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IntroductionPreprints have been increasingly used in biomedical sciences, providing the opportunity for research to be publicly assessed before journal publication. With the increase in attention over preprints during the COVID-19 pandemic, we decided to assess the content of comments left on preprint platforms.MethodsPreprints posted on bioRxiv and medRxiv in 2020 were accessed through each platform’s API, and a random sample of preprints that had received between 1 and 20 comments was analyzed. Comments were evaluated in triplicate by independent evaluators using an instrument that assessed their features and general content.Results7.3% of preprints received at least 1 comment during a mean follow-up of 7.5 months. Analyzed comments had a median size of 43 words. Criticisms, corrections or suggestions were the most prevalent type of content, followed by compliments or positive appraisals and questions. Most critical comments regarded interpretation, data collection and methodological design, while compliments were usually about relevance and implications.ConclusionsOnly a small percentage of preprints posted in 2020 in bioRxiv and medRxiv received comments in these platforms. When present, however, these comments address content that is similar to that analyzed by traditional peer review. A more precise taxonomy of peer review functions would be desirable to describe whether post-publication peer review fulfills these roles.

Make science more reliable by placing the burden of replicability on the community, not on individual laboratories. Make science more reliable by placing the burden of replicability on the community, not on individual laboratories.

FAPERJ (Funda??o de Amparo ? Pesquisa do Estado do Rio de Janeiro) Federal University of Rio de Janeiro. Institute of Medical Biochemistry Leopoldo de Meis. Rio de Janeiro, RJ, Brazil. Federal University of Rio de Janeiro. Institute of Medical Biochemistry Leopoldo de Meis. Rio de Janeiro, RJ, Brazil. Federal University of Rio de Janeiro. Institute of Medical Biochemistry Leopoldo de Meis. Rio de Janeiro, RJ, Brazil. Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Ananindeua, PA, Brasil / Universidade do Estado do Par?. Departamento de Morfologia e Ci?ncias Fisiol?gicas. Bel?m, PA, Brazil / Centro Universit?rio Metropolitano da Amaz?nia. Instituto Euro-Americano de Educa??o, Ci?ncia e Tecnologia. Bel?m, PA, Brazil. University of Groningen. Department of Neuroscience. Section Medical Physiology. Groningen, The Netherlands. Federal University of Rio de Janeiro. Biomedical Sciences Institute. Rio de Janeiro, RJ, Brazil. University of Edinburgh Medical School. Scotland, United Kingdom. Federal University of Rio de Janeiro. Institute of Medical Biochemistry Leopoldo de Meis. Rio de Janeiro, RJ, Brazil. Federal University of Rio de Janeiro. Institute of Medical Biochemistry Leopoldo de Meis. Rio de Janeiro, RJ, Brazil. Universidade Federal de S?o Paulo. Programa de P?s-Gradua??o em Psicobiologia. S?o Paulo, SP, Brazil. University of Minnesota. Department of Psychiatry. Minneapolis, MN, USA. Federal University of Rio de Janeiro. Institute of Medical Biochemistry Leopoldo de Meis. Rio de Janeiro, RJ, Brazil. Federal University of Rio de Janeiro. Biomedical Sciences Institute. Rio de Janeiro, RJ, Brazil. Institute of Microbiology of the Czech Academy of Sciences. Czech Republic. University of Illinois at Urbana-Champaign. Carl R Woese Institute for Genomic Biology. Urbana, Illinois, USA. Universidade do Estado do Par?. Departamento de Morfologia e Ci?ncias Fisiol?gicas. Bel?m, PA, Brazil / Centro Universit?rio Metropolitano da Amaz?nia. Instituto Euro-Americano de Educa??o, Ci?ncia e Tecnologia. Bel?m, PA, Brazil / Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Ananindeua, PA, Brasil. Universidade Federal do Rio Grande do Sul. Instituto de Ci?ncias B?sicas da Sa?de. Departamento de Bioqu?mica. Rio Grande do Sul, RS, Brazil. Federal University of Rio de Janeiro. Institute of Medical Biochemistry Leopoldo de Meis. Rio de Janeiro, RJ, Brazil. Preprint usage is growing rapidly in the life sciences; however, questions remain on the relative quality of preprints when compared to published articles. An objective dimension of quality that is readily measurable is completeness of reporting, as transparency can improve the reader?s ability to independently interpret data and reproduce findings. In this observational study, we compared random samples of articles published in bioRxiv and in PubMed-indexed journals in 2016 using a quality of reporting questionnaire. We found that peer-reviewed articles had, on average, higher quality of reporting than preprints, although this difference was small. We found larger differences favoring PubMed in subjective ratings of how clearly titles and abstracts presented the main findings and how easy it was to locate relevant reporting information. Interestingly, an exploratory analysis showed that preprints with figures and legends embedded within text had reporting scores similar to PubMed articles. These differences cannot be directly attributed to peer review or editorial processes, as manuscripts might already differ before submission due to greater uptake of preprints by particular research communities. Nevertheless, our results show that quality of reporting in preprints in the life sciences is within a similar range as that of peer-reviewed articles, albeit slightly lower on average, supporting the idea that preprints should be considered valid scientific contributions. An ongoing second phase of the project is comparing preprints to their own published versions in order to more directly assess the effects of peer review.

