RESUMO
Perinatal asphyxia is a peripartum event that can cause permanent sequelae to the newborns, affecting the brain development. Recently, it has been demonstrated that epigenetics mechanisms play an important role in this injury and that folic acid (FA) supplementation during pregnancy can affect these epigenetics modifications as well as gene expression. We have identified both positive and negative effects of FA treatment in rats submitted to a model of neonatal hypoxia-ischemia (HI). Considering that FA supplementation is already used in pregnant women and that HI occurs in the peripartum period, this study was designated to evaluate how gestational FA supplementation and neonatal HI affect: apoptosis (caspase-3) and expression of synaptic proteins (synapsin and PSD-95) and the methylation of histone H3 lysine (K) 4 and 27 in the rat hippocampus. Pregnant Wistar rats were divided according to the diets: standard (SD), supplemented with 2 mg/kg of FA or with 20 mg/kg of FA. HI procedure was performed at the 7th PND. Protein expression and H3 methylation were evaluated at the 60th PND in the rats' hippocampus. Neonatal HI increased caspase-3 expression decreased synapsin expression and reduced H3K4me2, -me3 and H3K27me2, -me3 in the ipsilateral hippocampus. FA only prevented the augment in caspase-3 expression. In conclusion, neonatal HI caused lasting effects on caspase-3-mediated cell death (prevented by the FA) and synaptic proteins in the rats' hippocampus. This is the first study to show that histone modifications may contribute to these pathological findings in the hippocampus of HI animals.
Assuntos
Caspase 3/metabolismo , Ácido Fólico/administração & dosagem , Hipocampo/efeitos dos fármacos , Histonas/metabolismo , Hipóxia-Isquemia Encefálica/metabolismo , Sinapsinas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Metilação de DNA , Feminino , Hipocampo/metabolismo , Masculino , Gravidez , Ratos , Ratos WistarRESUMO
Neonatal hypoxia-ischemia (HI) can lead to cognitive impairments and motor dysfunction. Acrobatic exercises (AE) were proposing as therapeutic option to manage HI motor deficits, however, the cognitive effects after this treatment are still poorly understood. Therefore, we evaluated the effects of AE protocol on memory impairments and brain plasticity markers after Rice-Vannucci HI rodent model. Wistar rats on the 7th postnatal day (PND) were submitted to HI model and after weaning (PND22) were trained for 5 weeks with AE protocol, then subsequently submitted to cognitive tests. Our results showed recovery in novel object recognition (NOR) memory, but not, spatial Morris Water Maze (WM) memory after AE treatment in HI rats. BDNF and synaptophysin neuroplasticity markers indicate plastic alterations in the hippocampus and striatum, with maintenance of synaptophysin despite the reduction of total volume tissue, besides, hippocampal HI-induced ipsilateral BDNF increased, and striatum contralateral BDNF decreased were noted. Nevertheless, the exercise promoted functional recovery and seems to be a promising strategy for HI treatment, however, future studies identifying neuroplastic pathway for this improvement are needed.
Assuntos
Hipóxia-Isquemia Encefálica/psicologia , Hipóxia-Isquemia Encefálica/reabilitação , Transtornos da Memória/psicologia , Transtornos da Memória/reabilitação , Condicionamento Físico Animal/psicologia , Reconhecimento Psicológico , Animais , Animais Recém-Nascidos , Atrofia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hipocampo/anatomia & histologia , Aprendizagem em Labirinto , Destreza Motora , Neostriado/anatomia & histologia , Desempenho Psicomotor , Ratos , Ratos Wistar , Recuperação de Função Fisiológica , Memória Espacial , Sinaptofisina/metabolismoRESUMO
BACKGROUND: Methylphenidate (MPH) is a stimulant drug mainly prescribed to treat cognitive impairments in attention-deficit/hyperactivity disorder (ADHD). We demonstrated that neonatal hypoxia-ischemia (HI) induced attentional deficits in rats and MPH administration reversed these deficits. However, MPH effects on memory deficits after the HI procedure have not been evaluated yet. AIMS: We aimed to analyze learning and memory performance of young hypoxic-ischemic rats after MPH administration and associate their performance with brain-derived neurotrophic factor (BDNF) levels in the prefrontal cortex and hippocampus. METHODS: Male Wistar rats were divided into four groups (n=11-13/group): control saline (CTS), control MPH (CTMPH), HI saline (HIS) and HIMPH. The HI procedure was conducted at post-natal day (PND) 7 and memory tasks between PND 30 and 45. MPH administration (2.5 mg/kg, i.p.) occurred 30 min prior to each behavioral session and daily, for 15 days, for the BDNF assay (n=5-7/group). RESULTS: As expected, hypoxic-ischemic animals demonstrated learning and memory deficits in the novel-object recognition (NOR) and Morris water maze (MWM) tasks. However, MPH treatment did not improve learning and memory deficits of these animals in the MWM-and even disrupted the animals' performance in the NOR task. Increased BDNF levels were found in the hippocampus of HIMPH animals, which seem to have been insufficient to improve memory deficits observed in this group. CONCLUSIONS: The MPH treatment was not able to improve memory deficits resulting from the HI procedure considering a dose of 2.5 mg/kg. Further studies investigating different MPH doses would be necessary to determine a dose-response relationship in this model.
Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Transtornos da Memória/tratamento farmacológico , Metilfenidato/farmacologia , Animais , Animais Recém-Nascidos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipóxia-Isquemia Encefálica/fisiopatologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/patologia , Ratos , Ratos WistarRESUMO
Genetic differential susceptibility states that individuals may vary both by exhibiting poor responses when exposed to adverse environments, and disproportionally benefiting from positive settings. The dopamine D4 receptor gene (DRD4) may be particularly implicated in these effects, including disturbed eating behaviors that might lead to obesity. Here, we explore differential susceptibility to positive environments according to the predicted genetically regulated gene expression of prefrontal cortex DRD4 gene. Using MAVAN as the discovery cohort (Maternal Adversity, Vulnerability and Neurodevelopment) and GUSTO as the replication cohort (Growing Up in Singapore Towards Healthy Outcomes), we analyzed the interaction between a) a Positive postnatal environmental score, that accounts for positive outcomes in the postnatal period and b) the genetically regulated gene expression of prefrontal DRD4, computed using a machine learning prediction method (PrediXcan). The outcome measures were the pro-intake domains (Emotional over-eating, Food Responsiveness, Food Enjoyment and Desire to Drink) from the Child Eating Behavior Questionnaire at 48 months of age (MAVAN) and 60 months of age (GUSTO). The interaction between the positive environment and the predicted prefrontal DRD4 gene expression was significant for emotional over-eating in MAVAN (ß = -0.403, p < 0.02), in which the high gene expression group had more or less emotional eating according to the exposure to lower or higher positive environment respectively, showing evidence of differential susceptibility criteria. In the replication cohort, a similar result was found with the pro-intake domain Desire to drink (ß = -0.583, p < 0.05). These results provide further evidence for the genetic differential susceptibility, accounting for the benefit of positive environments.
Assuntos
Comportamento Infantil/psicologia , Ingestão de Alimentos , Emoções , Comportamento Alimentar/psicologia , Relações Mãe-Filho , Receptores de Dopamina D4/genética , Meio Social , Adulto , Desenvolvimento Infantil , Pré-Escolar , Estudos de Coortes , Ingestão de Alimentos/genética , Ingestão de Alimentos/psicologia , Conflito Familiar , Feminino , Expressão Gênica , Predisposição Genética para Doença , Humanos , Hiperfagia , Lactente , Recém-Nascido , Aprendizado de Máquina , Masculino , Mães , Obesidade/etiologia , Obesidade/genética , Obesidade/metabolismo , Receptores de Dopamina D4/metabolismo , SingapuraRESUMO
BACKGROUND: Genetic polymorphisms of the dopamine transporter gene (DAT1) and perinatal complications associated with poor oxygenation are risk factors for attentional problems in childhood and may show interactive effects. METHODS: We created a novel expression-based polygenic risk score (ePRS) reflecting variations in the function of the DAT1 gene network (ePRS-DAT1) in the prefrontal cortex and explored the effects of its interaction with perinatal hypoxic-ischemic-associated conditions on cognitive flexibility and brain gray matter density in healthy children from two birth cohorts-MAVAN from Canada (n = 139 boys and girls) and GUSTO from Singapore (n = 312 boys and girls). RESULTS: A history of exposure to several perinatal hypoxic-ischemic-associated conditions was associated with impaired cognitive flexibility only in the high-ePRS group, suggesting that variation in the prefrontal cortex expression of genes involved in dopamine reuptake is associated with differences in this behavior. Interestingly, this result was observed in both ethnically distinct birth cohorts. Additionally, parallel independent component analysis (MAVAN cohort, n = 40 children) demonstrated relationships between single nucleotide polymorphism-based ePRS and gray matter density in areas involved in executive (cortical regions) and integrative (bilateral thalamus and putamen) functions, and these relationships differ in children from high and low exposure to hypoxic-ischemic-associated conditions. CONCLUSIONS: These findings reveal that the impact of conditions associated with hypoxia-ischemia on brain development and executive functions is moderated by genotypes associated with dopamine signaling in the prefrontal cortex. We discuss the potential impact of innovative genomic and environmental measures for the identification of children at high risk for impaired executive functions.
