Although neurotrophins are conventionally associated with the proper growth and survival of developing neurons, there is increasing evidence that they play an equally significant role in the functions of adult neurons. Specifically, brain derived neurotrophic factor activation of its preferred receptor TrkB is essential in the regulation of motoneuronal activity. Neurotrophin‐dependent and independent activation of TrkB regulates the motoneuronal dendritic integrity, and maintains unique classes of synapses. In addition, it regulates the expression and function of ion channels as well as the strength of inhibitory and excitatory synapses via different intracellular pathways. The recent physiological findings in the regulatory roles of TrkB are implicative of its presence on motoneuronal dendrites. Although, the expression of TrkB in the soma has long been confirmed, its distribution on the dendritic tree of motoneurons remains unknown. We aimed to examine the distribution of TrkB in the cytoplasm and membrane‐associated regions of the dendritic tree of adult neck motoneurons. We have determined, via confocal microscopy, that TrkB is present and abundant throughout the cytoplasm and the membrane‐associated regions of motoneuronal dendrites as well as the soma. TrkB is organized in clusters and its distribution is best described as punctated. We then developed a technique to separately extract and quantify the TrkB immunoreactivity associated with the membrane and the cytoplasm as function of distance from the soma and dendritic tree. We have demonstrated that there is no bias in TrkB immunoreactivity to a specific region of the dendritic tree in five trapezius motoneurons. These observations were confirmed for both cytoplasmic and membrane‐associated TrkB. There is compelling evidence that both mature full‐length and immature hypoglycosylated TrkB isoforms are active in strengthening the response to excitatory synapses in motoneurons. We identified the full length TrkB as well as 3 hypoglycosylated isoforms in cervical spinal segments that contain trapezius motoneurons and phrenic motoneurons. Taken together, these data indicate that TrkB is likely involved in regulating and maintaining different classes of ion channels and synapses on the dendrites as well as the soma. Various isoforms of TrkB may also be involved in regulating motoneuronal activity. / Thesis (Master, Neuroscience Studies) -- Queen's University, 2014-01-14 12:48:21.357

La gènesi i manteniment del sistema nerviós estan regulats per una sèrie de factors neurotròfics, d' entre els quals destaquen les neurotrofines (NGF, BDNF, NT-3 i NT-4/5) i els lligands de la família del GDNF o GFLs (GDNF, NRTN, PSPN i ARTN). Durant els darrers anys, s'han anat caracterizant les cascades de senyalització intracel·lular responsables dels efectes biològics exercits per aquests factors, amb especial atenció a l'NGF i les vies MEK/MAPK i PI 3-K/Akt, dues de les millors caracteritzades. En aquest treballs'han analitzat les vies de traducció de senyal engegades per TrkB (el receptor de BDNF i NT-4/5) i Ret el component comú del receptor per a tots els GFLs) i la seva participació en els processos de supervivència i creixement neurític en diversos paradigmes experimentals. En el cas de TrkB, i utilizant com a modelcèl·lules de neuroblastoma humà SH-SY5Y pre-tractades amb àcid retinoïc (RA), s'ha determinat que la via PI3-K/Akt és el principal mitjançador de la supervivència cel·lular, mentre que la via MEK/MAPK és necessària per als processos de creixement neurític. A més, s'ha caracteritzat el fenotip de les cèl·lules H-SY5Y pre-tractades amb RA i exposades durant temps llargs a BDNF, tot observant-se que aquestes es diferencien cap a un fenotip neuronal, expressant diversos marcadors neuronals específics i restant aturades en la fase G1 del cicle cel·lular. En el cas de Ret, s'ha observat que l'activitat PI 3-K és necessària per a la supervivència de motoneurones espinals de pollastre, neurones granulars del cerebel i neurones del gangli cervical superior, mentre que la via MEK/MAPK no sembla ésser important