The pressure for every research article to tell a clear story often leads researchers in the life sciences to exclude experiments that 'did not work' when they write up their results. However, this practice can lead to reporting bias if the decisions about which experiments to exclude are taken after data have been collected and analyzed. Here we discuss how to balance clarity and thoroughness when reporting the results of research, and suggest that predefining the criteria for excluding experiments might help researchers to achieve this balance.

Scientists have increasingly recognized that low methodological and analytical rigor combined with publish-or-perish incentives can make the published scientific literature unreliable. As a response to this, large-scale systematic replications of the literature have emerged as a way to assess the problem empirically. The Brazilian Reproducibility Initiative is one such effort, aimed at estimating the reproducibility of Brazilian biomedical research. Its goal is to perform multicenter replications of a quasi-random sample of at least 60 experiments from Brazilian articles published over a 20-year period, using a set of common laboratory methods. In this article, we describe the challenges of managing a multicenter project with collaborating teams across the country, as well as its successes and failures over the first two years. We end with a brief discussion of the Initiative’s current status and its possible future contributions after the project is concluded in 2021.

Aversive memories are at the heart of psychiatric disorders such as phobias and post-traumatic stress disorder (PTSD). Here, we present a new behavioral approach in rats that robustly attenuates aversive memories. This method consists of ‘deconditioning’ animals previously trained to associate a tone with a strong footshock by replacing it with a much weaker one during memory retrieval. Our results indicate that deconditioning-update is more effective than traditional extinction in reducing fear responses; moreover, such effects are long lasting and resistant to renewal and spontaneous recovery. Remarkably, this strategy overcame important boundary conditions for memory updating, such as remote or very strong traumatic memories. The same beneficial effect was found in other types of fear-related memories. Deconditioning was mediated by L-type voltage-gated calcium channels and is consistent with computational accounts of mismatch-induced memory updating. Our results suggest that shifting from fear to safety through deconditioning-update is a promising approach to attenuate traumatic memories.

Meta-analytic methods are powerful resources to summarize the existing evidence concerning a given research question and are widely used in many academic fields. Meta-analyzes can also be used to study sources of heterogeneity and bias among results, which should be considered to avoid inaccuracies. Many of these sources can be related to study authorship, as both methodological heterogeneity and researcher bias may lead to deviations in results between different research groups. In this work, we describe a method to objectively attribute study authorship within a given meta-analysis to different research groups by using graph cluster analysis of collaboration networks. We then provide empirical examples of how the research group of origin can impact effect size in distinct types of meta-analyzes, demonstrating how non-independence between within-group results can bias effect size estimates if uncorrected. Finally, we show that multilevel random-effects models using research group as a level of analysis can be a simple tool for correcting for authorship dependence in results.

Meta-analytic methods are powerful resources to summarize the existing evidence concerning a given research question, and are widely used in many academic fields. However, meta-analyses can be vulnerable to various sources of bias, which should be considered to avoid inaccuracies. Many of these sources can be related to study authorship, as both methodological choices and researcher bias may lead to deviations in results between different research groups. In this work, we describe a method to objectively attribute study authorship within a given meta-analysis to different research groups by using graph cluster analysis of collaboration networks. We then provide empirical examples of how the research group of origin can impact effect size in distinct types of meta-analyses, demonstrating how non-independence between within-group results can bias effect size estimates if uncorrected. Finally, we show that multilevel random-effects models using research group as a level of analysis can be a simple tool for correcting biases related to study authorship.

Most efforts to estimate the reproducibility of published findings have focused on specific areas of research, even though science is usually assessed and funded on a regional or national basis. Here we describe a project to assess the reproducibility of findings in biomedical science published by researchers based in Brazil. The Brazilian Reproducibility Initiative is a systematic, multicenter effort to repeat between 60 and 100 experiments: the project will focus on a set of common methods, repeating each experiment in three different laboratories from a countrywide network. The results, due in 2021, will allow us to estimate the level of reproducibility of biomedical science in Brazil, and to investigate what aspects of the published literature might help to predict whether a finding is reproducible.

