Behavioural and neurochemical consequences of chronic gut microbiota depletion during adulthood in the rat

Gut microbiota colonization is a key event for host physiology that occurs early in life. Disruption of this process leads to altered brain development which ultimately manifests as changes in brain function and behaviour in adulthood. Studies using germ-free mice highlight the extreme impact on brain health that results from life without commensal microbes, however the impact of microbiota disturbances occurring in adulthood is less studied. To this end, we depleted the gut microbiota of 10-week-old male Sprague Dawley rats via chronic antibiotic treatment. Following this marked, sustained depletion of the gut bacteria, we investigated behavioural and molecular hallmarks of gut-brain communication. Our results reveal that depletion of the gut microbiota during adulthood results in deficits in spatial memory as tested by Morris water maze, increased visceral sensitivity and a greater display of depressive-like behaviours in the forced swim test. In tandem with these clear behavioural alterations we found change in altered CNS serotonin concentration along with changes in the mRNA levels of corticotrophin releasing hormone receptor 1 and glucocorticoid receptor. Additionally, we found changes in the expression of BDNF, a hallmark of altered microbiota-gut-brain axis signaling. In summary, this model of antibiotic-induced depletion of the gut microbiota can be used for future studies interested in the impact of the gut microbiota on host health without the confounding developmental influence of early-life microbial alterations.

细胞外信号调节蛋白激酶-cAMP反应元件结合蛋白信号通路在应激所致抑郁行为障碍中的作用

Stress is the most important factor in the vulnerability to depression and other behavioral disorders, but the mechanisms that stress signals are transferred into depression are far from understanding. To date, the neurotransmitters, neurotrophins and signal pathway have been concerned in the topic focusing on the pathophysiology of depression, but there are still many puzzles. Increasing evidence has indicated that the alteration in neuronal plasticity is the “trace” of stress-induced damages. The extracellular signal-regulated protein kinase(ERK)-cyclic-AMP-responsive element（CRE）-binding protein(CREB)signal pathway is a powerful intracellular signal transduction pathway participating in neuronal plasticity which is involved in higher brain cognitive functions such as learning and memory. However, so far, little is known about the role of the ERK-CREB signal pathway in response to stress and emotional modulations. Thus the aim of the study was to systematically investigate the role of the ERK-CEB signal pathway in depressive-like behaviors induced by stress. Depression animal models, antidepressant agent treatment and disruption of signal pathway in specific brain regions were applied. In the present study, three experiment sessions were designed to make sure whether the ERK-CREB signal pathway was indeed one of pathophysiological mechanisms of depressive-like behaviors induced by stress. In experiment one, two different stress animal models were applied, chronic forced swim stress and chronic empty water bottle stress. After stress, all animals were tested behaviorally using open-field, elevated-plus maze and saccharine preference test, and brain samples were processed for determination of ERK, P-ERK, CREB and P-CREB using western blot. The relationships between the proteins of ERK, P-ERK, CREB and P-CREB in the brain and the behavioral variables were also analyzed. In experiment two, rats were treated with antidepressant agent fluoxetine once a day for 21 consecutive days, then the brain levels of ERK, P-ERK, CREB and P-CREB was determined, the depressive-like behaviors were also examined. In experiment three, mitogen activated extracellular-signal-regulated kinase kinase (MEK) inhibitor U0126 was administrated to inhabit the activation of ERK in the hippocampus and prefrontal cortex respectively, then behavioral measurements and protein detection were conducted. The main results of the study were as the following: (1) Chronic forced swim stress induced animals to suffer depression and disrupted the ERK-CREB signal pathway in hippocampus and prefrontal cortex. There were significant correlations between P-ERK2, P-CREB and multiple variables of depressive-like behaviors. (2) Chronic empty water bottle stress did not induce depressive-like behaviors. Such stress decreased the brain level of P-ERK2 in hippocampus and prefrontal cortex, but the level of P-CREB in the hippocampus was increased. (3) The antidepressant agent fluoxetine relieved depressive-like behaviors and increased the activities of the ERK-CREB signal pathway in stressed animals. (4) Animals treated with U0126 injection into hippocampus showed decreased activities of the ERK-CREB signal pathway in the hippocampus, and suffered depression comorbid with anxiety. (5) Animals treated with U0126 injection into prefrontal cortex showed decreased activities of the ERK-CREB signal pathway in the prefrontal cortex, and exhibited depressive-like behaviors. In conclusion, The ERK-CREB signal pathway in the hippocampus and prefrontal cortex was involved in stress responses and significantly correlated with depressive-like behaviors; The ERK-CREB signal pathway in the hippocampus and prefrontal cortex participated in the mechanism that fluoxetine reversed stress-induced behavioral disorders, and might be the target pathway of the therapeutic action of antidepressants; The disruption of the ERK-CREB signal pathway in the hippocampus or prefrontal cortex led to depressive-like behaviors in animals, suggesting that disruption of ERK-CREB pathway in the hippocampus or prefrontal cortex was involved in the pathophysiology of depression, and might be at least one of the mechanisms of depression induced by stress.