en els processos de supervivència. A més, c-Src sembla ser un mitjançador important en la senyalització per GFLs, estant implicat tant en la supervivència (actuant per sobre de PI 3-K) i el creixement neurític. La implicació de c-Src en aquests procesos, a més, podria ser específica dels GFLs, donat que aquesta proteïna no sembla estar implicada en la supervivència induïda per NGF. / La génesis y mantenimiento del sistema nervioso están regulados por una serie de factores neurotróficos, de entre los que destacan las neurotrofinas (NGF, BDNF, NT-3 y NT-4/5) y los ligandos de la familia del GDNF o GFLs (GDNF, NRTN, PSPN y ARTN). Durante los últimos años, se han ido caracterizando lascascadas de señalización intracelular responsables de los efectos biológicos ejercidos por estos factores, con especial atención al NGF y las vías MEK/MAPK y PI 3-K/Akt, dos de las mejores caracterizadas. En el presente trabajo se han analizado las vías de traducción de señal iniciadas por TrkB (el receptor de BDNF y NT-4/5) y Ret (el componente común del receptor para todos los GFLs) y su participación en los procesos de supervivencia y crecimiento neurítico en diversos paradigmas experimentales. En el caso deTrkB, y utilizando como modelo células de neuroblastoma humano SH-SY5Y pretratadas con ácido retinoico (RA), se ha determinado que la vía PI3-K/Akt es el principal mediador de la supervivencia celular, mientras que la vía MEK/MAPK es necesaria para los procesos de crecimiento neurítico. Además, se ha caracterizado el fenotipo de las células SH-SY5Y pretratadas con RA y expuestas durante tiempos largos a BDNF, observándose que éstas se diferencian hacia un fenotipo neuronal, expresando varios marcadores neuronales específicos y quedando detenidas en la fase G1 del ciclo celular. En el caso de Ret, se ha observado que la actividad PI 3-K es necesaria para la supervivencia de motoneuronas espinales de pollo, neuronas granulares del cerebelo y neuronas del ganglio cervical superior, mientras que la vía MEK/MAPK no parece ser importante en los procesos de supervivencia.Además, c-Src parece ser un mediador importante en la señalización por GFLs, estando implicado tanto en la supervivencia (actuando por encima de PI 3-K) y el crecimiento neurítico. La implicación de c-Src en estos procesos, además, podría ser específica de los GFLs, dado que esta proteína no parece estarimplicada en la supervivencia mediada por NGF. / The generation and maintenance of the nervous system is regulated by a series of neurotrophic factors that include the neurotrophins (NGF, BDNF, NT-3, and NT-4/5) and the GDNF family ligands (GFLs; GDNF, NRTN, PSPN, and ARTN). During the last years, the signaling cascades responsible for the biologic effects exerted by these factors are being characterized, with special attention to NGFand MEK/MAPK and PI 3-K/Akt pathways. In this work we have analyzed the transduction pathways engaged by TrkB (the receptor for BDNF and NT-4/5) and Ret (the common component of the receptor for GFLs) and their involvement in the processes of survival and neurite outgrowth in several experimental paradigms. Using SH-SY5Y human neuroblastoma cells pretreated with retinoic acid (RA) as a model system, we have determined that PI 3-K/Akt pathway is necessary for TrkB-induced survival, whereas MEK/MAPK pathway is necessary for neurite outgrowth. Moreover, we have characterizedthe phenotype of these cells after sequential RA pre-treatment and long-term BDNF exposure. Cells treated in that way differentiate towards a neuronal phenotype, express several neuronal markers, and are arrested at the G1 phase of the cell cycle. We have also observed that PI 3-K/Akt, but not MEK/MAPK pathway, is necessary for Ret-mediated survival in chicken spinal cord motor neurons, as well as in rat cerebellar and sympathetic neurons. Moreover, c-Src appears to mediate GFLs signaling, being involved in both neuronal survival (acting upstream of PI 3-K) and neurite outgrowth. The involvement of c-Src in such processes seems to be specific for GFLs, since this kinase is not needed for NGF-mediated survival.

