A high fat diet potentiates neonatal iron overload-induced memory impairments in rats.

PURPOSE: The present study aimed at evaluating possible synergistic effects between two risk factors for cognitive decline and neurodegenerative disorders, i.e. iron overload and exposure to a hypercaloric/hyperlipidic diet, on cognition, insulin resistance, and hippocampal GLUT1, GLUT3, Insr mRNA expression, and AKT phosporylation. METHODS: Male Wistar rats were treated with iron (30 mg/kg carbonyl iron) or vehicle (5% sorbitol in water) from 12 to 14th post-natal days. Iron-treated rats received a standard laboratory diet or a high fat diet from weaning to adulthood (9 months of age). Recognition and emotional memory, peripheral blood glucose and insulin levels were evaluated. Glucose transporters (GLUT 1 and GLUT3) and insulin signaling were analyzed in the hippocampus of rats. RESULTS: Both iron overload and exposure to a high fat diet induced memory deficits. Remarkably, the association of iron with the high fat diet induced more severe cognitive deficits. Iron overload in the neonatal period induced higher insulin levels associated with significantly higher HOMA-IR, an index of insulin resistance. Long-term exposure to a high fat diet resulted in higher fasting glucose levels. Iron treatment induced changes in Insr and GLUT1 expression in the hippocampus. At the level of intracellular signaling, both iron treatment and the high fat diet decreased AKT phosphorylation. CONCLUSION: The combination of iron overload with exposure to a high fat diet only led to synergistic deleterious effect on emotional memory, while the effects induced by iron and by the high fat diet on AKT phosphorylation were comparable. These findings indicate that there is, at least to some extent, an additive effect of iron combined with the diet. Further studies investigating the mechanisms associated to deleterious effects on cognition and susceptibility for the development of age-associated neurodegenerative disorders are warranted.

Odynophagia as the first symptom of monkeypox infection.

A 50-year-old patient with confirmed monkeypox infection presented with odynophagia and nocturnal dyspnea. Clinically, there was a lesion on the tongue without any skin lesions and fibrinous plaques on the right tonsil with asymmetry of the palatoglossal arch. Due to a suggested abscess in the CT scan, a tonsillectomy à chaud was performed. By pan-orthopox-specific polymerase chain reaction (PCR) the monkeypox infection was also confirmed in the tonsil tissue. Isolated oral findings may represent a monkeypox infection and should be considered as a currently important differential diagnosis, especially for patients at risks.

[Odynophagia as the first symptom of monkeypox infection]. / Odynophagie als erstes Symptom bei Affenpocken-Infektion.

A 50-year-old patient with confirmed monkeypox infection presented with odynophagia and nocturnal dyspnea. Clinically, there was a lesion on the tongue without any skin lesions and fibrinous plaques on the right tonsil with asymmetry of the palatoglossal arch. Due to a suggested abscess in the CT scan, a tonsillectomy à chaud was performed. By pan-orthopox-specific polymerase chain reaction (PCR) the monkeypox infection was also confirmed in the tonsil tissue. Isolated oral findings may represent a monkeypox infection and should be considered as a currently important differential diagnosis, especially for patients at risks.

The G protein-coupled estrogen receptor (GPER) regulates recognition and aversively-motivated memory in male rats.

Estrogens, particularly 17ß-estradiol (estradiol, E2), regulate memory formation. E2 acts through its intracellular receptors, estrogen receptors (ER) ERα and ERß, as well as a recently identified G protein-coupled estrogen receptor (GPER). Although the effects of E2 on memory have been investigated, studies examining the effects of GPER stimulation are scarce. Selective GPER agonism improves memory in ovariectomized female rats, but little information is available regarding the effects of GPER stimulation in male rodents. The aim of the present study was to investigate the effects of the GPER agonist, G1, on consolidation and reconsolidation of inhibitory avoidance (IA) and object recognition (OR) memory in male rats. Animals received vehicle, G1 (15, 75, 150 µg/kg; i.p.), or the GPER antagonist G15 (100 µg/kg; i.p.) immediately after training, or G1 (150 µg/kg; i.p.) 3 or 6 h after training. To investigate reconsolidation, G1 was administered immediately after IA retention Test 1. Results indicated that G1 administered immediately after training at the highest dose enhanced both OR and IA memory consolidation, while GPER blockade immediately after training impaired OR. No effects of GPER stimulation were observed when G1 was given 3 or 6 h after training or after Test 1. The present findings provide evidence that GPER is involved in the early stages of memory consolidation in both neutral and emotional memory tasks in male adult rats.