Reconsolidation is a process in which re-exposure to a reminder causes a previously acquired memory to undergo a process of destabilisation followed by subsequent restabilisation. Different molecular mechanisms have been postulated for destabilisation in the amygdala and hippocampus, including CB1 receptor activation, protein degradation and AMPA receptor exchange; however, most of the amygdala studies have used pre-reexposure interventions, while those in the hippocampus have usually performed them after reexposure. To test whether the temporal window for destabilisation is similar across both structures, we trained Lister Hooded rats in a contextual fear conditioning task, and 1 day later performed memory reexposure followed by injection of either the NMDA antagonist MK-801 (0.1 mg/kg) or saline in order to block reconsolidation. In parallel, we also performed local injections of either the CB1 antagonist SR141716A or its vehicle in the hippocampus or in the amygdala, either immediately before or immediately after reactivation. Infusion of SR141716A in the hippocampus prevented the reconsolidation-blocking effect of MK-801 when performed after reexposure, but not before it. In the amygdala, meanwhile, pre-reexposure infusions of SR141716A impaired reconsolidation blockade by MK-801, although the time-dependency of this effect was not as clear as in the hippocampus. Our results suggest the temporal windows for CB1-receptor-mediated memory destabilisation during reconsolidation vary between brain structures. Whether this reflects different time windows for engagement of these structures or different roles played by CB1 receptors in destabilisation across structures remains an open question for future studies.

Neuroscience is frequently used as an argument in various debates on mental health, such as the definition of some behaviors as pathological. To understand how this happens in the Brazilian media, we analyzed neuroscientific facts mentioned in articles about a controversial diagnosis: internet and or/video gaming addiction. Of 85 articles located in web searches of seven major press vehicles, 25% made allusions to neuroscience. The analysis of two frequently mentioned facts (the similarity between cerebral alterations observed in drug and technology addictions and the release of dopamine as a mediator of reward and addiction to video games) showed inconsistencies between media claims and the available empirical evidence. However, similar biases were already observable in the scientific literature itself, suggesting that the theory of a “dependent brain” in behavioral and chemical addictions seems to be favored by both journalists and scientists

Reconsolidation is a process in which re-exposure to a reminder causes a previously acquired memory to undergo a process of destabilisation followed by subsequent restabilisation. Different molecular mechanisms have been postulated for destabilisation in the amygdala and hippocampus, including CB1 receptor activation, protein degradation and AMPA receptor exchange; however, most of the amygdala studies have used pre-re-exposure interventions, while those in the hippocampus have performed them after re-exposure. To test whether the temporal window for destabilisation is similar across both structures, we trained Lister Hooded rats in a contextual fear conditioning task, and 1 day later performed memory re-exposure followed by injection of either the NMDA antagonist MK-801 (0.1 mg/kg) or saline in order to block reconsolidation. In parallel, we also performed local injections of either the CB1 antagonist SR141716A or its vehicle in the hippocampus or in the amygdala, either immediately before or immediately after reactivation. Infusion of SR141716A in the hippocampus prevented the reconsolidation-blocking effect of MK-801 when performed after re-exposure, but not before it. In the amygdala, meanwhile, pre-reexposure infusions of SR141716A impaired reconsolidation blockade by MK-801, although the time-dependency of this effect was not as clear as in the hippocampus. Our results suggest the temporal windows for CB1-receptor-mediated memory destabilisation during reconsolidation vary between brain structures. Whether this reflects different time windows for engagement of these structures or different roles played by CB1 receptors in destabilisation across structures remains an open question for future studies.

Reconsolidation is a process in which re-exposure to a reminder causes a previously acquired memory to undergo a process of destabilisation followed by subsequent restabilisation. Different molecular mechanisms have been postulated for destabilisation in the amygdala and hippocampus, including CB1 receptor activation, protein degradation and AMPA receptor exchange; however, most of the amygdala studies have used pre-reexposure interventions, while those in the hippocampus have usually performed them after reexposure. To test whether the temporal window for destabilisation is similar across both structures, we trained Lister Hooded rats in a contextual fear conditioning task, and 1 day later performed memory reexposure followed by injection of either the NMDA antagonist MK-801 (0.1 mg/kg) or saline in order to block reconsolidation. In parallel, we also performed local injections of either the CB1 antagonist SR141716A or its vehicle in the hippocampus or in the amygdala, either immediately before or immediately after reactivation. Infusion of SR141716A in the hippocampus prevented the reconsolidation-blocking effect of MK-801 when performed after reexposure, but not before it. In the amygdala, meanwhile, pre-reexposure infusions of SR141716A impaired reconsolidation blockade by MK-801, although the time-dependency of this effect was not as clear as in the hippocampus. Our results suggest the temporal windows for CB1-receptor-mediated memory destabilisation during reconsolidation vary between brain structures. Whether this reflects different time windows for engagement of these structures or different roles played by CB1 receptors in destabilisation across structures remains an open question for future studies.