Depression has been associated with a low-grade chronic inflammatory state, suggesting a potential therapeutic role for anti-inflammatory agents. Fisetin is a naturally occurring flavonoid in strawberries that has anti-inflammatory activities, but whether fisetin has antidepressant effects is unknown. In this study, we exposed mice to spatial restraint for 2 weeks with or without treatment with fisetin. Immobility time in the forced swimming and tail suspension test after this restraint increased in the untreated group, but this increase did not occur in the fisetin group. We administered fisetin to Abelson helper integration site-1 (Ahi1) knockout mice, which have depressive phenotypes. We found that fisetin attenuated the depressive phenotype of these Ahi1 knockout mice. We further investigated the potential mechanism of fisetin's antidepressant effects. Because TrkB is a critical signaling pathway in the mechanisms of depression, we examined whether phosphorylated TrkB was involved in the antidepressant effects of fisetin. We found that fisetin increased phosphorylated TrkB level without altering total TrkB; this increase was attenuated by K252a, a specific TrkB inhibitor. Taken together, our results demonstrated that fisetin may have therapeutic potential for treating depression and that this antidepressant effect may be mediated by the activation of the TrkB signaling pathway. (Figure presented.).

Autism is a neurodevelopmental disorder characterized by impairments in social communication and interaction and by repetitive patterns of behaviour, interests and activities. It is perhaps the most common and handicapping neurological disorder of childhood and as such represents a significant public health problem and a huge burden for education and social service systems. Currently there is no diagnostic test or cure available for autism and the molecular mechanisms underlying autistic behaviour remain to be elucidated. Mutations in genes linked to autism adversely affect molecules involved in synapse development and plasticity including brain-derived neurotrophic factor receptor (TrkB) and its downstream effector mammalian target of rapamycin (mTOR), which is increased in several forms of syndromic autism. Here, we investigated whether TrkB, mTOR and their signaling pathways are disrupted in postmortem brain tissue from subjects with idiopathic autism, that is, cases of autism without a known genetic cause and thought to be of environmental/epigenetic origin. We next further examined the contribution of defective TrkB signaling to autistic behaviour in mice exposed to the histone deacetylase inhibitor valproic acid (VPA), a well-established model of environmental/epigenetic origin of autism. We found that TrkB signaling pathways were reduced in idiopathic autism and that these disruptions were associated with decreased excitatory postsynaptic marker PSD-95, suggesting fewer excitatory synapses. Moreover, we showed that similar molecular deficits were present in VPA-exposed mice that lacked sociability and displayed increased repetitive, stereotyped behaviour. We also determined that behavioural deficits in these mice were rescued by administration of the partial TrkB agonist LM22A-4 but not by treatment with the active tripeptide fragment of the insulin-like growth factor-1, (1-3)IGF-1. Lastly, reduced TrkB signaling in VPA-exposed mice was normalized by LM22A-4 administration combined with behavioural enrichment. The present work provides a better understanding of the molecular mechanisms that contribute to autistic behaviour and implicates TrkB signaling in autism pathogenesis. Furthermore, these data demonstrate that molecular changes observed in brains of patients with idiopathic autism differ from syndromic forms and highlight that both too much and too little signaling can be equally disruptive. The present work also shows that maternal challenge with VPA resulted in social deficits, increased repetitive, restrictive behaviour and reduced TrkB signaling in mice, pointing to epigenetic modifications as a potential underlying mechanism of molecular and behavioural disruptions in autism. Lastly, these findings suggest that pharmacological activation of TrkB using compounds such as the partial TrkB agonist LM22A-4 might play a role in treating sociability and repetitive, perseverative behaviour in autism. / Thesis / Doctor of Philosophy (PhD)

No description available.