Effects of lipoic acid supplementation on age- and iron-induced memory impairment, mitochondrial DNA damage and antioxidant responses.

PURPOSE: To investigate the effects of lipoic acid (LA) supplementation during adulthood combined with supplementation later in life or LA administration only at old age on age-induced cognitive dysfunction, mitochondrial DNA deletions, caspase 3 and antioxidant response enzymes expression in iron-treated rats. METHODS: Male rats were submitted to iron treatment (30 mg/kg body wt of Carbonyl iron) from 12 to 14th post-natal days. Iron-treated rats received LA supplementation (50 mg/kg, daily) in adulthood and old age or at old age only for 21 days. Memory, mitochondrial DNA (mtDNA) complex I deletions, caspase 3 mRNA expression and antioxidant response enzymes mRNA expression were analyzed in the hippocampus. RESULTS: LA administration in adulthood combined with treatment later in life was able to reverse age-induced effects on object recognition and inhibitory avoidance memory, as well as on mtDNA deletions, nuclear factor (erythroid-derived 2)-like 2 (Nrf2) expression, and antioxidant enzymes disruption induced by iron in aged rats. LA treatment only at old age reversed iron-induced effects to a lesser extent when compared to the combined treatment. CONCLUSION: The present findings support the view that LA supplementation may be considered as an adjuvant against mitochondrial damage and cognitive decline related to aging and neurodegenerative disorders.

Differential impact of endurance, strength, or combined training on quality of life and plasma serotonin in healthy older women.

Aging is associated with a progressive decline in physical and neurophysiological functions, and some studies suggest that cerebral serotonin is decreased in older adults. These factors contribute to reduced ability to perform daily activities, influencing quality of life (QoL). Regular physical activity has demonstrated important benefits in reversing ageing effects; however, little is known whether different training protocols might induce differential effects on QoL. The aim of this study was to verify the effects of different types of training on QoL and its relation with plasma serotonin in healthy older women. Forty-eight older women were randomly assigned in four groups: Strength Training (ST), Endurance Training (ET), Combined Training (CT), and Control Group (CG) which was instructed not to engage in any physical exercise during the study time. Participants underwent 12 weeks of training twice a week. Plasma serotonin and a scoring system questionnaire SF-36 for evaluation of QoL were assessed at baseline and after the completion of training protocols. When comparing pre- and post-training periods all trained groups showed improvement in QoL, but the CT improved more domains. Plasma serotonin was significantly lower in the ST and in the CT groups in comparison with controls after the 12-week training. Significant correlations of plasma serotonin with physical functioning, role-physical, general health, vitality, and mental health were observed. CT resulted in higher amelioration in QoL, in comparison with ET or ST only. All training protocols induced significant reductions in peripheral serotonin levels, which were negatively correlated with improvements in QoL.

HCV modifies EGF signalling and upregulates production of CXCR2 ligands: Role in inflammation and antiviral immune response.

BACKGROUND & AIMS: To affect immune response and inflammation, the hepatitis C virus (HCV) substantially influences intercellular communication pathways that are decisive for immune cell recruitment. The present study investigates mechanisms by which HCV modulates chemokine-mediated intercellular communication from infected cells. METHODS: Chemokine expression was studied in HCVcc-infected cell lines or cell lines harbouring a subgenomic replicon, as well as in serum samples from patients. Expression or activity of mediators and signalling intermediates was manipulated using knockdown approaches or specific inhibitors. RESULTS: HCV enhances expression of CXCR2 ligands in its host cell via the induction of epidermal growth factor (EGF) production. Knockdown of EGF or of the p65 subunit of the NF-κB complex results in a substantial downregulation of HCV-induced CXCR2 ligand expression, supporting the involvement of an EGF-dependent mechanism as well as activation of NF-κB. Furthermore, HCV upregulates expression of CXCR2 ligands in response to EGF stimulation via downregulation of the T-cell protein tyrosine phosphatase (TC-PTP [PTPN2]), activation of NF-κB, and enhancement of EGF-inducible signal transduction via MEK1 (MAP2K1). This results in the production of a cytokine/chemokine pattern by the HCV-infected cell that can recruit neutrophils but not monocytes. CONCLUSIONS: These data reveal a novel EGF-dependent mechanism by which HCV influences chemokine-mediated intercellular communication. We propose that this mechanism contributes to modulation of the HCV-induced inflammation and the antiviral immune response. LAY SUMMARY: In most cases hepatitis C virus (HCV) results in chronic infection and persistent viral replication, taking decades until development of overt disease. To achieve such a course, the respective virus must have developed mechanisms to circumvent antiviral response, to modulate the inflammatory response and to utilise the infrastructure of its host with moderate effect on its viability. The present study provides novel data indicating that HCV induces epidermal growth factor production in its host cell, enhancing epidermal growth factor-inducible expression of chemokines that bind to the CXCR2 receptor and recruit neutrophile granulocytes. Importantly, chemokines are critical mediators determining the pattern of immune cells recruited to the site of injury and thereby the local inflammatory and immunological milieu. These data strongly suggest that HCV triggers mechanisms that enable the virus to influence the inflammatory and immunological processes of its host.

