Aversive memory reactivation: A possible role for delta oscillations in the hippocampus-amygdala circuit.

Memory labilization, the process by which memories become susceptible to update, is essential for memory reconsolidation and has been a target for novel therapies for traumatic memory-associated disorders. Maternal separation (MS) in male rats produced memories resistant to labilization in adulthood. Based on previous results, we hypothesized that temporal desynchronization between the dorsal hippocampus (DHc) and the basolateral amygdala (BLA), during memory retrieval, could be responsible for this impairment. Our goal was to investigate possible differences in oscillatory activity and synchrony between the DHc and BLA during fear memory reactivation, between MS and non-handled (NH) rats. We used male adult Wistar rats, NH or MS, with electrodes for local field potential (LFP) recordings implanted in the DHc and BLA. Animals were submitted to aversive memory reactivation by exposure to the conditioned context (Reat) or to pseudo-reactivation in a neutral context (pReat), and LFP was recorded. Plasticity markers linked to reconsolidation were evaluated one hour after reactivation. The power of delta oscillations and DHc-BLA synchrony in Reat animals was increased, during freezing. Besides, delta modulation of gamma oscillations amplitude in the BLA was associated with the increase in DHc Zif268 levels, an immediate early gene specifically associated with reconsolidation. Concerning early life stress, we found lower power of delta and strength of delta-gamma oscillations coupling in MS rats, compared to NH, which could explain the low Zif268 levels in a subgroup of MS animals. These results suggest a role for delta oscillations in memory reactivation that should be further investigated.

Olive oil-rich diet during pregnancy/lactation attenuated the early life stress effects on depressive-like behavior and altered energy metabolism in the dorsal hippocampus in a sex-specific manner.

METHODS: and results: Pregnant Wistar rats received diets enriched in soybean oil (SO) or OO during gestation/lactation. At birth, litters were subdivided into MS or intact groups. After weaning, the pups received standard chow until adulthood, when they were subjected to behavioral tasks. At PND90 biochemical analyses were performed. Maternal OO-enriched diet prevented MS-induced higher weight gain, and decreased MS-induced anhedonic behavior. Increased latency to immobility and shorter immobility time were observed in the maternal OO-enrich diet groups. Maternal OO-enrich diet groups also presented reduced reactive oxygen species and increased activity of antioxidant enzymes. In addition, this diet showed sex-specific effects, by decreasing mitochondrial mass and potential, reducing AMPK activation, and increasing synaptophysin and PSD-95 immunocontent in the DH of male rats. Early stress, on the other hand, decreased production of free radicals and decreased levels of SIRT1 in the DH of male rats. In females, OO prevented the anhedonic behavior induced by MS. CONCLUSIONS: Maternal OO-enrich diet attenuated MS-induced depressive behavior in both sexes. In addition, it affected energy metabolism in the DH of male rats, favored synaptic plasticity, and contributed to reducing pathophysiological conditions.

Pre- and early postnatal enriched environmental experiences prevent neonatal hypoxia-ischemia late neurodegeneration via metabolic and neuroplastic mechanisms.

Prenatal and early postnatal periods are important for brain development and neural function. Neonatal insults such as hypoxia-ischemia (HI) causes prolonged neural and metabolic dysregulation, affecting central nervous system maturation. There is evidence that brain hypometabolism could increase the risk of adult-onset neurodegenerative diseases. However, the impact of non-pharmacologic strategies to attenuate HI-induced brain glucose dysfunction is still underexplored. This study investigated the long-term effects of early environmental enrichment in metabolic, cell, and functional responses after neonatal HI. Thereby, male Wistar rats were divided according to surgical procedure, sham, and HI (performed at postnatal day 3), and the allocation to standard (SC) or enriched condition (EC) during gestation and lactation periods. In-vivo cerebral metabolism was assessed by means of [18 F]-FDG micro-positron emission tomography, and cognitive, biochemical, and histological analyses were performed in adulthood. Our findings reveal that HI causes a reduction in glucose metabolism and glucose transporter levels as well as hyposynchronicity in metabolic brain networks. However, EC during prenatal or early postnatal period attenuated these metabolic disturbances. A positive correlation was observed between [18 F]-FDG values and volume ratios in adulthood, indicating that preserved tissue by EC is metabolically active. EC promotes better cognitive scores, as well as down-regulation of amyloid precursor protein in the parietal cortex and hippocampus of HI animals. Furthermore, growth-associated protein 43 was up-regulated in the cortex of EC animals. Altogether, results presented support that EC during gestation and lactation period can reduce HI-induced impairments that may contribute to functional decline and progressive late neurodegeneration.