Le BDNF (brain-derived neurotrophic factor) a été découvert dans le cerveau et est largement impliqué dans la neuroplasticité, la mémoire et la cognition via l’activation des récepteurs TrkB (tropomyosin receptor kinase B) neuronaux. Nous avons récemment montré que le système cardiovasculaire contenait autant de BDNF que le cerveau et que le BDNF exogène était capable d’induire une relaxation vasculaire dépendante de l’endothélium. D’autres études ont suggéré que l’activation des récepteurs TrkB endothéliaux par le BDNF était impliquée dans les processus athérosclérotiques. Notre laboratoire soupçonne une interaction étroite entre NO et BDNF endothélial et a même envisagé la possibilité d’une implication du BDNF secrété par l’endothélium des microvaisseaux cérébraux dans la cognition. Les patients souffrant de polyarthrite rhumatoïde (PR), une maladie inflammatoire d’origine auto-immune, sont à risque cardiovasculaire et présentent une altération de la cognition avec notamment un risque plus élevé de dépression. Etonnamment, l’effet de la PR sur le BDNF est peu documenté. Les seules études disponibles rapportent une élévation du BDNF dans le sang et le liquide synovial en cas de PR. Notre hypothèse est qu’une réduction de l’expression endothéliale du BDNF pourrait contribuer au risque cardiovasculaire et au déficit cognitif associés à la PR. Ainsi, dans notre travail, nous avons étudié le BDNF vasculaire et cérébral et son récepteur TrkB sur le modèle rat d’arthrite induite à l’adjuvant.Nos principaux résultats montrent que l’arthrite conduit à 1) une réduction des taux aortiques de BDNF indépendamment de la sévérité des symptômes inflammatoires mais dépendante de la fonction endothéliale, 2) une diminution des taux cérébraux en BDNF indépendamment de la sévérité des symptômes inflammatoires mais en lien avec la fonction endothéliale, 3) une diminution de l’expression du BDNF et de son récepteur TrkB activé au niveau tant neuronal qu’endothélial dans les régions cérébrales impliquées dans la cognition, 4) une corrélation positive entre l’expression du BDNF par l’endothélium vasculaire et l’expression neuronale des TrkB activés, 5) une absence de corrélation entre les taux sériques de BDNF et ses taux cérébraux ou vasculaires mais en revanche l’existence d’une corrélation positive entre les taux sériques de BDNF et l’inflammation qu’elle soit clinique ou biologique.L’ensemble de ces données est en faveur de l’hypothèse selon laquelle le BDNF endothélial pourrait être impliqué dans le risque athérosclérotique et le déficit cognitif associé à l’arthrite. L’inflammation doit être considérée comme un facteur confondant lorsque les taux circulants de BDNF sont utilisés comme un reflet des taux présents dans le cerveau. / BDNF (brain-derived neurotrophic factor) has been discovered in the brain and is widely implicated in neuroplasticity, memory and cognition through the activation of neuronal TrkB (tropomyosin receptor kinase B) receptors. We have recently shown that the cardiovascular system contained as much BDNF as the brain and that exogenous BDNF was able to induce endothelium-dependent vascular relaxation. Other studies have suggested that activation of endothelial TrkB receptors by BDNF is involved in atherosclerotic processes. Our laboratory suspects a close interaction between endothelial NO and BDNF and has even considered the possibility of involvement of BDNF secreted by cerebral microvessel endothelium in cognition. Patients suffering from rheumatoid arthritis (RA), an inflammatory disease of autoimmune origin, are at risk of cardiovascular disease and have an impairment of cognition, including a higher risk of depression. Surprisingly, the effect of RA on BDNF is poorly documented. The only available studies report an increase of BDNF in the blood and synovial fluid in RA. Our hypothesis is that a reduction in endothelial expression of BDNF may contribute to the cardiovascular risk and cognitive deficit associated with RA. Thus, in our work, we studied vascular and cerebral BDNF and its TrkB receptor on the rat model of adjuvant-induced arthritis.Our main findings show that arthritis leads to 1) a decrease in BDNF levels in aortas independently of the severity of inflammatory symptoms but dependent on endothelial function, 2) a decrease in brain BDNF levels independent of the severity of inflammatory symptoms, but link with endothelial function, 3) a decreased expression of BDNF and its activated TrkB receptor at both neuronal and endothelial levels in the brain regions involved in cognition, 4) a positive correlation between endothelial expression of BDNF and neuronal expression of activated TrkB, 5) a lack of correlation between serum BDNF levels and its cerebral or vascular levels, but on the other hand the existence of a positive correlation between serum BDNF levels and inflammation, whether clinical or biological.All of these data support the hypothesis that endothelial BDNF may be involved in atherosclerotic risk and cognitive impairment associated with arthritis. Inflammation should be considered as a confounding factor when circulating levels of BDNF are used as a reflection of levels present in the brain.