Assuntos
Encéfalo/patologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Função Executiva/fisiologia , Substância Cinzenta/patologia , Hipóxia-Isquemia Encefálica/genética , Hipóxia-Isquemia Encefálica/patologia , Córtex Pré-Frontal/metabolismo , Criança , Pré-Escolar , Estudos de Coortes , Proteínas da Membrana Plasmática de Transporte de Dopamina/fisiologia , Feminino , Humanos , Masculino , Herança Multifatorial , Polimorfismo de Nucleotídeo ÚnicoRESUMO
The aim of this study was to evaluated motor function and morphological aspects of the components involved in motor control (sensorimotor cortex, spinal cord, sciatic nerve, neuromuscular junctions and skeletal muscle) in male Wistar rats exposed to a model of neonatal hypoxic-ischemic encephalopathy (HIE) and the possible influence of different physical exercise protocols - treadmill and acrobatic. Male Wistar rats at the 7th post-natal day (PND) were submitted to the HIE model and from the 22nd until 60th PND the exercise protocols (treadmill or acrobatic training) were running. After the training, the animals were evaluated in Open Field, Ladder Rung Walking and Rotarod tasks and after samples of the motor control components were collected. Our results evidenced that the acrobatic training reversed the hyperactivity and anxiety, caused locomotion improvement and decreased brain atrophy in HIE animals. We did not find morphological differences on sensorimotor cortex, spinal cord, sciatic nerve, neuromuscular junctions and skeletal muscle in the animals submitted to HIE model. These intriguing data support the statement of the Rice-Vannucci model does not seem to reproduce, in structures involved in control function, the damage found in humans that suffer HIE. Regarding the protocols of exercise, we proposed that the acrobatic exercise could be a good therapeutic option especially in children affected by neonatal HIE and can be responsible for good results in cognitive and motor aspects.
Assuntos
Hipóxia-Isquemia Encefálica/fisiopatologia , Atividade Motora/fisiologia , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Feminino , Hipóxia/fisiopatologia , Hipóxia-Isquemia Encefálica/metabolismo , Isquemia/fisiopatologia , Locomoção/fisiologia , Masculino , Condicionamento Físico Animal/métodos , Gravidez , Ratos , Ratos Wistar , Córtex Sensório-Motor/fisiopatologiaRESUMO
OBJECTIVES: The attention-deficit/hyperactivity disorder (ADHD) compromises the quality of life of individuals including adaptation to the social environment. ADHD aetiology includes perinatal conditions such as hypoxic-ischaemic events; preclinical studies have demonstrated attentional deficits and impulsive-hyperactive outcomes after neonatal hypoxic and/or ischaemic intervention, but data are missing to understand this relationship. Thus, the aim of this study was to evaluate executive function (EF) and impulsivity, and tissue integrity and dopaminergic function in the prefrontal cortex (PFC) of rats submitted to hypoxia-ischaemia (HI). METHODS: At postnatal day (PND) 7, male Wistar rats were divided into control (n = 10) and HI groups (n = 11) and the HI procedure was conducted. At PND60, the animals were tested in the attentional set-shifting (ASS) task to EF and in the tolerance to delay of reward for assessment of impulsivity. After, morphological analysis and the dopaminergic system were evaluated in the PFC. RESULTS: Animals subjected to HI had impairments in EF evidenced by a behavioural inflexibility that was correlated to PFC atrophy. Moreover, HI animals presented reduced D2 receptors in the ipsilateral side of ischaemia in the PFC. CONCLUSIONS: Animals submitted to HI presented impaired EF associated with tissue atrophy and dopaminergic disturbance in the PFC.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Função Executiva , Hipóxia-Isquemia Encefálica/fisiopatologia , Comportamento Impulsivo , Córtex Pré-Frontal/fisiopatologia , Animais , Atrofia , Atenção , Comportamento Animal , Dopamina/metabolismo , Hipóxia-Isquemia Encefálica/metabolismo , Masculino , Ratos , Ratos Wistar , RecompensaRESUMO