Prefrontal cortex VAMP1 gene network moderates the effect of the early environment on cognitive flexibility in children.

During development, genetic and environmental factors interact to modify specific phenotypes. Both in humans and in animal models, early adversities influence cognitive flexibility, an important brain function related to behavioral adaptation to variations in the environment. Abnormalities in cognitive functions are related to changes in synaptic connectivity in the prefrontal cortex (PFC), and altered levels of synaptic proteins. We investigated if individual variations in the expression of a network of genes co-expressed with the synaptic protein VAMP1 in the prefrontal cortex moderate the effect of early environmental quality on the performance of children in cognitive flexibility tasks. Genes overexpressed in early childhood and co-expressed with the VAMP1 gene in the PFC were selected for study. SNPs from these genes (post-clumping) were compiled in an expression-based polygenic score (PFC-ePRS-VAMP1). We evaluated cognitive performance of the 4 years-old children in two cohorts using similar cognitive flexibility tasks. In the first cohort (MAVAN) we utilized two CANTAB tasks: (a) the Intra-/Extra-dimensional Set Shift (IED) task, and (b) the Spatial Working Memory (SWM) task. In the second cohort, GUSTO, we used the Dimensional Change Card Sort (DCCS) task. The results show that in 4 years-old children, the PFC-ePRS-VAMP1 network moderates responsiveness to the effects of early adversities on the performance in attentional flexibility tests. The same result was observed for a spatial working memory task. Compared to attentional flexibility, reversal learning showed opposite effects of the environment, as moderated by the ePRS. A parallel ICA analysis was performed to identify relationships between whole-brain voxel based gray matter density and SNPs that comprise the PFC-ePRS-VAMP1. The early environment predicts differences in gray matter content in regions such as prefrontal and temporal cortices, significantly associated with a genetic component related to Wnt signaling pathways. Our data suggest that a network of genes co-expressed with VAMP1 in the PFC moderates the influence of early environment on cognitive function in children.

Chronic high-fat diet affects food-motivated behavior and hedonic systems in the nucleus accumbens of male rats.

Environmental variations can influence eating and motivated behaviors, as well as the brain's feeding circuits to predisposing overweight and obesity. The identification of mechanisms through which a long-term consumption of caloric-dense palatable foods and its association with early life stress can cause neuroadaptations and possible modify motivational behaviors are relevant to elucidate the mechanisms associated with obesity. Here, we investigated the long-term effects of a chronic high-fat diet (HFD), and its interaction with early social isolation on hedonic feeding responses in adult rats. Rats were subjected, or not, to social isolation between postnatal days 21-28 and were fed a control diet or HFD, for 10 weeks post weaning. Hedonic feeding behavior was evaluated during adulthood and parameters related to the dopaminergic, cannabinoid, and opioid systems were measured in the nucleus accumbens. Animals with chronic HFD intake were less motivated to obtain sweet palatable foods. This reduced motivation did not appear to be associated with less pleasure upon tasting sweet food, as no alteration in reactivity to sweet taste was observed. Interestingly, the animals receiving HFD presented decreased immunocontents of the D1 and CB1 receptors, while the stressed group displayed a reduction in dopamine turnover. In summary, chronic HFD causes a significant motivational impairment for sweet palatable foods; these changes may be associated with a decreased dopaminergic and cannabinoid neurotransmission in the nucleus accumbens. In contrast, a brief social isolation during the prepubertal period was unable to alter the behavioral parameters studied but caused a decreased dopaminergic turnover in the nucleus accumbens of adult rats. These findings highlight the importance of long-term HFD exposure on the modulation of hedonic feeding behavior and related neurochemical systems.