Meduloblastoma é o tumor maligno intracranial mais comum em crianças. A desregulação da sinalização BDNF/TrkB tem sido associada a aumento da proliferação, invasão e resistência a quimioterapia, em diversos tipos de câncer, incluindo tumores de sistema nervoso. No entanto, seus efeitos biológicos e relevância clínica em meduloblastoma não estão compreendidos. Neste estudo foram analisados os efeitos do inibidor seletivo de TrkB, ANA-12, na viabilidade, sobrevivência e ciclo celular de linhagens de meduloblastoma humano. Este estudo demonstrou que o bloqueio seletivo de TrkB reduziu significativamente a viabilidade e sobrevivência de linhagens celulares representativas de diferentes subgrupos moleculares de meduloblastoma. Estes resultados fornecem uma base racional para investigar a inibição de TrkB como uma nova e potencial estratégia para o tratamento de meduloblastoma. / Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Deregulation of BDNF/TrkB signaling has been associated with increased proliferative capabilities, invasiveness and chemo-resistance in several types of cancer. However, the relevance of this pathway in MB remains unknown. Here, we show that the selective TrkB inhibitor ANA-12 markedly reduced the viability and survival of human cell lines representative of different MB molecular subgroups. These findings provide a rationale to further investigate TrkB inhibition as a potential novel strategy for MB treatment.

Os efeitos benéficos da administração crônica de cafeína sobre a memória têm sido observados em diferentes condições e modelos animais, mas os mecanismos subjacentes aos seus efeitos permanecem desconhecidos. Este estudo buscou investigar se a administração crônica de cafeína pode melhorar o desempenho em uma tarefa de memória em ratos adultos e de meia-idade. Além disso, os efeitos da cafeína sobre o imunoconteúdo do fator neurotrófico derivado encéfalo(BDNF) foi analisado para estabelecer uma conexão entre os achados comportamentais e BDNF, uma das neurotrofinas estritamente envolvida na memória e processos de aprendizagem. Além disso, analisou-se o imunoconteúdo do receptor tirosina cinase (Trk B), o precursor do BDNF (proBDNF) e o fator de transcrição CREB. Ratos Wistar adultos (2 meses) e de meia-idade (12 meses de idade) receberam água ou cafeína (1 mg / mL) na água de beber durante 30 dias. Ambos os grupos foram submetidos às tarefas de avaliação da atividade locomotora e esquiva inibitória. Ratos de meia-idade apresentaram uma diminuição da atividade locomotora em relação aos adultos e o tratamento com cafeína não modificou esse parâmetro em nenhuma das idades. Na tarefa de esquiva inibitória, a memória de curta e longa duração foi avaliada. Ratos de meia-idade apresentaram um comprometimento total da memória de curta duração em relação aos adultos. Quando a memória de longa duração foi avaliada, os ratos de meia-idade apresentaram uma diminuição do seu desempenho em relação aos adultos, e tratamento de cafeína foi capaz de melhorar esse desempenho. Análise de Western blot do hipocampo de ratos tratados com cafeína revelou um aumento do imunoconteudo de BDNF no hipocampo em ratos de meia-idade, um efeito atenuado pelo tratamento crônico de cafeína. Além disso, o tratamento com cafeína aumentou o imunoconteúdo de pro-BDNF e CREB em ambas as idades, e, ainda, foi encontrado um aumento do imunoconteúdo de CREB em ratos de meia-idade. O imunoconteúdo de TrkB diminuiu no hipocampo de ratos de meia-idade quando comparados aos adultos, e o tratamento com cafeína foi capaz de diminuir o imunoconteúdo de TrkB em ambas as idades. Os dados encontrados indicam uma estreita associação entre a modificação do desempenho da memória e imunoconteúdo BDNF. Portanto, nossos dados sugerem