Prolonged increases in excitation can trigger cell-wide homeostatic responses in neurons, altering membrane channels, promoting morphological changes and ultimately reducing synaptic weights. However, how synaptic downscaling interacts with classical forms of Hebbian plasticity is still unclear. In this study, we investigated whether chronic optogenetic stimulation of hippocampus CA1 pyramidal neurons in freely-moving mice could (a) cause morphological changes reminiscent of homeostatic scaling, (b) modulate synaptic currents that might compensate for chronic excitation, and (c) lead to alterations in Hebbian plasticity. After 24 h of stimulation with 15-ms blue light pulses every 90 s, dendritic spine density and area were reduced in the CA1 region of mice expressing channelrhodopsin-2 (ChR2) when compared to controls. This protocol also reduced the amplitude of mEPSCs for both the AMPA and NMDA components in ex vivo slices obtained from ChR2-expressing mice immediately after the end of stimulation. Lastly, chronic stimulation impaired the induction of LTP and facilitated that of LTD in these slices. Our results indicate that neuronal responses to prolonged network excitation can modulate subsequent Hebbian plasticity in the hippocampus.

Proposals to increase research reproducibility frequently call for focusing on effect sizes instead of p values, as well as for increasing the statistical power of experiments. However, it is unclear to what extent these two concepts are indeed taken into account in basic biomedical science. To study this in a real-case scenario, we performed a systematic review of effect sizes and statistical power in studies on learning of rodent fear conditioning, a widely used behavioral task to evaluate memory. Our search criteria yielded 410 experiments comparing control and treated groups in 122 articles. Interventions had a mean effect size of 29.5%, and amnesia caused by memory-impairing interventions was nearly always partial. Mean statistical power to detect the average effect size observed in well-powered experiments with significant differences (37.2%) was 65%, and was lower among studies with non-significant results. Only one article reported a sample size calculation, and our estimated sample size to achieve 80% power considering typical effect sizes and variances (15 animals per group) was reached in only 12.2% of experiments. Actual effect sizes correlated with effect size inferences made by readers on the basis of textual descriptions of results only when findings were non-significant, and neither effect size nor power correlated with study quality indicators, number of citations or impact factor of the publishing journal. In summary, effect sizes and statistical power have a wide distribution in the rodent fear conditioning literature, but do not seem to have a large influence on how results are described or cited. Failure to take these concepts into consideration might limit attempts to improve reproducibility in this field of science.

Memory extinction involves the formation of a new associative memory that inhibits a previously conditioned association. Nonetheless, it could also depend on weakening of the original memory trace if extinction is assumed to have multiple components. The phosphatase calcineurin (CaN) has been described as being involved in extinction but not in the initial consolidation of fear learning. With this in mind, we set to study whether CaN could have different roles in distinct components of extinction. Systemic treatment with the CaN inhibitors cyclosporin A (CsA) or FK-506, as well as i.c.v. administration of CsA, blocked within-session, but not between-session extinction or initial learning of contextual fear conditioning. Similar effects were found in multiple-session extinction of contextual fear conditioning and in auditory fear conditioning, indicating that CaN is involved in different types of short-term extinction. Meanwhile, inhibition of protein synthesis by cycloheximide (CHX) treatment did not affect within-session extinction, but disrupted fear acquisition and slightly impaired between-session extinction. Our results point to a dissociation of within- and between-session extinction of fear conditioning, with the former being more dependent on CaN activity and the latter on protein synthesis. Moreover, the modulation of within-session extinction did not affect between-session extinction, suggesting that these components are at least partially independent.

The search for biomarkers has been one of the leading endeavours in biological psychiatry; nevertheless, in spite of hundreds of publications, hardly any marker has proved useful in clinical practice. To study how biomarker research has progressed over the years, we performed a systematic review of the literature to evaluate (a) the most studied peripheral molecular markers in major psychiatric disorders, (b) the main experimental design features of studies in which they are proposed as biomarkers and (c) whether their patterns of variation are similar across disorders. An automated search revealed that, out of the six molecules most commonly present as keywords in articles studying plasmatic markers of schizophrenia, major depressive disorder or bipolar disorder, five (BDNF, TNF-alpha, IL-6, C-reactive protein and cortisol) were the same across the three diagnoses. An analysis of the literature on these molecules showed that, whilst 66% of original articles compared their levels between patients and controls, only 35% were longitudinal studies, and only 10% presented an evaluation of diagnostic efficacy, a pattern that has not changed significantly over two decades. Interestingly, these molecules varied similarly across the three disorders, suggesting them to be nonspecific systemic consequences of psychiatric illness rather than diagnostic markers. On the basis of this, we discuss how research fragmentation between diagnoses and publication practices rewarding positive findings may be directing the biomarker literature to nonspecific targets, and what steps could be taken to increase clinical translation in the field.