Chronic Stress Causes Sex-Specific and Structure-Specific Alterations in Mitochondrial Respiratory Chain Activity in Rat Brain.

Chronic restraint stress (CRS) induces a variety of changes in brain function, some of which are mediated by glucocorticoids. The response to stress occurs in a sex-specific way, and may include mitochondrial and synaptic alterations. The synapse is highly dependent on mitochondrial energy supply, and when mitochondria become dysfunctional, they orchestrate cell death. This study aimed to investigate the CRS effects on mitochondrial respiratory chain activity, as well as mitochondrial potential and mass in cell body and synapses using hippocampus, cortex and striatum of male and female rats. Rats were divided into non-stressed (control) and stressed group (CRS during 40 days). Results showed that CRS increased complex I-III activity in hippocampus. We also observed an interaction between CRS and sex in the striatal complex II activity, since CRS induced a reduction in complex II activity in males, while in females this activity was increased. Also an interaction was observed between stress and sex in cortical complex IV activity, since CRS induced increased activity in females, while it was reduced in males. Glucocorticoid receptor (GR) content in cortex and hippocampus was sexually dimorphic, with female rats presenting higher levels compared to males. No changes were observed in GR content, mitochondrial potential or mass of animals submitted to CRS. It was concluded that CRS induced changes in respiratory chain complex activities, and some of these changes are sex-dependent: these activities are increased in the striatal mitochondria by CRS protocol mainly in females, while in males it is decreased.

Neonatal handling causes impulsive behavior and decreased pharmacological response to methylphenidate in male adult wistar rats.

Neonatal handling has an impact on adult behavior of experimental animals and is associated with rapid and increased palatable food ingestion, impaired behavioral flexibility, and fearless behavior to novel environments. These symptoms are characteristic features of impulsive trait, being controlled by the medial prefrontal cortex (mPFC). Impulsive behavior is a key component of many psychiatric disorders such as attention deficit hyperactivity disorder (ADHD), manic behavior, and schizophrenia. Others have reported a methylphenidate (MPH)-induced enhancement of mPFC functioning and improvements in behavioral core symptoms of ADHD patients. The aims of the present study were: (i) to find in vivo evidence for an association between neonatal handling and the development of impulsive behavior in adult Wistar rats and (ii) to test whether neonatal handling could have an impact on monoamine levels in the mPFC and the pharmacological response to MPH in vivo. Therefore, experimental animals (litters) were classified as: "non-handled" and "handled" (10[Formula: see text]min/day, postnatal days 1-10). After puberty, they were exposed to either a larger and delayed or smaller and immediate reward (tolerance to delay of reward task). Acute MPH (3[Formula: see text]mg/Kg. i.p.) was used to suppress and/or regulate impulsive behavior. Our results show that only neonatally handled male adult Wistar rats exhibit impulsive behavior with no significant differences in monoamine levels in the medial prefrontal cortex, together with a decreased response to MPH. On this basis, we postulate that early life interventions may have long-term effects on inhibitory control mechanisms and affect the later response to pharmacological agents during adulthood.

Mitochondrial and Oxidative Stress Aspects in Hippocampus of Rats Submitted to Dietary n-3 Polyunsaturated Fatty Acid Deficiency After Exposure to Early Stress.

