RESUMO
Acute stress impairs memory retrieval of several types of memories. An increase in glucocorticoids, several minutes after stressful events, is described as essential to the impairing retrieval-effects of stressors. Moreover, memory retrieval under stress can have long-term consequences. Through what process does the reactivated memory under stress, despite the disrupting retrieval effects, modify long-term memories? The reconsolidation hypothesis proposes that a previously consolidated memory reactivated by a reminder enters a vulnerability phase (labilization) during which it is transiently sensitive to modulation, followed by a re-stabilization phase. However, previous studies show that the expression of memories during reminder sessions is not a condition to trigger the reconsolidation process since unexpressed memories can be reactivated and labilized. Here we evaluate whether it is possible to reactivate-labilize a memory under the impairing-effects of a mild stressor. We used a paradigm of human declarative memory whose reminder structure allows us to differentiate between a reactivated-labile memory state and a reactivated but non-labile state. Subjects memorized a list of five cue-syllables associated with their respective response-syllables. Seventy-two hours later, results showed that the retrieval of the paired-associate memory was impaired when tested 20min after a mild stressor (cold pressor stress (CPS)) administration, coincident with cortisol levels increase. Then, we investigated the long-term effects of CPS administration prior to the reminder session. Under conditions where the reminder initiates the reconsolidation process, CPS impaired the long-term memory expression tested 24h later. In contrast, CPS did not show effects when administered before a reminder session that does not trigger reconsolidation. Results showed that memory reactivation-labilization occurs even when retrieval was impaired. Memory reactivation under stress could hinder -via reconsolidation- the probability of the traces to be expressed in the long term.
Assuntos
Aprendizagem por Associação/fisiologia , Consolidação da Memória/fisiologia , Rememoração Mental/fisiologia , Estresse Fisiológico/fisiologia , Pressão Sanguínea/fisiologia , Temperatura Baixa , Sinais (Psicologia) , Feminino , Humanos , Hidrocortisona/análise , Masculino , Testes Neuropsicológicos , Saliva/químicaRESUMO
Long-term exposure to stressful situations has deleterious effects on adult neurogenesis, behavior, and the immune system. We have previously shown that stressed BALB/c mice show poor learning performance, which correlates with an increase in the T helper 1/T helper 2 (Th1/Th2) cytokine balance. Glatiramer acetate (GA) can stimulate autoreactive T cells. In this work we investigated the effects of GA treatment on BALB/c mice exposed to chronic mild stress (CMS). Stressed mice exhibited a significant decline in their performance in the open field and Y-maze tasks, which was accompanied by a reduction in dentate gyrus neurogenesis and an altered Th1/Th2 balance. Interestingly, after 6 weeks of CMS exposure administration of GA reestablished normal levels of adult neurogenesis, restored the Th1/Th2 balance, and improved learning performance. These results demonstrate that GA treatment can reverse the learning impairment induced by stress through a mechanism that likely involves the regulation of the cytokine balance and adult neurogenesis.
Assuntos
Adjuvantes Imunológicos/farmacologia , Hipocampo/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Peptídeos/farmacologia , Estresse Psicológico/imunologia , Equilíbrio Th1-Th2/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Citocinas/efeitos dos fármacos , Feminino , Acetato de Glatiramer , Camundongos , Camundongos Endogâmicos BALB CRESUMO
Ionizing radiations induce oxidative stress on target tissues, mainly through the generation of reactive oxygen species (ROS). However, there are few data available on the behavioral effects of moderate doses of ionizing radiation. The aim of the present work was to evaluate the performance of adult rats irradiated at birth in different hippocampal-dependent behavioral tasks and to establish a relationship with the oxidative status and histological changes in rat hippocampus (Hip). Male Wistar rats were irradiated with 5 Gy of X rays between 24 and 48 h after birth. Thirty days later, rats were subjected to open field, object recognition and inhibitory avoidance tasks. In addition, oxidative status markers as well as protein kinase C (PKC) activity and histological changes were assessed in control and irradiated Hip. Results show an impairment in recognition and habituation memories in 30-day-old animals exposed to neonatal ionizing radiation, both at short- (ST) and at long-term (LT), whereas an improvement in associative memory was observed at ST. In addition, histological alterations were observed in irradiated Hip. Although an increase in ROS levels and PKC activity were found in irradiated Hip, no changes in the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) were observed. Taken together, our results support the hypothesis that an increased PKC activity, induced by neonatal ionizing radiation on rat Hip, could play a role in the generation of an imbalance between ROS levels and antioxidant systems and might underlie radiation-induced hippocampal histological damage as well as the Hip-dependent behavioral changes found in irradiated rats.