Hypoxia-ischemia (HI) represents one of the most common causes of neonatal encephalopathy. The central nervous system injury comprises several mechanisms, including inflammatory, excitotoxicity, and redox homeostasis unbalance leading to cell death and cognitive impairment. Exercise during pregnancy is a potential therapeutic tool due to benefits offered to mother and fetus. Swimming during pregnancy elicits a strong metabolic programming in the offspring's brain, evidenced by increased antioxidant enzymes, mitochondrial biogenesis, and neurogenesis. This article aims to evaluate whether the benefits of maternal exercise are able to prevent behavioral brain injury caused by neonatal HI. Female adult Wistar rats swam before and during pregnancy (30min/day, 5 days/week, 4 weeks). At 7(th) day after birth, the offspring was submitted to HI protocol and, in adulthood (60(th) day), it performed the behavioral tests. It was observed an increase in motor activity in the open field test in HI-rats, which was not prevented by maternal exercise. The rats subjected to maternal swimming presented an improved long-term memory in the object recognition task, which was totally reversed by neonatal HI encephalopathy. BDNF brain levels were not altered; suggesting that HI or maternal exercise effects were BDNF-independent. In summary, our data suggest a beneficial long-term effect of maternal swimming, despite not being robust enough to protect from HI injury.
Assuntos
Hipóxia-Isquemia Encefálica/psicologia , Comportamento Materno , Memória de Longo Prazo , Reconhecimento Psicológico , Animais , Animais Recém-Nascidos , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Feminino , Hipóxia-Isquemia Encefálica/complicações , Hipóxia-Isquemia Encefálica/metabolismo , Masculino , Transtornos da Memória/prevenção & controle , Ratos , Ratos Wistar , NataçãoRESUMO
Recent findings have demonstrated a dual effect of the folic acid (FA) supplementation on the nervous system of rats. We found that FA treatment prevented memory impairment and Na(+), K(+)- ATPase inhibition in the striatum and cortex in adult rats that suffered neonatal hypoxia-ischemia (HI). However, spatial memory deficit has been associated with FA supplementation. In the present study we investigated the role of FA supplementation on spatial memory and Na(+), K(+)-ATPase activity in the hippocampus, as well as on morphologic alterations in adolescent rats submitted to neonatal HI. Wistar rats of both sexes at postnatal day (PND) 7 were submitted to Levine-Rice HI procedure. Intraperitoneal doses of FA were administered immediately before HI and repeated daily until the maximum PND 40. Hippocampal volume and striatum area were estimated and Na(+), K(+)-ATPase activity in the hippocampus was measured at PND 31. Also, the performance of the animals in the water maze was assessed and Na(+), K(+)-ATPase activity measured again at PND 52. Interestingly, HI and FA resulted in spatial memory deficits in the Morris water maze and the Na(+), K(+)-ATPase activity was impaired at PND 31 in HI rats which received FA. Additionally, Na(+), K(+)-ATPase activity in adulthood showed a decrease after HI and a recovery in supplemented animals. Hippocampal and striatal atrophy were partially reversed by FA. To conclude, the present results support the hypothesis that FA supplementation during development contributes to memory deficits caused by HI and Na(+), K(+)-ATPase failure in adolescent rats, although, in adulthood, FA has been effective in reversing enzymatic activity in the hippocampus.