Effet des probiotiques Lactobacillus helveticus RO052 et Bifidobacterium longum RO175 sur la dépression post-infarctus du myocarde chez le rat

Nous avons déjà démontré que les probiotiques réduisaient l'apoptose observée dans le système limbique après un infarctus du myocarde (IM), suggérant un rôle anti-dépresseur potentiel des probiotiques. Cette étude a été conçue pour déterminer si les probiotiques pouvaient atténuer le comportement dépressif observé après un infarctus du myocarde. Un autre objectif visait à démontrer qu’une altération de la barrière intestinale pourrait avoir lieu lors d’un IM et que les probiotiques pourraient empêcher cette altération de la perméabilité intestinale. Méthodes: Des rats mâles Sprague-Dawley ont reçu des probiotiques (1 milliard de cellules bactériennes vivantes de Lactobacillus helveticus R0052 et Bifidobacterium longum R0175) ou le véhicule tous les jours en dilution dans leur eau, débutant 1 semaine avant l'induction d'une ischémie myocardique. Un infarctus a ensuite été induit chez la moitié des rats, par l'occlusion de l'artère coronaire antérieure gauche (40 minutes) suivie d'une reperfusion. Les rats témoins, l'autre moitié de la cohorte, ont été soumis à la même procédure sans occlusion coronarienne. Une semaine après l'infarctus, les animaux ont été resoumis au traitement préalable jusqu'au moment du sacrifice. Le comportement dépressif a été évalué par trois tests soit: l'interaction sociale, le test de nage forcée et le test d'évitement passif. Résultats: Les résultats obtenus indiquent qu'en absence d'infarctus, les probiotiques n'ont pas d'effet significatif. Toutefois, en dépit de taille similaire IM, des rats traités avec des probiotiques, ont démontré davantage d'interactions sociales et une meilleure performance dans le test de nage forcée et d'évitement passif, comparativement à des rats du groupe IM sans probiotique (p<0,05). Conclusion: Les probiotiques atténuent le comportement dépressif observé après infarctus du myocarde par un mécanisme qui pourrait impliquer l'intégrité des intestins.

Exercise test and glucose homeostasis in rats treated with alloxan during the neonatal period or fed a high calorie diet