Chronic dietary long-chain polyunsaturated fatty acids (PUFAs) deficiency may lead to changes in cortex and hippocampus neuronal membrane phospholipids, and may be linked to impaired central nervous system function. Particularly docosahexaenoic acid deficiency appears to be involved in neuropsychiatric disorders. On the other hand, adverse events early in life may also profoundly affect brain development, leading to long-lasting effects on neurophysiology, neurobiology and behavior. This research assessed if neonatal stress and a dietary n-3 PUFAs deficiency could interact to produce hippocampal alterations related to mitochondrial functions in adult rats. There were no effects of diet, neonatal intervention or interactions on superoxide dismutase or catalase enzymatic activities, mitochondrial membrane potential and respiratory chain complexes. Rats fed n-3 PUFAs deficient diet displayed higher levels of glutathione peroxidase and catalase activity, higher free radicals production and higher thiol content compared to rats fed n-3 PUFAs adequate diet. There were interactions among diets and neonatal stress, since glutathione peroxidase, free radicals production and thiol content were increased in groups that were subjected to neonatal interventions fed n-3 PUFAs deficient diet. Additionally, reduced mitochondrial potential was observed in handled animals. Total thiol revealed a neonatal stress effect, since animals subjected to neonatal interventions displayed lower thiol content. In conclusion, we observed that a chronic treatment with deficient n-3 PUFAs diet, from the puberty period on, increased free radicals production and imbalanced antioxidant enzymes activities, and these increases were higher in animals subjected to neonatal interventions.

Contextual fear conditioning in maternal separated rats: the amygdala as a site for alterations.

The first 2 weeks of life are a critical period for neural development in rats. Repeated long-term separation from the dam is considered to be one of the most potent stressors to which rat pups can be exposed, and permanently modifies neurobiological and behavioral parameters. Prolonged periods of maternal separation (MS) usually increase stress reactivity during adulthood, and enhance anxiety-like behavior. The aim of this study was to verify the effects of maternal separation during the neonatal period on memory as well as on biochemical parameters (Na(+), K(+)-ATPase and antioxidant enzymes activities) in the amygdala of adult rats. Females and male Wistar rats were subjected to repeated maternal separation (incubator at 32 °C, 3 h/day) during postnatal days 1-10. At 60 days of age, the subjects were exposed to a Contextual fear conditioning task. One week after the behavioral task, animals were sacrificed and the amygdala was dissected for evaluation of Na(+), K(+)-ATPase and antioxidant enzymes activities. Student-t test showed significant MS effect, causing an increase of freezing time in the three exposures to the aversive context in both sexes. Considering biochemical parameters Student-t test showed significant MS effect causing an increase of Na(+), K(+)-ATPase activity in both sexes. On the other hand, no differences were found among the groups on the antioxidant enzymes activities [superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT)] in male rats, but in females, we found a significant MS effect, causing an increase of CAT activity and no differences were found among the groups on SOD and GPx activities. Our results suggest a role of early rearing environment in programming fear learning and memory in adulthood. An early stress experience such as maternal separation may increase activity in the amygdala (as pointed by the increased activity of Na(+), K(+)-ATPase), affecting behaviors related to fear in adulthood, and this effect could be task-specific.

Neonatal environmental intervention alters the vulnerability to the metabolic effects of chronic palatable diet exposure in adulthood.

Previous studies have demonstrated that early environmental interventions influence the consumption of palatable food and the abdominal fat deposition in female rats chronically exposed to a highly caloric diet in adulthood. In this study, we verified the metabolic effects of chronic exposure to a highly palatable diet, and determine the response to its withdrawal in adult neonatally handled and non-handled rats. Consumption of foods (standard lab chow and chocolate), body weight gain, abdominal fat deposition, plasma triglycerides, and leptin, as well as serum butyrylcholinesterase (BuChE), and cerebral acetylcholinesterase (AChE) activities were measured during chronic chocolate exposure and after deprivation of this palatable food in female rats exposed or not to neonatal handling (10 minutes/day, 10 first days of life). Handled rats increased rebound chocolate consumption in comparison to non-handled animals after 1 week of chocolate withdrawal; these animals also decreased body weight in the first 24 hours but this effect disappeared after 7 days of withdrawal. Chocolate increased abdominal fat in non-handled females, and this effect remained after 30 days of withdrawal; no differences in plasma leptin were seen after 7 days of withdrawal. Chocolate also increased serum BuChE activity in non-handled females, this effect was still evident after 7 days of withdrawal, but it disappeared after 30 days of withdrawal. Chocolate deprivation decreased cerebral AChE activity in both handled and non-handled animals. These findings suggest that neonatal handling modulates the preference for palatable food and induces a specific metabolic response that may be more adaptive in comparison to non-handled rats.