Assuntos
Ácido Fólico/toxicidade , Hipocampo/enzimologia , Hipóxia-Isquemia Encefálica/enzimologia , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/enzimologia , ATPase Trocadora de Sódio-Potássio/metabolismo , Fatores Etários , Animais , Animais Recém-Nascidos , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Hipóxia-Isquemia Encefálica/patologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/patologia , Ratos , Ratos Wistar , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidoresRESUMO
Pregnancy is a critical period for brain metabolic programming, being affected by individual environment, such as nutrition, stress, and physical exercise. In this context, we previously reported a cerebral antioxidant upregulation and mitochondrial biogenesis in the offspring delivered from exercised mothers, which could provide neuroprotection against neonatal insults. Hypoxia-ischemia (HI) encephalopathy is one of the most studied models of neonatal brain injury; disrupting motor, cognitive, and learning abilities. Physiopathology includes oxidative stress, allied to mitochondria energy production failure, glutamatergic excitotoxicity, and cell death. In this study we evaluated the effect of maternal swimming during pregnancy on offspring׳s brain oxidative status evaluated fourteen days after HI stablishment. Swimming exercise was performed by female adult rats one week before and during pregnancy, in controlled environment. Their offspring was submitted to HI on postnatal day 7, and the brain samples for biochemical assays were obtained in the weaning. Contrary to our expectations, maternal exercise did not prevent the oxidative alterations observed in brain from HI-rats. In a general way, we found a positive modulation in the activities of antioxidant enzymes, measured two weeks after HI, in hippocampus, striatum, and cerebellum of pups delivered from exercised mothers. Reactive species levels were modulated differently in each structure evaluated. Considering the scenery presented, we concluded that HI elicited a neurometabolic adaptation in both brain hemispheres, particularly in hippocampus, parietal cortex, and cerebellum; while striatum appears to be most damaged. The protocol of aerobic maternal exercise was not enough to fully prevent HI-induced brain damages.
Assuntos
Encéfalo/metabolismo , Hipóxia-Isquemia Encefálica/metabolismo , Efeitos Tardios da Exposição Pré-Natal , Natação/fisiologia , Animais , Animais Recém-Nascidos , Antioxidantes/metabolismo , Modelos Animais de Doenças , Feminino , Fluoresceínas/metabolismo , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Estresse Oxidativo/fisiologia , Condicionamento Físico Animal/fisiologia , Gravidez , Ratos Wistar , Superóxido Dismutase/metabolismoRESUMO
Stroke causes disability and mortality worldwide and is divided into ischemic and hemorrhagic subtypes. Although clinical trials suggest distinct recovery profiles for ischemic and hemorrhagic events, this is not conclusive due to stroke heterogeneity. The aim of this study was to produce similar brain damage, using experimental models of ischemic (IS) and hemorrhagic (HS) stroke and evaluate the motor spontaneous recovery profile. We used 31 Wistar rats divided into the following groups: Sham (n=7), ischemic (IS) (n=12) or hemorrhagic (HS) (n=12). Brain ischemia or hemorrhage was induced by endotelin-1 (ET-1) and collagenase type IV-S (collagenase) microinjections, respectively. All groups were evaluated in the open field, cylinder and ladder walk behavioral tests at distinct time points as from baseline to 30 days post-surgery (30 PS). Histological and morphometric analyses were used to assess the volume of lost tissue and lesion length. Present results reveal that both forms of experimental stroke had a comparable long-term pattern of damage, since no differences were found in volume of tissue lost or lesion size 30 days after surgery. However, behavioral data showed that hemorrhagic rats were less impaired at skilled walking than ischemic ones at 15 and 30 days post-surgery. We suggest that experimentally comparable stroke design is useful because it reduces heterogeneity and facilitates the assessment of neurobiological differences related to stroke subtypes; and that spontaneous skilled walking recovery differs between experimental ischemic and hemorrhagic insults.