Iron chelator deferiprone rescues memory deficits, hippocampal BDNF levels and antioxidant defenses in an experimental model of memory impairment.

Brain-derived neurotrophic factor (BDNF) plays a key role in neural development and physiology, as well as in pathological states. Post-mortem studies demonstrate that BDNF is reduced in the brains of patients affected by neurodegenerative diseases. Iron accumulation has also been associated to the pathogenesis of neurodegenerative diseases. In rats, iron overload induces persistent memory deficits, increases oxidative stress and apoptotic markers, and decreases the expression of the synaptic marker, synaptophysin. Deferiprone (DFP) is an oral iron chelator used for the treatment of systemic iron overload disorders, and has recently been tested for Parkinson's disease. Here, we investigated the effects of iron overload on BDNF levels and on mRNA expression of genes encoding TrkB, p75NTR, catalase (CAT) and NQO1. We also aimed at investigating the effects of DFP on iron-induced impairments. Rats received iron or vehicle at postnatal days 12-14 and when adults, received chronic DFP or water (vehicle). Recognition memory was tested 19 days after the beginning of chelation therapy. BDNF measurements and expression analyses in the hippocampus were performed 24 h after the last day of DFP treatment. DFP restored memory and increased hippocampal BDNF levels, ameliorating iron-induced effects. Iron overload in the neonatal period reduced, while treatment with DFP was able to rescue, the expression of antioxidant enzymes CAT and NQO1.

Maternal separation induces hippocampal changes in cadherin-1 (CDH-1) mRNA and recognition memory impairment in adolescent mice.

In rodents, disruption of mother-infant attachment induced by maternal separation (MS) is associated with recognition memory impairment and long-term neurobiological consequences. Particularly stress-induced modifications have been associated to disruption of cadherin (CDH) adhesion function, which plays an important role in remodeling of neuronal connection and synaptic plasticity. This study investigated the sex-dependent effect of MS on recognition memory and mRNA levels of classical type I and type II CDH and the related ß -catenin (ß -Cat) in the hippocampus and prefrontal cortex of late adolescent mice. We provided evidence that the BALB/c mice exposed to MS present deficit in recognition memory, especially females. Postnatal MS induced higher hippocampal CDH-2 and CDH-8 mRNA levels, as well as an upregulation of CDH-1 in the prefrontal cortex in both males and females. MS-reared female mice presented lower CDH-1 mRNA levels in the hippocampus. In addition, hippocampal CDH-1 mRNA levels were positively correlated with recognition memory performance in females. MS-reared male mice exhibited higher ß -Cat mRNA levels in the hippocampus. Considering sex-specific effects on CDH mRNA levels, it has been demonstrated mRNA changes in CDH-1, ß -Cat, and CDH-6 in the hippocampus, as well as CDH-1, CDH-8 and CDH-11 in the prefrontal cortex. Overall, these findings suggest a complex interplay among MS, CDH mRNA expression, and sex differences in the PFC and hippocampus of adolescent mice.

Biochemical properties of the kinase PINK1 as sensor protein for mitochondrial damage signalling.

Defects of mitochondrial functions have been implicated in many different human diseases, in particular neurodegenerative diseases. The kinase PINK1 [phosphatase and tensin homologue (PTEN)-induced kinase 1] has been identified as a crucial player in a specific damage signalling pathway, eliminating defective mitochondria by an autophagic process. Mutations in PINK1 have been shown to cause familial cases of Parkinson's disease. In this review, we summarize the biochemical mechanisms that underlie the association of PINK1 with mitochondria under normal and pathological conditions. This unconventional mitochondrial localization pathway is discussed in the context of the role of PINK1 as a sensor of mitochondrial damage and a causative factor in Parkinson's disease.