Correlation between n-3 polyunsaturated fatty acids consumption and BDNF peripheral levels in adolescents.

BACKGROUND: Although several studies have reported an association between mental disorders and serum levels of brain-derived neurotrophic factor (BDNF), this association is still poorly understood. The study of factors associated with both BDNF levels and mental disorders, such as n-3 polyunsaturated fatty acids (n-3 PUFAs), may help to elucidate the mechanisms mediating the relationship between the two variables. Therefore, the present study aimed to evaluate whether the intake n-3 PUFAs correlates with serum levels of BDNF. FINDINGS: This study involved 137 adolescents drawn from a community sample, including a group with high levels of anxiety, assessed using the Screen for Children and Anxiety Related Emotional Disorders. Blood samples were collected and serum BDNF levels were measured. n-3 PUFAs were estimated using a food frequency questionnaire for adolescents. Correlations were performed to assess the association between n-3 PUFAs intake and BDNF levels. Effects of potential confounders (total fat consumption, age, gender and anxiety) were examined using linear regression models. There was a direct correlation between n-3 PUFAs consumption and serum BDNF levels, which remained significant even after accounting for potential confounders. CONCLUSIONS: We were able to detect a correlation between n-3 PUFAs intake and peripheral BDNF levels. Our study was limited by its small sample size, and our external validity may be restricted by the oversampling of anxious adolescents. Our findings may help determine the nature of the association between mental disorders and serum levels of BDNF. However, more studies are needed to elucidate the possible mechanisms by which n-3 PUFAs intake affects BDNF levels, and how this may lead to an increased vulnerability to psychiatric disorders.

Acrobatic training prevents learning impairments and astrocyte remodeling in the hippocampus of rats undergoing chronic cerebral hypoperfusion: sex-specific benefits.

Background: Chronic cerebral hypoperfusion (CCH) leads to memory and learning impairments associated with degeneration and gliosis in the hippocampus. Treatment with physical exercise carries different therapeutic benefits for each sex. We investigated the effects of acrobatic training on astrocyte remodeling in the CA1 and CA3 subfields of the hippocampus and spatial memory impairment in male and female rats at different stages of the two-vessel occlusion (2VO) model. Methods: Wistar rats were randomly allocated into four groups of males and females: 2VO acrobatic, 2VO sedentary, sham acrobatic, and sham sedentary. The acrobatic training was performed for 4 weeks prior to the 2VO procedure. Brain samples were collected for morphological and biochemical analysis at 3 and 7 days after 2VO. The dorsal hippocampi were removed and prepared for Western blot quantification of Akt, p-Akt, COX IV, cleaved caspase-3, PARP, and GFAP. GFAP immunofluorescence was performed on slices of the hippocampus to count astrocytes and apply the Sholl's circle technique. The Morris water maze was run after 45 days of 2VO. Results: Acutely, the trained female rats showed increased PARP expression, and the 2VO-trained rats of both sexes presented increased GFAP levels in Western blot. Training, mainly in males, induced an increase in the number of astrocytes in the CA1 subfield. The 2VO rats presented branched astrocytes, while acrobatic training prevented branching. However, the 2VO-induced spatial memory impairment was partially prevented by the acrobatic training. Conclusion: Acrobatic training restricted the astrocytic remodeling caused by 2VO in the CA1 and CA3 subfields of the hippocampus. The improvement in spatial memory was associated with more organized glial scarring in the trained rats and better cell viability observed in females.