G protein-coupled receptor oligomerization is a concept which is changing the understanding of classical pharmacology. Both, oligomerization and functional interaction between adenosine A 2A, dopamine D 2 and metabotropic glutamate type 5 receptors have been demonstrated in the striatum. However, the transcriptional consequences of receptors co-activation are still unexplored. We aim here to determine the changes in gene expression of striatal primary cultured neurons upon isolated or simultaneous receptor activation. Interestingly, we found that 95 genes of the total analyzed (15,866 transcripts and variants) changed their expression in response to simultaneous stimulation of all three receptors. Among these genes, we focused on the β-synuclein (β-Syn) gene ( SCNB) . Quantitative PCR verified the magnitude and direction of change in expression of SCNB . Since β-Syn belongs to the homologous synuclein family and may be considered a natural regulator of α-synuclein (α-Syn), it has been proposed that β-Syn might act protectively against α-Syn neuropathology.

G protein-coupled receptors are known to form homo-and heteromers at the plasma membrane, but the molecular properties of these oligomers are relatively unknown. Here, we show a method that allows the diffusion of G protein-coupled receptors oligomers in the plasma membrane to be monitored in single cells by combining Bimolecular Fluorescence Complementation and Fluorescence Correlation Spectroscopy. With this approach we have measured, for the first time, the membrane diffusional characteristics of adenosine A(1) and A(2A) receptor homo-and heterodimers in Chinese Hamster Ovary cells. Interestingly, both homodimers display similar diffusion co-efficients (D) when expressed in living cells (D=5.0 and 4.8x10(-9) cm(2)/s, respectively) but the heterodimer formed by these receptors exhibit a significantly faster plasma membrane diffusion co-efficent (D=5.6x10(-9) cm(2)/s) when compared to the adenosine A(1) receptor tagged with the full-length yellow fluorescent protein (D=4.0x10(-9) cm(2)/s). Overall, these results demonstrate differences in plasma membrane diffusion between adenosine receptor homo-and heterodimers, providing new insights into the molecular plasticity of G protein-coupled receptor oligomerization.

Despite some caveats, G protein-coupled receptor oligomerization is a phenomenon that is becoming largely accepted. Within these oligomers, however, stoichiometry remains to be elucidated. Here, by using bimolecular fluorescence complementation, we visualized adenosine A2A receptor homodimers in living cells, showing no apparent difference in the subcellular distribution when compared to the YFP-labelled adenosine A2A receptor protomer. Interestingly, the combination of bimolecular fluorescence complementation and bioluminescence resonance energy transfer techniques allowed us to detect the occurrence of adenosine A2A receptors oligomers containing more than two protomers. These results provide new insights into the molecular composition of G protein-coupled receptor oligomers.Structured summaryMINT-6700472:A2A (uniprotkb:P29274), A2A (uniprotkb:P29274) and A2A (uniprotkb:P29274) physically interact (MI:0218) by bioluminescence resonance energy transfer (MI:0012)MINT-6699330:A2A (uniprotkb:P29274) and A2A (uniprotkb:P29274) physically interact (MI:0218) by bimolecular fluorescence complementation (MI:0809)MINT-6699346:A2A (uniprotkb:P29274) and A2A (uniprotkb:P29274) physically interact (MI:0218) by bioluminescence resonance energy transfer (MI:0012)

Molecular accounts of memory consolidation suggest that new learning generates persistent synaptic modifications through activation of an extensive set of neuronal receptors and intracellular signal transduction pathways, accompanied by RNA and protein synthesis. This traditional cellular consolidation theory has been challenged by evidence that reactivation of a previously consolidated memory might render this memory again susceptible to disruption by amnesic treatments, a process generally referred to as reconsolidation. Current evidence indicates that reconsolidation can be disrupted by administration of a variety of pharmacological agents after memory reactivation. Previous studies have indicated that the gastrin-releasing preferring type of bombesin receptor (GRPR) and the N-methyl-D-aspartate glutamate receptor (NMDAR) in the rat hippocampus are involved in consolidation of inhibitory avoidance (IA), a fear-related memory task. We show here that blockade of hippocampal GRPRs or NMDARs after memory reactivation temporarily disrupts memory retention. Post-retrieval intra-hippocampal infusion of the GRPR antagonist RC-3095 or the NMDAR antagonist aminophosphonopentanoic acid (AP5) produced an impairment of IA performance tested 2 days after training in rats. However, this impairment was transient and recovered to levels of control rats in a subsequent test 3 days after training. The drug effects were only present after memory reactivation and not in its absence. These findings provide evidence that GRPR or NMDAR inactivation after retrieval can impair fear memory.