Background: Animal models appear well-suited for studies into the role of exercise in the prevention of non-insulin-dependent diabetes mellitus (NIDDM). The aim of the present study was to analyze glucose homeostasis and blood lactate during an exercise swimming test in rats treated with alloxan during the neonatal period and/or fed a high calorie diet from weaning onwards.Methods: Rats were injected with alloxan (200 mg/kg, i.p.) or vehicle (citrate buffer) at 6 days of age. After weaning, rats were divided into four groups and fed either a balanced diet or a high-caloric diet as follows: C, control group (vehicle + normal diet); A, alloxan-treated rats fed the normal diet; H, vehicle-treated rats fed the high-caloric diet; and HA, alloxan-treated rats fed the high-caloric diet.Results: Fasting serum glucose levels were higher in groups A and AH compared with the control group. The Homeostatic Model Assessment index varied in the groups as follows: H > A > HA = C. There were no differences in free fatty acids or blood lactate concentrations during the swim test.Conclusions: Alloxan-treated rats fed a normal or high-caloric diet have the potential to be used in studies analyzing the role physical exercise plays in the prevention of NIDDM.

Changes in hippocampal gene expression by 7-nitroindazole in rats submitted to forced swimming stress

Nitric oxide (NO) is an atypical neurotransmitter that has been related to the pathophysiology of major depression disorder. Increased plasma NO levels have been reported in depressed and suicidal patients. Inhibition of neuronial nitric oxide synthase (nNOS), on the other hand, induces antidepressant effects in clinical and pre-clinical trials. The mechanisms responsible for the antidepressant-like effects of nNOS inhibitors, however, are not completely understood. In this study, genomic and proteomic analyses were used to investigate the effects of the preferential nNOS inhibitor 7-nitroindazole (7-NI) on changes in global gene and protein expression in the hippocampus of rats submitted to forced swimming test (FST). Chronic treatment (14 days, i.p.) with imipramine (15 mg/kg daily) or 7-NI (60 mg/kg daily) significantly reduced immobility in the FST. Saturation curves for Serial analysis of gene expression libraries showed that the hippocampus of animals submitted to FST presented a lower number of expressed genes compared to non-FST stressed groups. Imipramine, but not 7-NI, reverted this effect. GeneGo analyses revealed that genes related to oxidative phosphorylation, apoptosis and survival controlled by HTR1A signaling and cytoskeleton remodeling controlled by Rho GTPases were significantly changed by FST. 7-NI prevented this effect. In addition, 7-NI treatment changed the expression of genes related to transcription in the cAMP response element-binding pathway. Therefore, this study suggests that changes in oxidative stress and neuroplastic processes could be involved in the antidepressant-like effects induced by nNOS inhibition.

Beta-Endorphin Modulates the Effect of Stress on Novelty-Suppressed Feeding

Although stress is implicated in the pathophysiology of mood and anxiety disorders, not all individuals who suffer stressful life events develop psychopathology. Differential susceptibility to stress may be influenced by genetically mediated differences in hypothalamic-pituitary-adrenal (HPA) axis activity and moderation of the stress response by the opioid peptide beta-endorphin (beta-E). The present study investigated genetic contributions to coping behavior by examining anxious behavior of transgenic mice with varying capacities to synthesize beta-E [B6.129S2-Pomc(tm1Low)/J; regulated by insertion of a premature stop codon into one or both copies of the proopiomelanocortin (POMC) gene], both under normal conditions and following 3 min of forced swim (FS). Ten minutes after this stress exposure or a control manipulation, acutely food-deprived female and male transgenic mice were subjected to a novelty-suppressed feeding (NSF) test, during which their interaction with an almond slice located in the center of an open field box was measured. There was an interaction between genotype and stress for latency to approach the almond and whether or not the almond was approached, such that mice with low or absent beta-E displayed a stronger aversion to novelty-feeding after stress exposure than did mice with normal levels. These data provide evidence for a moderating effect of beta-E on the behavioral response to stress. Genotypic differences in anxious behavior emerged when mice were stressed prior to behavioral assessment, suggesting that beta-E plays a role in coping behavior. These findings indicate that genetic variability in sensitivity of the beta-E system to stress may contribute, at least in part, to heritable differences in stress reactivity as well as vulnerability to stress-related psychopathology.