que a cafeína é capaz de normalizar o desempenho da memória durante o envelhecimento e pode estar relacionada à capacidade da cafeína de normalizar os níveis de BDNF. / The beneficial effects of chronic caffeine administration in memory performance have been observed in different conditions and animal models but the underlying mechanisms remain unknown. This study was designed to investigate whether chronic caffeine administration could improve the performance in different memory tasks used in adult and middle-aged rats. In addition, the effects of caffeine on brain derived neurotrophic factor (BDNF) immunocontent was analyzed to establish a connection between the behavioral findings and BDNF, one of the neurotrophins strictly involved in memory and learning processes. Moreover, it was analyzed the immunocontent of tirosine kinase receptor (Trk B), the precursor of BDNF (proBDNF) and the transcription factor CREB. Adult (2 months old) and middle-aged (12 months old) Wistar rats received either drinking water or caffeine (1 mg/mL) during 30 days. Both groups were submitted to open field and inhibitory avoidance tasks. Middle-aged rats presented decreased locomotor activity as compared to adults and caffeine was devoid of effect at any age. In the inhibitory avoidance task, short- and long-term memory was evaluated. Middle-aged rats presented impaired performance compared to adult ones for short-term memory. When long-term memory was evaluated, middle-aged rats showed a decreased in their perfomances compared to adult rats, and caffeine treatment was able to improve it. Western blot analysis of hippocampus from caffeine-treated rats revealed that BDNF increased by aging and caffeine treatment prevented it. In addition, caffeine treatment increased the pro-BDNF and CREB immunocontent in both ages. Furthermore, CREB densities increased with aging. TrkB immunocontent was decreased in the hippocampus from middle-aged rats when compared to adult ones, and caffeine decreased the density of TrkB in both ages. The present findings indicate a close association between the modification of memory performance and BDNF immunocontent. Therefore, our data suggest caffeine normalyze memory performance upon aging and may be related to the ability of caffeine to normalyze the levels of BDNF.

Meduloblastoma é o tumor maligno intracranial mais comum em crianças. A desregulação da sinalização BDNF/TrkB tem sido associada a aumento da proliferação, invasão e resistência a quimioterapia, em diversos tipos de câncer, incluindo tumores de sistema nervoso. No entanto, seus efeitos biológicos e relevância clínica em meduloblastoma não estão compreendidos. Neste estudo foram analisados os efeitos do inibidor seletivo de TrkB, ANA-12, na viabilidade, sobrevivência e ciclo celular de linhagens de meduloblastoma humano. Este estudo demonstrou que o bloqueio seletivo de TrkB reduziu significativamente a viabilidade e sobrevivência de linhagens celulares representativas de diferentes subgrupos moleculares de meduloblastoma. Estes resultados fornecem uma base racional para investigar a inibição de TrkB como uma nova e potencial estratégia para o tratamento de meduloblastoma. / Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Deregulation of BDNF/TrkB signaling has been associated with increased proliferative capabilities, invasiveness and chemo-resistance in several types of cancer. However, the relevance of this pathway in MB remains unknown. Here, we show that the selective TrkB inhibitor ANA-12 markedly reduced the viability and survival of human cell lines representative of different MB molecular subgroups. These findings provide a rationale to further investigate TrkB inhibition as a potential novel strategy for MB treatment.