A wide range of data in the literature suggests that environmental enrichment has beneficial effects on various cognitive parameters in rodents. However, the magnitude of these effects and their persistence after the cessation of enrichment vary markedly across studies, with the use of different enrichment protocols probably playing a significant role in this variation. Using an open field habituation task as a paradigm, we investigate whether the duration and starting age of environmental enrichment affect the magnitude and persistence of its behavioral effects on male CF-1 albino mice. Our data shows that, at least in our protocol, (a) environmental enrichment, both after weaning and in early adulthood, decreases locomotion in an open field task, probably by increasing habituation; (b) a minimum enrichment period is necessary to induce this behavioral effect; (c) the effect of enrichment can persist at least partially for many months after its cessation; and (d) the degree of this persistence appears to be somewhat greater in animals exposed to longer durations of enrichment.

The reconsolidation hypothesis, which predicts that consolidated memories become labile and sensitive to amnestic agents upon reactivation, has been one of the most debated topics in memory research over recent years. One of the main criticisms to this hypothesis is the fact that some studies have shown the effects of "reconsolidation blockade" to be transient. Here we show that muscimol inactivation of the dorsal hippocampus following memory reactivation produces a reversible impairment of step-down inhibitory avoidance memory in rats. Moreover, we show that the reversal of this effect is dependent on the passage of time, and not on repeated testing. The implications of the findings to the interpretation of the phenomenon of transient retrieval impairment induced by post-reactivation pharmacological interventions on memory systems are discussed.

The search for biological causes of mental disorders has up to now met with limited success, leading to growing dissatisfaction with diagnostic classifications. However, it is questionable whether most clinical syndromes should be expected to correspond to specific microscale brain alterations, as multiple low-level causes could lead to similar symptoms in different individuals. In order to evaluate the potential multifactoriality of alterations related to psychiatric illness, we performed a parametric exploration of published computational models of schizophrenia. By varying multiple parameters simultaneously, such as receptor conductances, connectivity patterns, and background excitation, we generated 5625 different versions of an attractor-based network model of schizophrenia symptoms. Among networks presenting activity within valid ranges, 154 parameter combinations out of 3002 (5.1%) presented a phenotype reminiscent of schizophrenia symptoms as defined in the original publication. We repeated this analysis in a model of schizophrenia-related deficits in spatial working memory, building 3125 different networks, and found that 41 (4.9%) out of 834 networks with valid activity presented schizophrenia-like alterations. In isolation, none of the parameters in either model showed adequate sensitivity or specificity to identify schizophrenia-like networks. Thus, in computational models of schizophrenia, even simple network phenotypes related to the disorder can be produced by a myriad of causes at the molecular and circuit levels. This suggests that unified explanations for either the full syndrome or its behavioral and network endophenotypes are unlikely to be expected at the genetic and molecular levels.

Studies have shown that supplementation with berries rich in anthocyanins are effective in reducing oxidative stress associated with aging, and are beneficial in reversing age-related neuronal and behavioral changes. However, there are few reports on other biological activities of these polyphenols, such as genoprotective effects. The present experiments were performed to study the possible effects of 30-day administration of a lyophilized extract of Vaccinium ashei berries on cognitive performance using step-down inhibitory avoidance, open-field habituation and elevated plus-maze tasks, as well as on DNA damage in the hippocampus and cerebral cortex. The present study showed that the extract significantly enhanced long-term memory in the inhibitory avoidance task, induced an increase in the number of crossings during open-field habituation and had an anxiolytic effect in the elevated plus-maze task. Moreover, the extract reduced oxidative DNA damage in brain tissue in vitro. These results suggest that supplementation with V. ashei berries to mice improves performance on memory tasks and has a protective effect on DNA damage, possibly due to the antioxidant activity of polyphenols, including anthocyanins.