Behavioural alterations are independent of sickness behaviour in chronic experimental Chagas disease

The existence of the nervous form of Chagas disease is a matter of discussion since Carlos Chagas described neurological disorders, learning and behavioural alterations in Trypanosoma cruzi-infected individuals. In most patients, the clinical manifestations of the acute phase, including neurological abnormalities, resolve spontaneously without apparent consequence in the chronic phase of infection. However, chronic Chagas disease patients have behavioural changes such as psychomotor alterations, attention and memory deficits, and depression. In the present study, we tested whether or not behavioural alterations are reproducible in experimental models. We show that C57BL/6 mice chronically infected with the Colombian strain of T. cruzi (150 days post-infection) exhibit behavioural changes as (i) depression in the tail suspension and forced swim tests, (ii) anxiety analysed by elevated plus maze and open field test sand and (iii) motor coordination in the rotarod test. These alterations are neither associated with neuromuscular disorders assessed by the grip strength test nor with sickness behaviour analysed by temperature variation sand weight loss. Therefore, chronically T. cruzi-infected mice replicate behavioural alterations (depression and anxiety) detected in Chagas disease patients opening an opportunity to study the interconnection and the physiopathology of these two biological processes in an infectious scenario.

Neurotrophins and neuronal plasticity in the action of antidepressants and morphine

Neuronal plasticity is a well characterized phenomenon in the developing and adult brain. It refers to capasity of a single neuron to modify morphology, synaptic connections and activity. Neuronal connections and capacity for plastic events are compromised in several pathological disorders, such as major depression. In addition, neuronal atrophy has been reported in depressive patients. Neurotrophins are a group of secretory proteins functionally classified as neuronal survival factors. Neurotrophins, especially brain derived neurotrophic factor (BDNF), have also been associated with promoting neuronal plasticity in dysfunctional neuronal networks. Chronic antidepressant treatment increases plastic events including neurogenesis and arborization and branching of neurites in distinct brain areas, such as the hippocampus. One suggested mode of action is where the antidepressants elevate the synaptic levels of BDNF thus further activating several signaling cascades via trkB-receptor. In our studies we have tried to clarify the mechanisms of action for antidepressants and to resolve the role of BDNF in this process. We found that chronic antidepressant treatment increases amount of markers of neuronal plasticity in both hippocampus and in the medial prefrontal cortex, both of which are closely linked to the etiology of major depression. Secondary actions of antidepressants include rapid activation of the trkB receptor followed by a phosphorylation of transcription factor CREB. In addition, activation of CREB by phosphorylation appears responsible for the regulation of the expression of the BDNF gene. Using transgenic mice we found that BDNF-induced trkB-mediated signaling proved crucial for the behavioral effects of antidepressants in the forced swimming test and for the survival of newly-born neurons in the adult hippocampus. Antidepressants not only increased neurogenesis in the adult hippocampus but also elevated the turnover of hippocampal neurons. During these studies we also discovered that another trkB ligand, NT-4, is involved in morphine-mediated anti-nociception and tolerance. These results present a novel role for trkB-mediated signaling in plastic events present in the opioid system. This thesis evaluates neuronal plasticity and trkB as a target for future antidepressant treatments.

Nicotina e/ou estresse por contenção durante a adolescência de camundongos: efeitos em comportamentos de ansiedade, sociabilidade e comportamentos associados à depressão

