RESUMO
During exercise, multiple sensory information such as visual outflow, proprioception, and vestibular information promote an increase in arousal state, which may convey positive effects on cognitive abilities such as memory. Nevertheless, which of the components of the ascending arousal system (AAS) are engaged during physical activity and which of them are critical for cognitive enhancement, induced by exercise is still unclear. Two experiments were conducted, to answer these questions: in the first one, the neuronal activity of different components of the AAS was evaluated by c-Fos immunoreactivity (Fos-ir) in running rats exposed to a lock or unlock running wheel. We found a specific Fos-ir increase in the tuberomammillary nucleus (TMN) associated with physical exercise. In the second experiment sedentary and exercised rats were challenged to conduct an object recognition memory task, and the activity of the AAS after learning was evaluated by c-Fos immunoreactivity. The exercised group showed a higher performance in the object recognition memory task which gets correlated with an increase on Fos-ir in the TMN, but not with the other components of the AAS, suggesting that the increase on TMN activity induced by exercise may be the foremost contributor of the AAS to memory enhancement observed in exercised animals.
Assuntos
Memória/fisiologia , Condicionamento Físico Animal/fisiologia , Proteínas Proto-Oncogênicas c-fos/genética , Animais , Nível de Alerta/fisiologia , Encéfalo/fisiologia , Cognição/fisiologia , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/fisiologia , Região Hipotalâmica Lateral/fisiologia , Aprendizagem/fisiologia , Masculino , Atividade Motora/fisiologia , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
A mounting body of evidence indicates that adolescents are specially more susceptible to alcohol influence than adults. However, the mechanisms underlying this phenomenon remain poorly understood. Astrocyte-mediated gliotransmission is crucial for hippocampal plasticity and recently, the opening of hemichannels and pannexons has been found to participate in both processes. Here, we evaluated whether adolescent rats exposed to ethanol exhibit changes in the activity of astrocyte hemichannels and pannexons in the hippocampus, as well as alterations in astrocyte arborization and cytokine levels. Adolescent rats were subjected to ethanol (3.0 g/kg) for two successive days at 48-h periods over 14 days. The opening of hemichannels and pannexons was examined in hippocampal slices by dye uptake, whereas hippocampal cytokine levels and astroglial arborization were determined by ELISA and Sholl analysis, respectively. We found that adolescent ethanol exposure increased the opening of connexin 43 (Cx43) hemichannels and pannexin-1 (Panx1) channels in astrocytes. Blockade of p38 mitogen-activated protein kinase (MAPK), inducible nitric oxide synthase (iNOS) and cyclooxygenases (COXs), as well as chelation of intracellular Ca2+, drastically reduced the ethanol-induced channel opening in astrocytes. Importantly, ethanol-induced Cx43 hemichannel and Panx1 channel activity was correlated with increased levels of interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), IL-6 in the hippocampus, as well as with profound alterations in astrocyte arbor complexity. Thus, we propose that uncontrolled opening of astrocyte hemichannels and pannexons may contribute not only to the glial dysfunction and neurotoxicity caused by adolescent alcohol consumption, but also to the pathogenesis of alcohol use disorders in the adulthood.
RESUMO
We have studied the effect of low doses of two widely used antidepressants, fluoxetine (Flx) and reboxetine (Rbx), on excitatory synapses of rat brain cortex and hippocampus. After 15 days of Flx treatment (0.67 mg/kg/day), its plasma level was 20.7+/-5.6 ng/ml. Analysis of postsynaptic densities (PSDs) by immunoblotting revealed no changes in the glutamate receptor subunits GluR1, NR1, NR2A/B, mGluR1alpha nor in the neurotrophin receptor p75(NTR). However, the brain-derived neurotrophic factor (BDNF) receptor TrkB decreased by 42.8+/-6%, and remained decreased after 6 weeks of treatment. The BDNF and TrkB content in homogenates of cortex and hippocampus began to rise at 9 and 15 days, respectively, and remained high for up to 6 weeks. Similar results were obtained following chronic Rbx administration at 0.128 mg/kg/day. We propose that BDNF, whose synthesis is increased by antidepressants, and which is in part released at synaptic sites, binds to TrkB in PSDs, leading to the internalization of the BDNF-TrkB complex and, thus, to a decrease of TrkB in the PSDs. This was paralleled by greater levels of phosphorylated (ie activated) TrkB in the light membrane fraction, that contains signaling endosomes. The retrograde transport of endocyted BDNF/TrkB complexes from spines to cell bodies, where it activates the synthesis of more BDNF, is a protracted process, potentially requiring several cycles of TrkB/BDNF complex endocytosis and transport. This positive feedback mechanism may help explain the time-lag between drug administration and its therapeutic effect, that is, the antidepressant drug paradox.