Histoplasmosis of the central nervous system occurs in a significant percentage of patients with Histoplasma capsulatum infection, but has usually been described in association with immunosuppression and/or disseminated histoplasmosis. We aim to review the clinical and laboratory features of isolated histoplasmosis of the central nervous system in the immunocompetent host by presenting a series of 11 cases with this condition. Most of these patients presented with headache, meningeal irritation signs and mental status changes, comprising a somewhat different picture from that described in immunosuppressed patients. Moreover, almost all patients had signs of ventricular dilatation in neuroimaging studies, and 8 of the 11 patients had a ventriculoperitoneal shunt at the time of diagnosis, suggesting hydrocephalus to be an important feature of this condition and/or the possibility of shunt infection by the fungus. Immunodiffusion analysis of the cerebrospinal fluid appeared to be the most efficient way to reach the diagnosis and should be considered in immunocompetent patients with chronic lymphocytic meningitis, especially in those who have ventricular shunt or live in endemic areas of Histoplasma capsulatum.

Although many studies have investigated the function of cellular prion protein (PrPc), its physiologic role remains elusive. PrPc null mice have been reported to develop normally and to show normal performance in most behavioural tests. In the present study we investigated whether this also holds true after episodes of acute stress. PrPc gene ablated (Prnp0/0) and wild-type mice were subjected to restraint stress, electric foot shock, or swimming and compared with non-stressed animals. Immediately after the stressful situation, the anxiety levels and locomotion of the animals were measured using plus-maze and open-field tests. Among non-stressed animals, there was no significant difference in performance between Prnp0/0 and wild type animals in either test. However, after acute stress provoked by a foot shock or a swimming trial, Prnp0/0 animals showed a significant decrease in anxiety levels when compared with control animals. Moreover, after the swimming test, knockout mice presented decreased locomotion when compared to wild-type mice. Because of this observation, we also assessed both types of mice in a forced swimming test with the objective of better evaluating muscle function and found that Prnp0/0 animals presented reduced forced swimming capacity when compared to controls. As far as we know, this is the first report suggesting that cellular prion protein is involved in modulation of anxiety or muscular activity after acute psychic or physical stress.

Eclampsia is defined as the occurrence of seizures and/or coma resulting from hypertensive encephalopathy on a background of preeclampsia (1). Eclampsia appears to be caused by a failure of the brain’s autoregulatory response to increases in blood pressure, leading to an increase in cerebral perfusion pressure with overperfusion injury similar to that observed in hypertensive encephalopathy (2)(3). Brain edema and hemorrhage ensue, as observed in imaging studies (4)(5), and there is evidence to suggest that these alterations can cause ischemia to brain cells. These events lead to neurologic symptoms (6), including seizures as well as cortical blindness, aphasia, limb weakness, psychosis, coma, and cerebrovascular accidents. Studies have analyzed various diagnostic methods, such as transcranial Doppler measurements, as a way to evaluate neurologic involvement in preeclampsia (3)(7). To date, however, there is no reliable laboratory marker to identify patients at risk for eclampsia or its related complications. S100B is a 21-kDa protein physiologically produced and released primarily by astrocytes in the central nervous system (CNS), where it exerts neurotrophic and gliotrophic actions (8). Because ∼95% of S100B is located in the CNS, the results of several studies have suggested that an increase in S100B in blood and cerebrospinal fluid could be a potential marker of neural injury, indicating reactive gliosis, astrocytic death, and/or blood–brain barrier dysfunction. Accordingly, increased S100B concentrations in cerebrospinal fluid and/or blood have been reported in several pathologic conditions causing acute and chronic brain injury, such as head trauma (9), stroke (10), schizophrenia (11), and human T-lymphotropic virus type 1-associated myelopathy (12). Some studies have also evaluated S100B as a marker of recent seizures. Although S100B has been shown to be increased in both cerebrospinal fluid and brain tissue of patients with temporal lobe epilepsy (13)(14), studies in which …

Reconsolidation and extinction are two processes occurring upon memory retrieval that have received great attention in memory research over the last decade, partly due to their purported potential in the treatment of anxiety disorders. Due to their opposite behavioral effects, the two phenomena have usually been considered as separate entities, with few attempts to build a unified view of how both could be produced by similar mechanisms. Based on computational modeling, we have previously proposed that reconsolidation and extinction are behavioral outcomes of the same set of plasticity systems, albeit working at different synapses. One of these systems seems to be pharmacologically similar to the one involved in initial memory consolidation, and likely involves traditional Hebbian plasticity, while the second seems to be more involved with the labilization of existing memories and/or synaptic changes. In this article, we review the evidence for the existence of a plasticity system specifically involved in memory labilization, as well as its possible molecular requirements, anatomical substrates, synaptic mechanisms and physiological roles. Based on these data, we propose that the field of memory updating might ultimately benefit from a paradigm shift in which reconsolidation and extinction are viewed not as separate processes but as different instantiations of plasticity systems responsible for reinforcement and labilization of synaptic changes.