Há um extenso número de evidências apontando para o estresse como tendo um papel crítico na iniciação, manutenção e relapso após a retirada, do hábito do tabagismo. De modo geral, adolescentes são mais sensíveis aos efeitos no sistema nervoso central de ambos estresse e nicotina, principal componente psicoativo do cigarro. No entanto, há uma escassez de estudos em neurobiologia básica que avaliem as possíveis interações entre os efeitos no sistema nervoso central entre nicotina e estresse nesta idade. Deste modo, o objetivo do presente estudo foi avaliar os efeitos da exposição à nicotina e estresse durante a adolescência de camundongos em comportamentos sociais e comportamentos associados a ansiedade e depressão. Para este estudo utilizamos camundongos Suíços de ambos os sexos. A partir do 30 dia pós-natal (PN) camundongos foram expostos à nicotina (até PN40) e/ou estresse (até PN38 para os animais avaliados em PN39-40 e PN40 para os animais avaliados nas outras idades). Desta forma, utilizamos quatro grupos experimentais: 1) Exposição concomitante de solução de nicotina (diluida na água potável, 50g/ml) e estresse por contenção (1h/dia); 2) Exposição somente à nicotina via oral; 3) Exposição somente ao estresse por contenção; 4) Grupo controle. Para a avaliação comportamental utilizamos: o teste do labirinto em cruz elevado (LCE), o teste de abordagem social de três câmaras (TS) e o teste do nado forçado (FST). Cada animal foi avaliado nos três testes, em um entre três momentos: ao final do período de exposição (PN39/40), após um curto período a partir do término da exposição (PN44/45) ou na vida adulta (PN69/70). A exposição ao estresse promoveu menor ganho de massa corporal durante a adolescência, sendo o consumo de nicotina incapaz de alterar este parâmetro. Além disso, o estresse não afetou o consumo da solução de nicotina. Nosso modelo não foi capaz de alterar os parâmetros de ansiedade avaliados pelo teste do LCE. Entretanto, a exposição de estresse em concomitância com nicotina gerou hiperatividade ao final do período de exposição em ambos os sexos. Na avaliação do TS e do FST observamos alterações significativas somente após período de retirada. Após um curto período de abstinência pela nicotina, fêmeas apresentaram aumento do comportamento associado à depressão, tendo este efeito sido revertido pela exposição concomitante ao estresse. De forma contrária, na mesma idade, somente a exposição combinada promoveu aumento do comportamento associado à depressão em machos. Além disso, nossos resultados sugerem um aumento de sociabilidade no grupo submetido a exposição combinada após longo período de interrupção da exposição durante a vida adulta. O presente trabalho fornece evidências experimentais que indicam que nicotina e estresse interagem durante a adolescência resultando em alterações na resposta emocional durante o período de exposição e tardiamente, após a sua interrupção causando alterações que perduram até o início da vida adulta.

16/6-idiotype expressing antibodies induce brain inflammation and cognitive impairment in mice: the mosaic of central nervous system involvement in lupus

Background: The 16/6-idiotype (16/6-Id) of the human anti-DNA antibody was found to induce experimental lupus in naive mice, manifested by production of autoantibodies, leukopenia and elevated inflammatory markers, as well as kidney and brain involvement. We assessed behavior and brain pathology of naive mice injected intracerebra-ventricularly (ICV) with the 16/6-Id antibody. Methods: C3H female mice were injected ICV to the right hemisphere with the human 16/6-Id antibody or commercial human IgG antibodies (control). The mice were tested for depression by the forced swimming test (FST), locomotor and explorative activity by the staircase test, and cognitive functions were examined by the novel object recognition and Y-maze tests. Brain slices were stained for inflammatory processes. Results: 16/6-Id injected mice were cognitively impaired as shown by significant differences in the preference for a new object in the novel object recognition test compared to controls (P = 0.012). Similarly, the preference for spatial novelty in the Y-maze test was significantly higher in the control group compared to the 16/6-Id-injected mice (42% vs. 9%, respectively, P = 0.065). Depression-like behavior and locomotor activity were not significantly different between the16/6-Id-injected and the control mice. Immunohistochemistry analysis revealed an increase in astrocytes and microglial activation in the hippocampus and amygdala, in the 16/6-Id injected group compared to the control. Conclusions: Passive transfer of 16/6-Id antibodies directly into mice brain resulted in cognitive impairments and histological evidence for brain inflammation. These findings shed additional light on the diverse mosaic pathophysiology of neuropsychiatric lupus.