Os efeitos benéficos da administração crônica de cafeína sobre a memória têm sido observados em diferentes condições e modelos animais, mas os mecanismos subjacentes aos seus efeitos permanecem desconhecidos. Este estudo buscou investigar se a administração crônica de cafeína pode melhorar o desempenho em uma tarefa de memória em ratos adultos e de meia-idade. Além disso, os efeitos da cafeína sobre o imunoconteúdo do fator neurotrófico derivado encéfalo(BDNF) foi analisado para estabelecer uma conexão entre os achados comportamentais e BDNF, uma das neurotrofinas estritamente envolvida na memória e processos de aprendizagem. Além disso, analisou-se o imunoconteúdo do receptor tirosina cinase (Trk B), o precursor do BDNF (proBDNF) e o fator de transcrição CREB. Ratos Wistar adultos (2 meses) e de meia-idade (12 meses de idade) receberam água ou cafeína (1 mg / mL) na água de beber durante 30 dias. Ambos os grupos foram submetidos às tarefas de avaliação da atividade locomotora e esquiva inibitória. Ratos de meia-idade apresentaram uma diminuição da atividade locomotora em relação aos adultos e o tratamento com cafeína não modificou esse parâmetro em nenhuma das idades. Na tarefa de esquiva inibitória, a memória de curta e longa duração foi avaliada. Ratos de meia-idade apresentaram um comprometimento total da memória de curta duração em relação aos adultos. Quando a memória de longa duração foi avaliada, os ratos de meia-idade apresentaram uma diminuição do seu desempenho em relação aos adultos, e tratamento de cafeína foi capaz de melhorar esse desempenho. Análise de Western blot do hipocampo de ratos tratados com cafeína revelou um aumento do imunoconteudo de BDNF no hipocampo em ratos de meia-idade, um efeito atenuado pelo tratamento crônico de cafeína. Além disso, o tratamento com cafeína aumentou o imunoconteúdo de pro-BDNF e CREB em ambas as idades, e, ainda, foi encontrado um aumento do imunoconteúdo de CREB em ratos de meia-idade. O imunoconteúdo de TrkB diminuiu no hipocampo de ratos de meia-idade quando comparados aos adultos, e o tratamento com cafeína foi capaz de diminuir o imunoconteúdo de TrkB em ambas as idades. Os dados encontrados indicam uma estreita associação entre a modificação do desempenho da memória e imunoconteúdo BDNF. Portanto, nossos dados sugerem que a cafeína é capaz de normalizar o desempenho da memória durante o envelhecimento e pode estar relacionada à capacidade da cafeína de normalizar os níveis de BDNF. / The beneficial effects of chronic caffeine administration in memory performance have been observed in different conditions and animal models but the underlying mechanisms remain unknown. This study was designed to investigate whether chronic caffeine administration could improve the performance in different memory tasks used in adult and middle-aged rats. In addition, the effects of caffeine on brain derived neurotrophic factor (BDNF) immunocontent was analyzed to establish a connection between the behavioral findings and BDNF, one of the neurotrophins strictly involved in memory and learning processes. Moreover, it was analyzed the immunocontent of tirosine kinase receptor (Trk B), the precursor of BDNF (proBDNF) and the transcription factor CREB. Adult (2 months old) and middle-aged (12 months old) Wistar rats received either drinking water or caffeine (1 mg/mL) during 30 days. Both groups were submitted to open field and inhibitory avoidance tasks. Middle-aged rats presented decreased locomotor activity as compared to adults and caffeine was devoid of effect at any age. In the inhibitory avoidance task, short- and long-term memory was evaluated. Middle-aged rats presented impaired performance compared to adult ones for short-term memory. When long-term memory was evaluated, middle-aged rats showed a decreased in their perfomances compared to adult rats, and caffeine treatment was able to improve it. Western blot analysis of hippocampus from caffeine-treated rats revealed that BDNF increased by aging and caffeine treatment prevented it. In addition, caffeine treatment increased the pro-BDNF and CREB immunocontent in both ages. Furthermore, CREB densities increased with aging. TrkB immunocontent was decreased in the hippocampus from middle-aged rats when compared to adult ones, and caffeine decreased the density of TrkB in both ages. The present findings indicate a close association between the modification of memory performance and BDNF immunocontent. Therefore, our data suggest caffeine normalyze memory performance upon aging and may be related to the ability of caffeine to normalyze the levels of BDNF.