When 5-lipoxygenase (5-LO) is inhibited, roughly half of the CNS effect of the prototypic endocannabinoid anandamide (AEA) is lost. Therefore, we decided to investigate whether inhibiting this enzyme would influence physiological functions classically described as being under control of the endocannabinoid system. Although 5-LO inhibition by MK-886 reduced lipoxin A4 levels in the brain, no effect was found in the elevated plus maze (EPM), even at the highest possible doses, via i.p. (10 mg/kg,) or i.c.v. (500 pmol/2 µl) routes. Accordingly, no alterations in anxiety-like behavior in the EPM test were observed in 5-LO KO mice. Interestingly, aged mice, which show reduced circulating lipoxin A4 levels, were sensitive to MK-886, displaying an anxiogenic-like state in response to treatment. Moreover, exogenous lipoxin A4 induced an anxiolytic-like profile in the EPM test. Our findings are in line with other reports showing no difference between FLAP KO or 5-LO KO and their control strains in adult mice, but increased anxiety-like behavior in aged mice. We also show for the first time that lipoxin A4 affects mouse behavior. In conclusion, we propose an age-dependent relevancy of endogenous 5-LO derivatives in the modulation of anxiety-like behavior, in addition to a potential for exogenous lipoxin A4 in producing an anxiolytic-like state.

Benzodiazepines are among the most prescribed and consumed medication groups in the world. Although benzodiazepines are used in the treatment of several psychiatric and non-psychiatric disorders, and are generally safe and well-tolerated, the potential for misuse and abuse is considerable. This makes the study and regulation of benzodiazepine prescription and consumption an item of concern in public health around the world. Most developed countries have consistent data of benzodiazepine sales and consumption; however, data from developing countries is scarce, making health policies on the use of benzodiazepines a much tougher issue in these countries. This article aims to review the epidemiology of benzodiazepine use in Brazil, as well as to analyze how legislation, physician misinformation and economic factors might contribute to making benzodiazepine abuse a problem in the country.

The ectonucleotidase pathway is an important metabolic source of extracellular adenosine. Adenosine has potent anticonvulsant effects on various models of epilepsy. One of these models is pentylenetetrazol (PTZ) kindling, in which repeated administration of subconvulsive doses of this drug induces progressive intensification of seizure activity. In this study, we examine the effect of a single convulsive injection (60 mg/kg, i.p.) or 10 successive (35 mg/kg, i.p.) injections of PTZ on synaptosomal ectonucleotidases. Our results have shown that no changes in ectonucleotidase activities were seen at 0, 1, and 24 h or at 5 days after a single convulsive PTZ injection. However, after PTZ-kindling, rats which were more resistant to seizure development presented an increase in ATP hydrolysis in synaptosomes from hippocampus and cerebral cortex (44% and 28%, respectively). These results suggest that changes in nucleotide hydrolysis may represent an important mechanism in the modulation of chronic epileptic activity in this model.

Although different hypotheses have been formulated to explain schizophrenia pathogenesis, the links between them are weak. The observation that five psychotic patients on chronic warfarin therapy for deep-vein thrombosis showed long-term remission of psychotic symptoms made us suspect that abnormalities in the coagulation pathway, specifically low tissue plasminogen activator (tPA) activity, could be one of the missing links. Our hypothesis is supported by a high prevalence of conditions affecting tPA activity in drug-naive schizophrenia, such as antiphospholipid antibodies, elevated cytokine levels, hyperinsulinemia and hyperhomocysteinemia. We recently screened a group of schizophrenia patients and controls for conditions affecting tPA activity. Free-protein S deficiency was highly prevalent among patients, but not found in controls. Free-protein S and functional protein C are natural anticoagulants that form complexes that inhibit tPA inhibitors. All participants had normal protein C levels, suggesting that protein S could have a role in schizophrenia, independent of protein C. Chronic patients and those studied during acute episodes had between three and six conditions affecting tPA and/or protein S activity, while patients in remission had up to two, which led us to postulate that multiple conditions affecting tPA and/or protein S activity could contribute to the full expression of schizophrenia phenotype. This paper describes the physiological roles of tPA and protein S, reviewing how their activity influences pathogenesis and comorbidity of schizophrenia. Next, it analyzes how activity of tPA and protein S is influenced by biochemical abnormalities found in schizophrenia. Last, it suggests future directions for research, such as studies on animal models and on therapeutic approaches for schizophrenia aiming at increasing tPA and protein S activity.