The effects of distraction on metacognition and metacognition on distraction: evidence from recognition memory

The effects of auditory distraction in memory tasks have been examined to date with procedures that minimize participants’ control over their own memory processes. Surprisingly little attention has been paid to metacognitive control factors which might affect memory performance. In this study, we investigate the effects of auditory distraction on metacognitive control of memory, examining the effects of auditory distraction in recognition tasks utilizing the metacognitive framework of Koriat and Goldsmith (1996), to determine whether strategic regulation of memory accuracy is impacted by auditory distraction. Results replicated previous findings in showing that auditory distraction impairs memory performance in tasks minimizing participants’ metacognitive control (forced-report test). However, the results revealed also that when metacognitive control is allowed (free-report tests), auditory distraction impacts upon a range of metacognitive indices. In the present study, auditory distraction undermined accuracy of metacognitive monitoring (resolution), reduced confidence in responses provided and, correspondingly, increased participants’ propensity to withhold responses in free-report recognition. Crucially, changes in metacognitive processes were related to impairment in free-report recognition performance, as the use of the ‘don’t know’ option under distraction led to a reduction in the number of correct responses volunteered in free-report tests. Overall, the present results show how auditory distraction exerts its influence on memory performance via both memory and metamemory processes.

Stressor categorization : acute physical and psychological stressors elicit distinctive recruitment patterns in the amygdala and in medullary noradrenergic cell groups

It has been hypothesized that the brain categorizes stressors and utilizes neural response pathways that vary in accordance with the assigned category. If this is true, stressors should elicit patterns of neuronal activation within the brain that are category-specific. Data from previous immediate–early gene expression mapping studies have hinted that this is the case, but interstudy differences in methodology render conclusions tenuous. In the present study, immunolabelling for the expression of c-fos was used as a marker of neuronal activity elicited in the rat brain by haemorrhage, immune challenge, noise, restraint and forced swim. All stressors elicited c-fos expression in 25–30% of hypothalamic paraventricular nucleus corticotrophin-releasing-factor cells, suggesting that these stimuli were of comparable strength, at least with regard to their ability to activate the hypothalamic–pituitary–adrenal axis. In the amygdala, haemorrhage and immune challenge both elicited c-fos expression in a large number of neurons in the central nucleus of the amygdala, whereas noise, restraint and forced swim primarily elicited recruitment of cells within the medial nucleus of the amygdala. In the medulla, all stressors recruited similar numbers of noradrenergic (A1 and A2) and adrenergic (C1 and C2) cells. However, haemorrhage and immune challenge elicited c-fos expression in subpopulations of A1 and A2 noradrenergic cells that were significantly more rostral than those recruited by noise, restraint or forced swim. The present data support the suggestion that the brain recognizes at least two major categories of stressor, which we have referred to as ‘physical’ and ‘psychological’. Moreover, the present data suggest that the neural activation footprint that is left in the brain by stressors can be used to determine the category to which they have been assigned by the brain.

Depression therapy: Future prospects.

Current biological approaches to the treatment of depression focus mainly on modification of monoaminergic neurotransmission. New agents targeting these neurotransmitters are under development. Many novel antidepressant targets are however under investigation. These include the neurokinins, glutamate, purinoceptors, opioids and trophic factors. While many of these potential targets are likely to fail clinical development, exciting novel therapeutic options are likely to emerge.

