National Institute for Translational Medicine INCT TM

Rio de Janeiro, Brazil

National Institute for Translational Medicine INCT TM

Rio de Janeiro, Brazil
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Seibt K.J.,Pontifical Catholic University of Rio Grande do Sul | Oliveira R.D.L.,Pontifical Catholic University of Rio Grande do Sul | Zimmermann F.F.,Pontifical Catholic University of Rio Grande do Sul | Capiotti K.M.,Pontifical Catholic University of Rio Grande do Sul | And 5 more authors.
Behavioural Brain Research | Year: 2010

Glutamate N-methyl-d-aspartate (NMDA) receptor antagonists, such as dizocilpine (MK-801), elicit schizophrenia-like symptoms in humans and a behavioral syndrome in rodents, characterized by hyperlocomotion and stereotyped actions, which is antagonized by antipsychotic drugs. Animal models of schizophrenia have been established and used for the development of new antipsychotic drugs. In this work we characterized the behavioral effects of MK-801 and investigated the effect of typical and atypical antipsychotic treatments on locomotor activity as well on the hyperlocomotion induced by MK-801 in zebrafish. MK-801 (20μM) increased the locomotor behavior as measured by the number of line crossings, distance traveled, and the mean speed in the tank test after 15, 30, and 60. min of exposure. All tested antipsychotics counteracted MK-801-induced hyperactivity on all parameters analyzed and at doses that, given alone, had no effect on spontaneous locomotor activity. The results suggest a similar profile between typical and atypical antipsychotics in the reversal of locomotor disorders induced by MK-801. Moreover, an anxiolytic effect was verified at 30 and 60. min of MK-801 exposure, which was not reversed by antipsychotics tested in this work. In addition, olanzapine, which alone caused an anxiolytic response, when given with MK-801 potentiated the latter's effect on anxiety. In this work we demonstrated the value of the zebrafish, a simple to use animal model, in developing some behavioral features observed in schizophrenia, which may indicate a new approach for drug screening. © 2010 Elsevier B.V.

Correa M.S.,University of Porto | Balardin J.B.,University of Porto | Caldieraro M.A.K.,Hospital Of Clinicas Of Porto Alegre | Fleck M.P.,Hospital Of Clinicas Of Porto Alegre | And 5 more authors.
Biological Psychology | Year: 2012

Objectives: To investigate the effect of cognitive support (an associative orienting instruction at encoding) on contextual memory in depressed patients. Methods: Seventeen patients (age 20-40. years, 14 women) diagnosed with major depressive disorder (MDD) and 22 healthy controls matched for age, gender and education completed a recognition memory task for item (object) and context (location), with or without an incidental binding cue at encoding. In addition, participants completed the vocabulary subtest of the Wechsler Adult Intelligence Scale (WAIS III) and the Wisconsin Card Sorting Test (WCST). Salivary samples were collected at 7. AM, 4. PM and 10. PM on the day of testing for cortisol and DHEA level measurement. Results: Depressed patients showed a deficit in contextual memory in the absence of a binding cue but did not differ from healthy controls in item memory or when a binding cue was present. Cortisol and cortisol/DHEA ratios were lower in depressed patients compared to healthy controls and correlated with memory deficits. Conclusions: Contextual memory deficits in MDD patients can be reduced by providing cognitive support at encoding. © 2011 Elsevier B.V.

Jobim P.F.C.,Federal University of Rio Grande do Sul | Jobim P.F.C.,National Institute for Translational Medicine INCT TM | Pedroso T.R.,Federal University of Rio Grande do Sul | Pedroso T.R.,National Institute for Translational Medicine INCT TM | And 8 more authors.
Neurobiology of Learning and Memory | Year: 2012

Mammalian target of rapamycin (mTOR), a central regulator of protein synthesis in neurons, has been implicated in synaptic plasticity and memory. Here we show that mTOR inhibition by rapamycin in the basolateral amygdala (BLA) or dorsal hippocampus (DH) impairs both formation and reconsolidation of memory for inhibitory avoidance (IA) in rats. Male Wistar rats received bilateral infusions of vehicle or rapamycin into the BLA or DH before or after IA training or retrieval. Memory retention was tested at different time points after drug infusion. Rapamycin impaired long-term IA retention when given before or immediately after training or retrieval into the BLA. When infused into the DH, rapamycin produced memory impairment when given before training or immediately after retrieval. The impairing effects of post-retrieval rapamycin required memory retrieval and were not reversed by a reminder shock. The results provide the first evidence that mTOR in the BLA and DH might play a role in IA memory reconsolidation. © 2011 Elsevier Inc.