Neuroinflammation, blood-brain barrier dysfunction, hippocampal atrophy and delayed neurodevelopment: Contributions for a rat model of congenital Zika syndrome.

The congenital Zika syndrome (CZS) has been characterized as a set of several brain changes, such as reduced brain volume and subcortical calcifications, in addition to cognitive deficits. Microcephaly is one of the possible complications found in newborns exposed to Zika virus (ZIKV) during pregnancy, although it is an impacting clinical sign. This study aimed to investigate the consequences of a model of congenital ZIKV infection by evaluating the histopathology, blood-brain barrier, and neuroinflammation in pup rats 24 h after birth, and neurodevelopment of the offspring. Pregnant rats were inoculated subcutaneously with ZIKV-BR at the dose 1 × 107 plaque-forming unit (PFU mL-1) of ZIKV isolated in Brazil (ZIKV-BR) on gestational day 18 (G18). A set of pups, 24 h after birth, was euthanized. The brain was collected and later evaluated for the histopathology of brain structures through histological analysis. Additionally, analyses of the blood-brain barrier were conducted using western blotting, and neuroinflammation was assessed using ELISA. Another set of animals was evaluated on postnatal days 3, 6, 9, and 12 for neurodevelopment by observing the developmental milestones. Our results revealed hippocampal atrophy in ZIKV animals, in addition to changes in the blood-brain barrier structure and pro-inflammatory cytokines expression increase. Regarding neurodevelopment, a delay in important reflexes during the neonatal period in ZIKV animals was observed. These findings advance the understanding of the pathophysiology of CZS and contribute to enhancing the rat model of CZS.

Coping with the experience of frustration throughout life: Sex- and age-specific effects of early life stress on the susceptibility to reward devaluation.

Early life stress may lead to lifelong impairments in psychophysiological functions, including emotional and reward systems. Unpredicted decrease in reward magnitude generates a negative emotional state (frustration) that may be involved with susceptibility to psychiatric disorders. We evaluated in adolescents and adult rats of both sexes whether maternal separation (MS) alters the ability to cope with an unexpected reduction of reward later in life. Litters of Wistar rats were divided into controls (non handled - NH) or subjected to MS. Animals were trained to find sugary cereal pellets; later the amount was reduced. Increased latency to reach the reward-associated area indicates higher inability to regulate frustration. The dorsal hippocampus (dHC) and basolateral amygdala (BLA) were evaluated for protein levels of NMDA receptor subunits (GluN2A/GluN2B), synaptophysin, PSD95, SNAP-25 and CRF1. We found that adult MS males had greater vulnerability to reward reduction, together with decreased GluN2A and increased GluN2B immunocontent in the dHC. MS females and adolescents did not differ from controls. We concluded that MS enhances the response to frustration in males. The change in the ratio of GluN2A and GluN2B subunits in dHC could be related to a stronger, more difficult to update, memory of the aversive experience.

Stress during the pre-pubertal period leads to long-term diet-dependent changes in anxiety-like behavior and in oxidative stress parameters in male adult rats.

Social isolation during early development is one of the most potent stressors that can cause alterations in the processes of brain maturation, leading to behavioral and neurochemical changes that may persist to adulthood. Exposure to palatable diets during development can also affect neural circuits with long-term consequences. The aims of the present study were to investigate the long-term effects of isolation stress during the pre-pubertal period on the exploratory and anxiety-like behavior, the oxidative stress parameters and the respiratory chain enzymes activities in the hippocampus of adult male rats under chronic palatable diets. The results showed that isolated rats receiving either normal or high-fat diet during the pre-pubertal period presented an anxiolytic-like behavior. The animals exposed to stress and treated with high-carbohydrate diet, rich in disaccharides, on the other hand, presented the opposite pattern of behavior. Stress in the pre-pubertal period also leads to decreased activity of the antioxidant enzymes and the mitochondrial respiratory chain complexes II and IV and decreased total thiol content. These effects were reversed by high-fat diet when it was associated with stress. The effects of a sub-acute pre-pubertal isolation stress on anxiety-like behavior and on hippocampal oxidative imbalance during adulthood appear to be modulated by different types of diets, and probably different mechanisms are involved.