Two waves of proteasome-dependent protein degradation in the hippocampus are required for recognition memory consolidation.

Healthy neuronal function and synaptic modification require a concert of synthesis and degradation of proteins. Increasing evidence indicates that protein turnover mediated by proteasome activity is involved in long-term synaptic plasticity and memory. However, its role in different phases of memory remains debated, and previous studies have not examined the possible requirement of protein degradation in recognition memory. Here, we show that the proteasome inhibitor, lactacystin (LAC), infused into the CA1 area of the hippocampus at two specific time points during consolidation, impairs 24-retention of memory for object recognition in rats. Administration of LAC after retrieval did not affect retention. These findings provide the first evidence for a requirement of proteasome activity in recognition memory, indicate that protein degradation in the hippocampus is necessary during selective time windows of memory consolidation, and further our understanding of the role of protein turnover in memory formation.

Long-lasting recognition memory impairment and alterations in brain levels of cytokines and BDNF induced by maternal deprivation: effects of valproic acid and topiramate.

Exposure to stressful events early in life may have permanent deleterious consequences on nervous system function and increase the susceptibility to psychiatric conditions later in life. Maternal deprivation, commonly used as a source of neonatal stress, impairs memory in adult rats and reduces hippocampal brain-derived neurotrophic factor (BDNF) levels. Inflammatory cytokines, such as interleukins (IL) and tumor necrosis factor-α (TNF-α) have been shown to be increased in the peripheral blood of patients with psychiatric disorders. The aim of the present study was to investigate the effects of maternal separation on the levels of IL-10 and TNF-α, and BDNF in the hippocampus and prefrontal cortex of adult rats. We also evaluated the potential ameliorating properties of topiramate and valproic acid on memory deficits and cytokine and BDNF changes associated with maternal deprivation. The results indicated that, in addition to inducing memory deficits, maternal deprivation increased the levels of IL-10 in the hippocampus, and TNF-α in the hippocampus and in the cortex, and decreased hippocampal levels of BDNF, in adult life. Neither valproic acid nor topiramate were able to ameliorate memory deficits or the reduction in BDNF induced by maternal separation. The highest dose of topiramate was able to reduce IL-10 in the hippocampus and TNF-α in the prefrontal cortex, while valproate only reduced IL-10 levels in the hippocampus. These findings may have implications for a better understanding of the mechanisms associated with alterations observed in adult life induced by early stressful events, and for the proposal of novel therapeutic strategies.

Basolateral amygdala activity is required for enhancement of memory consolidation produced by histone deacetylase inhibition in the hippocampus.

Histone acetylation, a type of chromatin modification that allows increased gene transcription and can be pharmacologically promoted by histone deacetylase (HDAC) inhibitors (HDACis), has been consistently associated with promoting memory formation in the hippocampus. The basolateral nucleus of the amygdala (BLA) is a brain area crucially involved in enabling hormones and drugs to influence memory formation. Here, we show that BLA activity is required for memory enhancement by intrahippocampal administration of an HDACi. Two different HDACis, sodium butyrate (NaB) and trichostatin A (TSA), differentially enhanced the retention of memory for inhibitory avoidance (IA) when administered to the dorsal hippocampus after training. TSA showed a biphasic pattern of response during consolidation, in which infusions given immediately or 3h after training produced memory enhancement, whereas no effect was observed when it was infused 1.5 or 6h posttraining. Muscimol (MUS)-induced unilateral functional inactivation of the BLA prevented the enhancement of memory retention produced by posttraining infusion of TSA into the ipsilateral hippocampus. TSA did not affect IA extinction or reconsolidation. These results indicate that HDACis can increase IA memory retention when given into the hippocampus, and, most importantly, BLA activity is necessary for enabling HDACi-induced influences on memory formation.

Effects of the AMPAR Antagonist, Perampanel, on Cognitive Function in Rats Exposed to Neonatal Iron Overload.