Garcia V.A.,University of Porto | Garcia V.A.,National Institute for Translational Medicine INCT TM | Souza De Freitas B.,University of Porto | Busato S.B.,University of Porto | And 4 more authors.
Neuropharmacology | Year: 2013

Modafinil is a wake-promoting drug and has been approved for the treatment of excessive daytime sleepiness in narcolepsy and obstructive sleep apnea. Modafinil was shown to improve learning and memory in rodents, and to reverse memory deficits induced by sleep deprivation or stress. However, depending on the memory paradigm used, modafinil might also impair memory. We aimed to investigate the effects of modafinil on memory consolidation and retrieval for object recognition and inhibitory avoidance in naïve adult rats. We also investigated whether acute or chronic administration of modafinil would reverse memory deficits induced by iron overload, a model of memory impairment related to neurodegenerative disorders. Adult naïve rats received modafinil (0.0, 0.75, 7.5 or 75 mg/kg) either immediately after training or 1 h prior to testing in object recognition or inhibitory avoidance. Iron-treated rats received modafinil immediately after training in object recognition. In order to investigate the effects of chronic modafinil, iron-treated rats received daily injections of modafinil for 17 days, and 24 h later they were trained in object recognition or inhibitory avoidance. Acute modafinil does not affect memory consolidation or retrieval in naive rats. A single injection of modafinil at the highest dose was able to recover recognition memory in iron-treated rats. Chronic modafinil completely recovered iron-induced recognition memory and emotional memory deficits. Additional preclinical and clinical studies are necessary in order to support the applicability of modafinil in recovering memory impairment associated with neurodegenerative disorders. © 2013 Elsevier Ltd. All rights reserved.

Berk M.,University of Melbourne | Berk M.,Swanston Center | Berk M.,Oak Street Health | Kapczinski F.,National Institute for Translational Medicine INCT TM | And 19 more authors.
Neuroscience and Biobehavioral Reviews | Year: 2011

There is now strong evidence of progressive neuropathological processes in bipolar disorder (BD). On this basis, the current understanding of the neurobiology of BD has shifted from an initial focus on monoamines, subsequently including evidence of changes in intracellular second messenger systems and more recently to, incorporating changes in inflammatory cytokines, corticosteroids, neurotrophins, mitochondrial energy generation, oxidative stress and neurogenesis into a more comprehensive model capable of explaining some of the clinical features of BD. These features include progressive shortening of the inter-episode interval with each recurrence, occurring in consort with reduced probability of treatment response as the illness progresses. To this end, emerging data shows that these biomarkers may differ between early and late stages of BD in parallel with stage-related structural and neurocognitive alterations. This understanding facilitates identification of rational therapeutic targets, and the development of novel treatment classes. Additionally, these pathways provide a cogent explanation for the efficacy of seemingly diverse therapies used in BD, that appear to share common effects on oxidative, inflammatory and neurotrophic pathways. © 2010 Elsevier Ltd.

Roesler R.,Federal University of Rio Grande do Sul | Roesler R.,National Institute for Translational Medicine INCT TM | Kent P.,University of Ottawa | Kent P.,Ottawa Health Research Institute | And 6 more authors.
Neurobiology of Learning and Memory | Year: 2014

Neuropeptides act as signaling molecules that regulate a range of aspects of brain function. Gastrin-releasing peptide (GRP) is a 27-amino acid mammalian neuropeptide, homolog of the amphibian peptide bombesin. GRP acts by binding to the GRP receptor (GRPR, also called BB2), a member of the G-protein coupled receptor (GPCR) superfamily. GRP produced by neurons in the central nervous system (CNS) plays a role in synaptic transmission by activating GRPRs located on postsynaptic membranes, influencing several aspects of brain function. Here we review the role of GRP/GRPR as a system mediating both stress responses and the formation and expression of memories for fearful events. GRPR signaling might integrate the processing of stress and fear with synaptic plasticity and memory, serving as an important component of the set of neurobiological systems underlying the enhancement of memory storage by aversive information. © 2013 Elsevier Inc.