Bumetanide Attenuates Cognitive Deficits and Brain Damage in Rats Subjected to Hypoxia-Ischemia at Two Time Points of the Early Postnatal Period.

Neonatal hypoxia-ischemia (HI) is one of the main causes of tissue damage, cell death, and imbalance between neuronal excitation and inhibition and synaptic loss in newborns. GABA, the major inhibitory neurotransmitter of the central nervous system (CNS) in adults, is excitatory at the onset of neurodevelopment and its action depends on the chloride (Cl-) cotransporters NKCC1 (imports Cl-) and KCC2 (exports Cl-) expression. Under basal conditions, the NKCC1/KCC2 ratio decreases over neurodevelopment. Thus, changes in this ratio caused by HI may be related to neurological disorders. The present study evaluated the effects of bumetanide (NKCC cotransporters inhibitor) on HI impairments in two neurodevelopmental periods. Male Wistar rat pups, 3 (PND3) and 11 (PND11) days old, were submitted to the Rice-Vannucci model. Animals were divided into 3 groups: SHAM, HI-SAL, and HI-BUM, considering each age. Bumetanide was administered intraperitoneally at 1, 24, 48, and 72 h after HI. NKCC1, KCC2, PSD-95, and synaptophysin proteins were analyzed after the last injection by western blot. Negative geotaxis, righting reflex, open field, object recognition test, and Morris water maze task were performed to assess neurological reflexes, locomotion, and memory function. Tissue atrophy and cell death were evaluated by histology. Bumetanide prevented neurodevelopmental delay, hyperactivity, and declarative and spatial memory deficits. Furthermore, bumetanide reversed HI-induced brain tissue damage, reduced neuronal death and controlled GABAergic tone, maintained the NKCC1/KCC2 ratio, and synaptogenesis close to normality. Thereby, bumetanide appears to play an important therapeutic role in the CNS, protecting the animals against HI damage and improving functional performance.

Long-lasting effects of maternal separation on an animal model of post-traumatic stress disorder: effects on memory and hippocampal oxidative stress.

Adverse early life events, such as periodic maternal separation, may alter the normal pattern of brain development and subsequently the vulnerability to a variety of mental disorders in adulthood. Patients with a history of early adversities show higher frequency of post-traumatic stress disorder (PTSD). This study was undertaken to verify if repeated long-term separation of pups from dams would affect memory and oxidative stress parameters after exposure to an animal model of PTSD. Nests of Wistar rats were divided into intact and subjected to maternal separation (incubator at 32°C, 3 h/day) during post-natal days 1-10. When adults, the animals were subdivided into exposed or not to a PTSD model consisting of exposure to inescapable footshock, followed by situational reminders. One month after exposure to the shock, the animals were exposed to a memory task (Morris water maze) and another month later animals were sacrificed and DNA breaks and antioxidant enzymes activities were measured in the hippocampus. Rats exposed to shock or maternal separation plus shock showed long-lasting effects on spatial memory, spending more time in the opposite quadrant of the water maze. This effect was higher in animals subjected to both maternal separation and shock. Both shock and maternal separation induced a higher score of DNA breaks in the hippocampus. No differences were observed on antioxidant enzymes activities. In conclusion, periodic maternal separation may increase the susceptibility to the effects of a stressor applied in adulthood on performance in the water maze. Increased DNA breaks in hippocampus was induced by both, maternal separation and exposure to shock.

Maternal depression model: long-lasting effects on the mother following separation from pups.