Assuntos
Isquemia Encefálica/psicologia , Encéfalo/patologia , Hemorragias Intracranianas/psicologia , Recuperação de Função Fisiológica , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/psicologia , Animais , Isquemia Encefálica/induzido quimicamente , Isquemia Encefálica/complicações , Isquemia Encefálica/patologia , Colagenases/administração & dosagem , Endotelina-1/administração & dosagem , Hemorragias Intracranianas/induzido quimicamente , Hemorragias Intracranianas/complicações , Hemorragias Intracranianas/patologia , Masculino , Microinjeções , Atividade Motora/efeitos dos fármacos , Destreza Motora/efeitos dos fármacos , Ratos , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/diagnósticoRESUMO
Hypoxia-ischemia (HI) is the main cause of mortality in the perinatal period and morbidity, in survivors, which is characterized by neurological disabilities. The immature brain is highly susceptible to hypoxic-ischemic insult and is responsive to environmental stimuli, such as environmental enrichment (EE). Previous results indicate that EE recovered memory deficits in adult rats without reversing hippocampal atrophy related to HI. The aim of this study was to investigate behavioral performance in the open field and rota-rod apparatuses, in object recognition and inhibitory avoidance tasks, as well as dendritic spine density in the hippocampus, in rats undergoing HI and exposed to EE. Seven-day old male rats were submitted to the HI procedure and divided into 4 groups: control maintained in standard environment (CTSE), controls submitted to EE (CTEE), HI in standard environment (HISE) and HI in EE (HIEE). Behavioral and morphological parameters were evaluated 9 weeks after the environmental stimulation. Results indicate impairment in the object recognition task after HI that was recovered by enrichment; however the aversive memory impairment in the inhibitory avoidance task shown by hypoxic-ischemic rats was independent of the environment condition. Hypoxic-ischemic groups showed more crossing responses during the first minute in the open field, when compared to controls, but no differences were found between experimental groups in the rota-rod test. Dendritic spine density in the CA1 subfield of the right hippocampus (ipsilateral to the artery occlusion) was decreased after the HI insult, and increased in enriched controls; interestingly enriched HI rats did not differ from CTSE. In conclusion, EE was effective in recovering declarative memory impairment in object recognition and preserved hippocampal dendritic spine density loss after neonatal HI injury.
Assuntos
Comportamento Animal/fisiologia , Espinhas Dendríticas/patologia , Meio Ambiente , Hipocampo/patologia , Hipóxia-Isquemia Encefálica , Análise de Variância , Animais , Animais Recém-Nascidos , Aprendizagem da Esquiva/fisiologia , Modelos Animais de Doenças , Comportamento Exploratório/fisiologia , Hipocampo/ultraestrutura , Hipóxia-Isquemia Encefálica/enfermagem , Hipóxia-Isquemia Encefálica/patologia , Hipóxia-Isquemia Encefálica/fisiopatologia , Inibição Psicológica , Masculino , Desempenho Psicomotor/fisiologia , Ratos , Ratos Wistar , Reconhecimento Psicológico/fisiologia , Teste de Desempenho do Rota-Rod , Coloração pela PrataRESUMO
Folic acid plays an important role in neuroplasticity and acts as a neuroprotective agent, as observed in experimental brain ischemia studies. The aim of this study was to investigate the effects of folic acid on locomotor activity, aversive memory and Na(+),K(+)-ATPase activity in the frontal cortex and striatum in animals subjected to neonatal hypoxia-ischemia (HI). Wistar rats of both sexes at postnatal day 7 underwent HI procedure and were treated with intraperitoneal injections of folic acid (0.011 µmol/g body weight) once a day, until the 30th postnatal day. Starting on the day after, behavioral assessment was run in the open field and in the inhibitory avoidance task. Animals were sacrificed by decapitation 24 h after testing and striatum and frontal cortex were dissected out for Na(+),K(+)-ATPase activity analysis. Results show anxiogenic effect in the open field and an impairment of aversive memory in the inhibitory avoidance test in HI rats; folic acid treatment prevented both behavioral effects. A decreased Na(+),K(+)-ATPase activity in striatum, both ipsilateral and contralateral to ischemia, was identified after HI; a total recovery was observed in animals treated with folic acid. A partial recovery of Na(+),K(+)-ATPase activity was yet seen in frontal cortex of HI animals receiving folic acid supplementation. Presented results support that folic acid treatment prevents memory deficit and anxiety-like behavior, as well as prevents Na(+),K(+)-ATPase inhibition in the striatum and frontal cortex caused by neonatal hypoxia-ischemia.