Wegner M.,University of Bern | Helmich I.,University Institute of Health Sciences | Machado S.,Federal University of Rio de Janeiro | Machado S.,National Institute for Translational Medicine INCT TM | And 7 more authors.
CNS and Neurological Disorders - Drug Targets | Year: 2014

Anxiety and depression are the most frequently diagnosed psychological diseases showing a high co-morbidity. They have a severe impact on the lives of the persons concerned. Many meta-analytical studies suggested a positive anxiolytic and depression-reducing effect of exercise programs. The aim of the present article is to synthesize metaanalyses on the effects of exercise on anxiety and depression and to describe average effect sizes. For this purpose 37 meta-analyses were included reporting 50 effect sizes for anxiety scores of 42,264 participants and depression scores of 48,207 persons. The average documented anxiolytic effect of exercise in these reviews was small, 0.34. In contrast, the effect of exercise on depression was significantly higher and at a moderate level, 0.56. Data of randomized controlled trials suggest higher sizes for the effect of exercise on anxiety and depression leading to increases up to moderate and large effects, respectively. Additionally, exercise seems to be more beneficial for patients compared to participants within a non-clinical, normal range of psychological disease. Especially for the effect of exercise on anxiety, more high quality meta-analyses of randomized controlled trials are needed. Finally, possible neurobiological explanations are suggested for the positive effect of exercise on psychological disorders like anxiety and depression. © 2014 Bentham Science Publishers.

Mochcovitch M.D.,Federal University of Rio de Janeiro | Mochcovitch M.D.,National Institute for Translational Medicine INCT TM | Nardi A.E.,National Institute for Translational Medicine INCT TM | Nardi A.E.,Federal University of Rio de Janeiro | And 2 more authors.
Revista Brasileira de Psiquiatria | Year: 2012

Introduction: Since the first publication of Cloninger ́s psychobiological model of personality, the relationship between temperament and character dimensions and psychiatric disorders has been widely studied. The exact nature of this interaction, however, is still unclear. Different models have been proposed (state-dependency, vulnerability, continuous spectrum etc). Objective: To analyze the relationship between temperament and character dimensions with depression and panic disorder. Method: Systematic review on interventional studies published up until December 2011 on MEDLINE and ISI databases. Also, a brief review on genetic studies is hereby undertaken, aiming to discuss the gene-environment interaction in relation to this topic. Results: Thirteen studies were included: 10 related to depression and 3 to panic disorder (or unspecific anxiety symptoms). All of them showed association between high harm avoidance (HA) and low selfdirectedness (SD) with depression and anxiety symptoms. Longitudinal studies demonstrated that these traits may not be just state-dependent. Conclusions: HA and SD dimensions are associated with both the occurrence of depressive and anxiety symptoms. There is also some evidence to suggest that high HA and low SD indicates susceptibility to depression. Longitudinal studies are not sufficient to affirm the same about panic disorder up to the present moment. ©2012 Elsevier Editora Ltda. All rights reserved.

Roesler R.,Federal University of Rio Grande do Sul | Roesler R.,National Institute for Translational Medicine INCT TM | Schroder N.,National Institute for Translational Medicine INCT TM | Schroder N.,University of Porto
Pharmacology Biochemistry and Behavior | Year: 2011

Biological research has unraveled many of the molecular and cellular mechanisms involved in the formation of long-lasting memory, providing new opportunities for the development of cognitive-enhancing drugs. Studies of drug enhancement of cognition have benefited from the use of pharmacological treatments given after learning, allowing the investigation of mechanisms regulating the consolidation phase of memory. Modulatory systems influencing consolidation processes include stress hormones and several neurotransmitter and neuropeptide systems. Here, we review some of the findings on memory enhancement by drug administration in animal models, and discuss their implications for the development of cognitive enhancers. © 2011 Elsevier Inc.

Schroder N.,University of Porto | Schroder N.,National Institute for Translational Medicine INCT TM | Figueiredo L.S.,University of Porto | De Lima M.N.M.,University of Porto
Journal of Alzheimer's Disease | Year: 2013

Over the last decades, studies from our laboratory and other groups using animal models have shown that iron overload, resulting in iron accumulation in the brain, produces significant cognitive deficits. Iron accumulation in the hippocampus and the basal ganglia has been related to impairments in spatial memory, aversive memory, and recognition memory in rodents. These results are corroborated by studies showing that the administration of iron chelators attenuates cognitive deficits in a variety of animal models of cognitive dysfunction, including aging and Alzheimer's disease models. Remarkably, recent human studies using magnetic resonance image techniques have also shown a consistent correlation between cognitive dysfunction and iron deposition, mostly in the hippocampus, cortical areas, and basal ganglia. These findings may have relevant implications in the light of the knowledge that iron accumulates in brain regions of patients suffering from neurodegenerative diseases. A better understanding of the functional consequences of iron dysregulation in aging and neurological diseases may help to identify novel targets for treating memory problems that afflict a growing aging population. © 2013 - IOS Press and the authors. All rights reserved.

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