que o tratamento crônico com GA, assim como os tratamentos com LPS e GA-LPS, causaram um déficit no aprendizado espacial dos ratos jovens. No entanto, foi observado que o tratamento com GA-LPS produziu um maior prejuízo na memória espacial comparado com os outros tratamentos. Em seguida foi observado que nenhum dos tratamentos alterou o peso ou a atividade locomotora/exploratória dos animais. Verificou-se também que o tratamento crônico com GA, assim como os tratamentos com LPS e GA-LPS, aumentaram os níveis hipocampais de IL-1β e TNF-α nos ratos jovens. Além disso, foi observado que tratamentos com GA, LPS e GA-LPS causaram uma redução no volume hipocampal total dos ratos jovens. Finalmente verificou-se que os tratamentos com GA, LPS e GA-LPS causaram uma redução na atividade da subunidade α1 da enzima Na+,K+-ATPase. Por outro lado, foi observado que os tratamentos com GA e LPS causaram um aumento na atividade das subunidades α2/3 da enzima. Assim, somente o tratamento com GA-LPS apresentou uma redução na atividade total da enzima Na+,K+-ATPase no hipocampo dos ratos jovens. Estes dados indicam que o prejuízo no aprendizado espacial observado nos ratos tratados com GA, LPS e GA-LPS parece estar relacionado a um aumento nos níveis de citocinas inflamatórias, a uma redução no volume hipocampal e a uma inibição na atividade da subunidade α1 da enzima Na+,K+-ATPase. No entanto, o maior prejuízo na memória espacial observado nos ratos tratados com GA-LPS ocorreu devido a inibição na atividade total da enzima Na+,K+-ATPase, que foi específica das isoformas α2/3, já que somente este grupo não apresentou resposta compensatória na atividade destas subunidades. Portanto, esta segunda parte do estudo demonstrou que o tratamento crônico com GA causou um déficit no aprendizado espacial de ratos jovens, e que a presença de um processo inflamatório potencializou o prejuízo na memória espacial induzida pelo GA sozinho. Assim, o entendimento dos mecanismos envolvidos nas convulsões e no déficit cognitivo observados nos paciente com GA-I frente a um processo inflamatório é importante para o desenvolvimento de novas terapias para o tratamento dessa patologia, bem como de outras doenças associadas à presença de mediadores inflamatórios.

La formation des souvenirs repose sur un dialogue entre l’hippocampe et le cortex préfrontal médian (CPFm) qui se met en place progressivement et durablement après l’encodage de l’information. La lésion des noyaux reuniens et rhomboïde (ReRh), relai anatomo-fonctionnel entre ces deux structures, perturbe la consolidation à long terme d’un souvenir spatial. A ce jour, les mécanismes mis en jeu ne sont, pas connus. Nous avons donc étudié les processus moléculaires impliqués dans la formation d’un souvenir spatial, au sein de l’hippocampe et du CPFm, et les conséquences induites par la lésion des noyaux ReRh. Pour cela, nous avons lésé les noyaux ReRh de rats, puis nous les testés dans une tâche de piscine de Morris pendant trois jours. Nous avons alors effectué un séquençage des ARNm des sous-régions hippocampiques CA1 dorsale et ventrale, une analyse par RT-qPCR des ARNm du CPFm, ainsi qu’une analyse de l’activation de ces structures par quantification de la protéine issue du gène immédiat c-fos. Nos résultats montrent que la lésion des noyaux ReRh modifie les processus transcriptionnels et traductionnels qui prennent place dans l’hippocampe et le CPFm, dès trois jours d’apprentissage spatial. Ces résultats pourraient expliquer la non persistance d’un souvenir spatial et les déficits comportementaux qui en résultent à la suite d’une lésion des noyaux ReRh. / Memorization relies on a dialogue between the hippocampus and the medial prefrontal cortex (mPFC). This dialog takes place progressively after the encoding of an event. Given their connectivity, the thalamic nuclei named reuniens and rhomboid (ReRh) may modulate the functional loop between these two structures. Indeed, a lesion of these nuclei impairs the persistence of a spatial memory. The mechanisms underlying this process are still unknown. Therefore, we analyzed the molecular mechanisms underlying spatial memory consolidation within the hippocampus and the mPFC, and the consequences of a lesion of the ReRh nuclei. After a stereotaxic lesion of the ReRh nuclei, rats were subjected to three days of a spatial training in the Morris water maze. We then performed a RNA sequencing of the dorsal and ventral hippocampus (CA1 regions), RT-qPCR analysis of the mPCF, and a quantification of the expression of c-fos in these two structures. Results show that ReRh nuclei lesion impairs the transcriptional and translational mechanisms within the hippocampus and the mPFC as soon as after three days of a spatial learning. These alterations could lead to the retrieval deficit observed after a long post-acquisition delay.

Ce travail de thèse avait pour objectif d’étudier le rôle de l’hippocampe (HPC) ventral et des noyaux reuniens (Re) et rhomboïde (Rh) du thalamus dans les processus cognitifs qui sous-tendent la mémoire spatiale chez le Rat. Par l’utilisation d’approches complémentaires combinant l’imagerie cérébrale, la lésion excitotoxique, l’inactivation fonctionnelle réversible et des évaluations comportementales, nos résultats ont mis en évidence : (1) l’implication spécifique de l’HPC ventral uniquement dans le rappel d’informations spatiales ; (2) un rôle-clé des noyaux Re et Rh dans la persistance d’un souvenir spatial ; (3) l’implication des noyaux Re et Rh dans le labyrinthe du double-H, un nouveau test nécessitant d’une part, l’utilisation d’informations spatiales dépendant de l’intégrité de l’HPC dorsal, et d’autre part, une flexibilité comportementale, impliquant le cortex préfrontal médian. Ainsi, l’ensemble de ces résultats permet de proposer l’existence d’un circuit HPC-préfronto-thalamique impliqué dans divers aspects du traitement des informations spatiales. / The main objective of this thesis was to investigate the role of the ventral hippocampus (HPC) and the reuniens (Re) and rhomboid (Rh) thalamic nuclei in the cognitive processes underlying spatial memory in the Rat. If our results first confirmed, in the Morris water maze, the role of the dorsal HPC in the acquisition and retrieval of a spatial reference memory, we demonstrated the specific involvement of the ventral HPC only in the recall of spatial information. In addition, by using complementary approaches combining brain imaging, excitotoxic lesion and reversible functional inactivation, we were able to show for the first time a key role for the Re and Rh in the persistence of a spatial memory (25 days). Finally, the third set of experiments has highlighted the involvement of the Re and Rh in a mnemonic task performed in a new test, the double-H maze, which requires the use of spatial information depending on the integrity of the dorsal HPC, and a behavioral flexibility, involving the medial prefrontal cortex. Thus, taken together, these results suggest the involvement of a HPC-prefronto-thalamic network in various aspects of spatial information processing.