This study was carried out to ascertain the effects of maternal separation (3 h per day) of mothers from their pups in the neonatal period in rats, which has been suggested to induce a depressive-like state, would have long lasting effects on different parameters including hippocampal Na(+), K(+)-ATPase activity, NO production, free radical production and antioxidant enzymes activities in dams. Fourty-eight Wistar rats were divided into 3 groups: control, brief separation (10 min) and long separation (3 h). The neonatal interventions were done on postpartum days 1-10. At 35 days post-partum the dams were killed and the hippocampal Na(+), K(+)-ATPase activity were measured, as well as the activity of the antioxidant enzymes catalase, glutathione peroxidase, superoxide dismutase, free radicals production, and the production of nitric oxide. Hippocampal Na(+), K(+)-ATPase activity was decreased in the brief separated group and in dams subjected to 3 h separation from their pups. A reduction in nitric oxide levels in the hippocampus in dams of the long separated group was also observed. It is concluded that the withdrawal of pups from their mothers make the mothers more susceptible to the development of neurochemical alterations that could be related to depressive features.

The influence of early life interventions on olfactory memory related to palatable food, and on oxidative stress parameters and Na+/K+-ATPase activity in the hippocampus and olfactory bulb of female adult rats.

The effects of neonatal handling and the absence of ovarian hormones on the olfactory memory related to a palatable food in adulthood were investigated. Oxidative stress parameters and Na+/K+-ATPase activity in the hippocampus and olfactory bulb of adult pre-puberty ovariectomized female rats handled or not in the neonatal period were also evaluated. Litters were non-handled or handled (10 min/day, days 1-10 after birth). Females from each litter were divided into: OVX (subjected to ovariectomy), sham, and intact. When adults, olfactory memory related to a palatable food (chocolate) was evaluate using the hole-board olfactory task. Additionally, oxidative stress parameters and Na+/K+-ATPase activity were measured in the hippocampus and olfactory bulb. No difference between groups was observed considering olfactory memory evaluation. Neonatal handled rats presented an increase in Na+/K+-ATPase activity in the hippocampus and in the olfactory bulb, compared to non-handled ones. Considering the surgical procedure, there was a decrease in Na+/K+-ATPase and catalase activities in sham and OVX groups, compared to intact animals in the olfactory bulb. We concluded that olfactory memory related to a palatable food in adulthood was not affected by neonatal handling or by pre-puberty surgery, with or without removal of ovaries. The difference observed between groups in catalase and Na+/K+-ATPase activity does not seem to be related to the olfactory memory. Additionally, the increase in Na+/K+-ATPase activity (an enzyme that maintains the neurochemical gradient necessary for neuronal excitability) induced by neonatal handling may be related to neuroplastic changes in the hippocampus and olfactory bulb.

Effects of Early Life Adversities upon Memory Processes and Cognition in Rodent Models.

Exposure to stressors in early postnatal life induces long-lasting modifications in brain function. This plasticity, an essential characteristic of the brain that enables adaptation to the environment, may also induce impairments in some psychophysiological functions, including learning and memory. Early life stress (ELS) has long-term effects on the hypothalamic-pituitary-adrenal axis response to stressors, and has been reported to lead to neuroinflammation, altered levels of neurotrophic factors, modifications in neurogenesis and synaptic plasticity, with changes in neurotransmitter systems and network functioning. In this review, we focus on early postnatal stress in animal models and their effects on learning and memory. Many studies have reported ELS-induced impairments in different types of memories, including spatial memory, fear memory, recognition (both for objects and social) memory, working memory and reversal learning. Studies are not always in agreement, however, no effects, or sometimes facilitation, being reported, depending on the nature and intensity of the early intervention, as well as the age when the outcome was evaluated and the sex of the animals. When considering processes occurring after consolidation, related with memory maintenance/persistence or transformation, there are a very reduced number of reports. Future studies addressing the mechanisms underlying memory changes for ELS should shed some light on the understanding of the different effects induced by stressors of different types and intensities on cognitive functions.