Assuntos
Antidepressivos/farmacologia , Encéfalo/efeitos dos fármacos , Fluoxetina/farmacologia , Morfolinas/farmacologia , Receptor trkB/metabolismo , Sinapses/efeitos dos fármacos , Animais , Antidepressivos/sangue , Western Blotting/métodos , Encéfalo/citologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Fluoxetina/sangue , Ácido Glutâmico/metabolismo , Imunoprecipitação/métodos , Masculino , Morfolinas/sangue , Fosfotirosina/metabolismo , Ratos , Ratos Sprague-Dawley , Reboxetina , Frações Subcelulares/efeitos dos fármacos , Fatores de Tempo , Proteínas rab5 de Ligação ao GTP/metabolismoRESUMO
Perinatal asphyxia (PA) is associated with long-term neuronal damage and cognitive deficits in adulthood, such as learning and memory disabilities. After PA, specific brain regions are compromised, including neocortex, hippocampus, basal ganglia, and ascending neuromodulatory pathways, such as dopamine system, explaining some of the cognitive disabilities. We hypothesize that other neuromodulatory systems, such as histamine system from the tuberomammillary nucleus (TMN), which widely project to telencephalon, shown to be relevant for learning and memory, may be compromised by PA. We investigated here the effect of PA on (i) Density and neuronal activity of TMN neurons by double immunoreactivity for adenosine deaminase (ADA) and c-Fos, as marker for histaminergic neurons and neuronal activity respectively. (ii) Expression of the histamine-synthesizing enzyme, histidine decarboxylase (HDC) by western blot and (iii) thioperamide an H3 histamine receptor antagonist, on an object recognition memory task. Asphyxia-exposed rats showed a decrease of ADA density and c-Fos activity in TMN, and decrease of HDC expression in hypothalamus. Asphyxia-exposed rats also showed a low performance in object recognition memory compared to caesarean-delivered controls, which was reverted in a dose-dependent manner by the H3 antagonist thioperamide (5-10mg/kg, i.p.). The present results show that the histaminergic neuronal system of the TMN is involved in the long-term effects induced by PA, affecting learning and memory.
Assuntos
Asfixia/tratamento farmacológico , Histamina/metabolismo , Região Hipotalâmica Lateral/metabolismo , Memória , Animais , Asfixia/metabolismo , Asfixia/patologia , Dopamina/metabolismo , Feminino , Antagonistas dos Receptores Histamínicos/farmacologia , Região Hipotalâmica Lateral/efeitos dos fármacos , Região Hipotalâmica Lateral/patologia , Memória/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Wistar , Receptores Histamínicos/efeitos dos fármacosRESUMO
Brain-derived neurotrophic factor (BDNF) and its receptor TrkB are essential regulators of synaptic function in the adult CNS. A TrkB-mediated effect at excitatory synapses is enhancement of NMDA receptor (NMDA-R)-mediated currents. Recently, opposing effects of TrkB and the pan-neurotrophin receptor p75(NTR) on long-term synaptic depression and long-term potentiation have been reported in the hippocampus. To further study the regulation of NMDA-Rs by neurotrophin receptors in their native protein environment, we micro-transplanted rat forebrain post-synaptic densities (PSDs) into Xenopus oocytes. One-minute incubations of oocytes with BDNF led to dual effects on NMDA-R currents: either TrkB-dependent potentiation or TrkB-independent inhibition were observed. Pro-nerve growth factor, a ligand for p75(NTR) but not for TrkB, produced a reversible, dose-dependent, TrkB-independent and p75(NTR)-dependent inhibition of NMDA-Rs. Fractionation experiments showed that p75(NTR) is highly enriched in the PSD protein fraction. Immunoprecipitation and pull-down experiments further revealed that p75(NTR) is a core component of the PSD, where it interacts with the PDZ3 domain of the scaffolding protein SAP90/PSD-95. Our data provide striking evidence for a rapid inhibitory effect of p75(NTR) on NMDA-R currents that antagonizes TrkB-mediated NMDA-R potentiation. These opposing mechanisms might be present in a large proportion of forebrain synapses and may contribute importantly to synaptic plasticity.