Assuntos
Hipocampo/fisiopatologia , Transtornos da Memória/etiologia , Transtornos da Memória/patologia , Estresse Oxidativo/efeitos da radiação , Lesões Experimentais por Radiação/complicações , Animais , Animais Recém-Nascidos , Aprendizagem da Esquiva/efeitos da radiação , Comportamento Animal/efeitos da radiação , Catalase/metabolismo , Comportamento Exploratório/efeitos dos fármacos , Feminino , Hipocampo/patologia , Hipocampo/efeitos da radiação , Masculino , Testes Neuropsicológicos , Estresse Oxidativo/fisiologia , Gravidez , Proteína Quinase C/metabolismo , Lesões Experimentais por Radiação/patologia , Radiação Ionizante , Ratos , Ratos Wistar , Tempo de Reação/fisiologia , Tempo de Reação/efeitos da radiação , Espécies Reativas de Oxigênio/metabolismo , Reconhecimento Psicológico/efeitos da radiação , Superóxido Dismutase/metabolismo , Fatores de TempoRESUMO
Nitric oxide (NO) has been involved in many pathophysiological brain processes. Recently, we showed that neuronal nitric oxide synthase (nNOS)-mediated decrease in NO production is involved in memory impairment induced by chronic mild stress (CMS) in BALB/c mice. Two genetically different inbred murine strains, C57BL/6 and BALB/c, show distinct behavioral responses, neurodevelopmental and neurochemical parameters. Here, we perform a comparative study on CMS effects upon learning and memory in both strains, analyzing the role of NO production and its regulation by protein kinase C (PKC). Stressed BALB/c, but not C57Bl/6 mice, showed a poor learning performance in both the open field and passive avoidance inhibitory tasks. Also, CMS induced a diminished NO production by nNOS, associated with an increment in gamma and zeta PKC isoenzymes in BALB/c mice. In C57BL/6 mice, CMS had no effect on NO production, but increased delta and decreased betaI PKC isoforms. In vivo administration of a NOS inhibitor induced behavioral alterations in both strains. These results suggest a differential effect of stress, with BALB/c being more vulnerable to stress than C57BL/6 mice. This effect could be related to a differential regulation of NOS and PKC isoenzymes, pointing to an important role of NO in learning and memory.
Assuntos
Comportamento Animal/efeitos dos fármacos , Aprendizagem , Memória , Óxido Nítrico Sintase Tipo I/metabolismo , Óxido Nítrico/biossíntese , Proteína Quinase C/metabolismo , Estresse Psicológico/psicologia , Animais , Aprendizagem da Esquiva , Comportamento Exploratório/efeitos dos fármacos , Feminino , Hipocampo/enzimologia , Memória/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Estresse Psicológico/fisiopatologiaRESUMO
Nitric oxide (NO) has been involved in many pathophysiological brain processes. However, the exact role of NO in the cognitive deficit associated to chronic stress exposure has not been elucidated. In this study, we investigated the participation of hippocampal NO production and their regulation by protein kinase C (PKC) in the memory impairment induced in mice subjected to chronic mild stress model (CMS). CMS mice showed a poor learning performance in both open field and passive avoidance inhibitory task respect to control mice. Histological studies showed a morphological alteration in the hippocampus of CMS mice. On the other hand, chronic stress induced a diminished NO production by neuronal nitric oxide synthase (nNOS) correlated with an increment in gamma and zeta PKC isoenzymes. Partial restoration of nNOS activity was obtained after PKC activity blockade. NO production by inducible nitric oxide synthase isoform was not detected. The magnitude of oxidative stress, evaluated by reactive oxygen species production, after excitotoxic levels of NMDA was increased in hippocampus of CMS mice. Moreover, ROS formation was higher in the presence of nNOS inhibitor in both control and CMS mice. Finally, treatment of mice with nNOS inhibitors results in behavioural alterations similar to those observed in CMS animals. These findings suggest a novel role for nNOS showing protective activity against insults that trigger tissue toxicity leading to memory impairments.