Iron accumulation has been associated with the pathogenesis of neurodegenerative diseases and memory decline. As previously described by our research group, iron overload in the neonatal period induces persistent memory deficits and increases oxidative stress and apoptotic markers. The neuronal insult caused by iron excess generates an energetic imbalance that can alter glutamate concentrations and thus trigger excitotoxicity. Drugs that block glutamatergic receptor eligibly mitigate neurotoxicity; among them is perampanel (PER), a reversible AMPA receptor (AMPAR) antagonist. In the present study, we sought to investigate the neuroprotective effects of PER in rats subjected to iron overload in the neonatal period. Recognition and aversive memory were evaluated, AMPAR subunit phosphorylation, as well as the relative expression of genes such as GRIA1, GRIA2, DLG4, and CAC, which code proteins involved in AMPAR anchoring. Male rats received vehicle or carbonyl iron (30 mg/kg) from the 12th to the 14th postnatal day and were treated with vehicle or PER (2 mg/kg) for 21 days in adulthood. The excess of iron caused recognition memory deficits and impaired emotional memory, and PER was able to improve the rodents' memory. Iron increased the phosphorylation of GLUA1 subunit, which was reversed by PER. Furthermore, iron overload increased the expression of the GRIA1 gene and decreased the expression of the DLG4 gene, demonstrating the influence of metal accumulation on the metabolism of AMPAR. These results suggest that iron can interfere with AMPAR functionality, through altered phosphorylation of its subunits, and the expression of genes that code for proteins critically involved in the assembly and anchoring of AMPAR. The blockade of AMPAR with PER is capable of partially reversing the cognitive deficits caused by iron overload.

Administration of the phosphodiesterase type 4 inhibitor rolipram into the amygdala at a specific time interval after learning increases recognition memory persistence.

Here we show that administration of the phosphodiesterase type 4 (PDE4) inhibitor rolipram into the basolateral complex of the amygdala (BLA) at a specific time interval after training enhances memory consolidation and induces memory persistence for novel object recognition (NOR) in rats. Intra-BLA infusion of rolipram immediately, 1.5 h, or 6 h after training had no effect on retention tested at 1, 7, and 14 d later. However, rolipram infused 3 h post-training promoted memory persistence for up to at least 14 d. The findings suggest that PDE4 inhibition in the BLA can enhance long-term memory formation when induced specifically 3 h after learning.

The Role of Ca2+ Permeable AMPA Receptors in Neurodegeneration, Neurotoxicity, and Neuroinflammation.

It is believed that degenerative conditions that give rise to neurological diseases may share an abnormal influx of Ca2+, mainly through glutamate receptors. Current research on the glutamatergic system indicates that the N-methyl-D-aspartate receptor (NMDAR) is not the only receptor permeable to Ca2+. Under certain conditions, α -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are able to rapidly and potently mediate a neurotoxic Ca2+ influx. AMPARs are encoded by four genes designated GluR 1-4. The presence of the edited GluA2 subunit makes the heteromeric AMPAR impermeable to Ca2+ (CI-AMPAR's). On the other hand, the lack of GluA2 or disruptions in its post-translational editing result in Ca2+-permeable AMPA receptors (CP-AMPARs). In addition to triggering behavioral changes, the increase in CP-AMPARs is documented in several neurodegenerative, neuroinflammatory and neurotoxic conditions, demonstrating that AMPAR changes may play a role in the emergence and evolution of pathological conditions of the central nervous system (CNS). Seeking to better understand how CP-AMPARs influence CNS neuropathology, and how it may serve as a pharmacological target for future molecules, in this article, we summarize and discuss studies investigating changes in the composition of AMPARs and their cellular and molecular effects, to improve the understanding of the therapeutic potential of the CP-AMPAR in neurodegenerative, neurotoxic and neuroinflammatory diseases.

Behavior, BDNF and epigenetic mechanisms in response to social isolation and social support in middle aged rats exposed to chronic stress.