Antidepressivos modificam a extinção de uma memória aversiva em ratas

Treatment of major depression, posttraumatic stress disorder and other psychopathologies with antidepressants can be associated with improvement of the cognitive deficits related to these disorders. Although the mechanisms of these effects are not completely elucidated, alterations in extinction of aversive memories are believed to be present in these psychopathologies. Moreover, researches with laboratory animals usually focus on male subjects, and we have recently verified that extinction of an aversive task is reduced in female rats when compared to males. In the present study, female rats were long-term treated with clinically used antidepressants (fluoxetine, nortriptyline or mirtazapine) and tested in the plus-maze discriminative avoidance and forced swimming tests in order to evaluate learning, memory, extinction, anxiety and depression-related behaviors. All groups learned the task, but learning was somewhat faster in nortriptyline and mirtazapine-treated animals . Task retrieval was also showed by all experimental groups. Chronic treatment with fluoxetine, but not with the other antidepressants, increased extinction of the discriminative task. In the forced swimming test, animals treated with fluoxetine and mirtazapine showed decreased immobility duration. In conclusion, antidepressants interfere with learning and female rats treated with fluoxetine presented increased extinction of the aversive memory task. On the other hand, both fluoxetine and mirtazapine were effective in the forced swimming test, suggesting dissociation between the antidepressant effects and the extinction of aversive memories

Efeitos do tratamento com lítio na memória aversiva, comportamentos relacionados à ansiedade e depressão e na expressão de BDNF em ratos

Lithium (Li) is the first choice to treat bipolar disorder, a psychiatric illness characterized by mood oscillations between mania and depression. However, studies have demonstrated that this drug might influence mnemonic process due to its neuroprotector, antiapoptotic and neurogenic effects. The use of Li in the treatment of cognitive deficits caused by brain injury or neurodegenerative disorders have been widely studied, and this drug shows to be effective in preventing or even alleviating the memory impairment. The effects of Li on anxiety and depression are controversial and the relationship of the effects of lithium on memory, anxiety and depression remain unknown. In this context, this study aims to: evaluate the effects of acute and chronic administration of lithium carbonate in aversive memory and anxiety, simultaneously, using the plus maze discriminative avoidance task (PMDAT); test the antidepressant effect of the drug through the forced swimming test (FS) and analyze brainderived neurotrophic factor (BDNF) expression in structures related to memory and emotion. To evaluation of the acute effects, male Wistar rats were submitted to i.p. administration of lithium carbonate (50, 100 or 200 mg/kg) one hour before the training session (PMDAT) or lithium carbonate (50 or 100 mg/kg) one hour before the test session (FS). To evaluation of the chronic effects, the doses administered were 50 or 100 mg/kg or vehicle once a day for 21 days before the beginning of behavioral tasks (PMDAT and FS). Afterwards, the animals were euthanized and their brains removed and submitted to immunohistochemistry procedure to quantify BDNF. The animals that received acute treatment with 100 and 200 mg/kg of Li did not discriminated between the enclosed arms (aversive and non-aversive) in the training session of PMDAT, showing that these animal did not learned the task. This lack of discrimination was also observed in the test session, showing that the animals did not recall the aversive task. We also observed an increased exploration of the open arms of these same groups, indicating an anxiolytic effect. The same groups showed a reduction of locomotor activity, however, this effect does not seem to be related with the anxiolytic effect of the drug. Chronic treatment with Li did not promote alterations on learning or memory processes. Nevertheless, we observed a reduction of open arms exploration by animals treated with 50 mg/kg when compared to the other groups, showing an anxiogenic effect caused by this dose. This effect it is not related to locomotor alterations since there were no alterations in these parameters. Both acute and chronic treatment were ineffective in the FS. Chronic treatment with lithium was not able to modify BDNF expression in hippocampus, amygdala and pre-frontal cortex. These results suggest that acute administration of lithium promote impairments on learning in an aversive task, blocking the occurrence of memory consolidation and retrieval. The reduction of anxiety following acute treatment may have prevented the learning of the aversive task, as it has been found that optimum levels of anxiety are necessary for the occurrence of learning with emotional context. With continued, treatment the animals recover the ability to learn and recall the task. Indeed, they do not show differences in relation to control group, and the lack of alterations on BDNF expression corroborates this result. Possibly, the regimen of treatment used was not able to promote cognitive improvement. Li showed acute anxiolytic effect, however chronic administration 4 promoted the opposite effect. More studies are necessary to clarify the potential beneficial effect of Li on aversive memory