Social deprivation can be stressful for group-living mammals. On the other hand, an amazing response of these animals to stress is seeking social contact to give and receive joint protection in threatening situations. We explored the effects of social isolation and social support on epigenetic and behavioral responses to chronic stress. More specifically, we investigated the behavioral responses, corticosterone levels, BDNF gene expression, and markers of hippocampal epigenetic alterations (levels of H3K9 acetylation and methylation, H3K27 methylation, HDAC5, DNMT1, and DNMT3a gene expressions) in middle-aged adult rats maintained in different housing conditions (isolation or accompanied housing) and exposed to the chronic unpredictable stress protocol (CUS). Isolation was associated with decreased basal levels of corticosterone, impaired long-term memory, and decreased expression of the BDNF gene, besides altering the balance of H3K9 from acetylation to methylation and increasing the DNMT1 gene expression. The CUS protocol decreased H3K9 acetylation, besides increasing H3K27 methylation and DNMT1 gene expression, but had no significant effects on memory and BDNF gene expression. Interestingly, the effects of CUS on corticosterone and HDAC5 gene expression were seen only in isolated animals, whereas the effects of CUS on DNMT1 gene expression were more pronounced in isolated than accompanied animals. In conclusion, social isolation in middle age showed broader effects than chronic unpredictable stress on behavioral and epigenetic alterations potentially associated with decreased BDNF expression. Moreover, social support prevented the adverse effects of CUS on HPA axis functioning, HDAC5, and DNMT1 gene expressions.

Bombesin receptor regulation of emotional memory.

Mammalian bombesin-like peptides neuromedin B (NMB) and gastrin-releasing peptide (GRP) act by activating NMB receptors (NMBR, BBl) and GRP receptors (GRPR,BB2), respectively. These two bombesin receptors are members of the G-protein-coupled receptor (GPCR) superfamily.In the brain, NMBR and GRPR are highly expressed in the brain areas involved in memory processing and emotional responses, such as the hippocampus and the amygdaloid nuclei. An increasing number of pharmacological and genetic studies in rodents indicate that NMBRs and GRPRs in brain regions including the dorsal hippocampus,the nucleus tractus solitarius, the basolateral amygdala,and cortical areas, regulate memory formation and expression, particularly for memories related to emotionally arousing tasks. GRPR signaling interacts with multiple protein kinase pathways as well as with other neurotransmitter,hormone, and growth factor systems in influencing memory formation. Together with evidence from human studies, the findings from rodent experiments suggest that bombesin receptors may be therapeutic targets in brain disorders involving memory dysfunction and anxiety.

Rescue of social behavior impairment by clozapine and alterations in the expression of neuronal receptors in a rat model of neurodevelopmental impairment induced by GRPR blockade.

We have previously shown that pharmacological blockade of the gastrin-releasing peptide receptor (GRPR) during the neonatal period in rats produces behavioral features of developmental neuropsychiatric disorders. Here, we show that social interaction deficits in this model are reversed by the atypical antipsychotic clozapine given in the adulthood. In addition, we analyzed the mRNA expression of three neuronal receptors potentially involved in the etiology of disorders of the autism spectrum. Rats were injected with the GRPR antagonist RC-3095 or saline (SAL) from postnatal days 1-10, and tested for social behavior and recognition memory in the adulthood. One hour prior to the behavioral testing, rats were given a systemic injection of clozapine or saline. The mRNA expression of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor, the epidermal growth factor receptor (EGFR), and GRPR was measured in the hippocampus and cortex of a separate set of rats given RC-3095 or SAL neonatally. Rats given neonatal RC-3095 showed decreased social interaction and impaired object recognition memory. Clozapine rescued the social interaction impairment. Neonatal treatment with RC-3095 also resulted in dose-dependent decreases in the expression of GRPR, NR1, and EGFR in the cortex, whereas all three receptor mRNAs were increased in the hippocampus in rats treated with the lower dose of RC-3095. The results contribute to further validate the novel rat model of neurodevelopmental disorders induced by GRPR blockade, and shows alterations in the expression of neuronal receptors in this model.

Early life stress exacerbates cognitive dysfunction induced by d-amphetamine: amelioration by valproic acid.

It has been demonstrated that experiences taking place early in life have a profound influence on brain development, interacting with the genetic background and determining differences in the vulnerability to the onset of bipolar disorder when the individual is exposed to a second adverse event later in life. Here, we investigated the effects of exposure to an early adverse life event (maternal deprivation) and to a later adverse life event [D-amphetamine (AMPH)] on cognition in an animal model of mania. We have previously demonstrated that that repeated AMPH exposure produces severe and persistent cognitive impairment, which was more pronounced when the animals were maternal deprived, suggesting that the early adverse life event could be potentiating the effects of the exposure to the second adverse life event later in life. Here, we show that valproic acid ameliorated the cognitive deficits induced by AMPH, but it was not effective when the animals were exposed to both stressors: maternal deprivation and AMPH treatment.