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Conselho Nacional de Desenvolvimento Científico e Tecnológico, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, e Fundação de Apoio à Pesquisa do Estado do Rio Grande do Norte. Journal impact factors have become an important criterion to judge the quality of scientific publications over the years, influencing the evaluation of institutions and individual researchers worldwide. However, they are also subject to a number of criticisms. Here we point out that the calculation of a journal’s impact factor is mainly based on the date of publication of its articles in print form, despite the fact that most journals now make their articles available online before that date. We analyze 61 neuroscience journals and show that delays between online and print publication of articles increased steadily over the last decade. Importantly, such a practice varies widely among journals, as some of them have no delays, while for others this period is longer than a year. Using a modified impact factor based on online rather than print publication dates, we demonstrate that online-to-print delays can artificially raise a journal’s impact factor, and that this inflation is greater for longer publication lags. We also show that correcting the effect of publication delay on impact factors changes journal rankings based on this metric. We thus suggest that indexing of articles in citation databases and calculation of citation metrics should be based on the date of an article’s online appearance, rather than on that of its publication in print.

Scientific activity in Brazil has experienced an accelerated growth in the past decades, with an increase in productivity that greatly surpasses the international average. This growth has occurred mostly at the expense of centers of excellence in public universities, which account for the vast majority of the country's scientific output. The aim of this study was to evaluate the production of the Department of Biochemistry of a large public university in southern Brazil (Universidade Federal do Rio Grande do Sul), as well as to identify internal and external policies that have influenced this growing production profile. We have performed a historical analysis of the scientific output of this Department of Biochemistry, which accounts for a considerable share of the indexed scientific production at this university. By focusing on the temporal course of its growth and drawing correlations between scientific output and important events in the history of the Department of Biochemistry and of the Brazilian science policies, we concluded that internal factors (as the creation of a postgraduation program, collaboration among researchers, experienced abroad researchers, qualification of faculty members) and external factors (as investments in the postgraduate education, the establishment of national scientific policies, such as financial stimuli for productive researchers and evaluation systems) influence scientific productivity in Brazil.A atividade científica no Brasil apresentou um crescimento acelerado nas últimas décadas, com um aumento na produtividade que ultrapassou os valores médios internacionais. Este crescimento tem ocorrido através dos centros de excelência em pesquisa nas Universidades Públicas, as quais são responsáveis pela maior parte da produção científica do país. O presente estudo tem como objetivo avaliar a produção do Departamento de Bioquímica de uma grande universidade pública do sul do Brasil (Universidade Federal do Rio Grande do Sul - UFRGS), bem como identificar os fatores internos e externos que influenciaram este perfil crescente de produção. Foi realizada uma análise histórica da produção científica do Departamento, a qual representa uma parte considerável da produção científica da Universidade. Ao enfocar a evolução temporal do seu crescimento e o estudo das correlações entre a produção científica e eventos importantes na história do Departamento de Bioquímica e das políticas científicas brasileiras, podemos concluir que os fatores internos (como a criação de um programa de pós-graduação, a colaboração entre pesquisadores, a experiência no exterior por parte dos pesquisadores, a qualificação dos docentes) e fatores externos (como os investimentos na formação de pós-graduandos, o estabelecimento de políticas nacionais científicas, tais como estímulos financeiros para os pesquisadores produtivos e sistemas de avaliação) influenciam a produção científica no Brasil.

The processes of memory reconsolidation and extinction have received increasing attention in recent experimental research, as their potential clinical applications begin to be uncovered. A number of studies suggest that amnestic drugs injected after reexposure to a learning context can disrupt either of the two processes, depending on the behavioral protocol employed. Hypothesizing that reconsolidation represents updating of a memory trace in the hippocampus, while extinction represents formation of a new trace, we have built a neural network model in which either simple retrieval, reconsolidation or extinction of a stored attractor can occur upon contextual reexposure, depending on the similarity between the representations of the original learning and reexposure sessions. This is achieved by assuming that independent mechanisms mediate Hebbian-like synaptic strengthening and mismatch-driven labilization of synaptic changes, with protein synthesis inhibition preferentially affecting the former. Our framework provides a unified mechanistic explanation for experimental data showing (a) the effect of reexposure duration on the occurrence of reconsolidation or extinction and (b) the requirement of memory updating during reexposure to drive reconsolidation.

OSAN, R. , TORT, A. B. L. , AMARAL, O. B. . A mismatch-based model for memory reconsolidation and extinction in attractor networks. Plos One, v. 6, p. e23113, 2011. Centro de Neurociências, da Universidade de Boston, EUA (RO), Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brasil (ABLT e OBA), e Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro, Brasil (OBA). The processes of memory reconsolidation and extinction have received increasing attention in recent experimental research, as their potential clinical applications begin to be uncovered. A number of studies suggest that amnestic drugs injected after reexposure to a learning context can disrupt either of the two processes, depending on the behavioral protocol employed. Hypothesizing that reconsolidation represents updating of a memory trace in the hippocampus, while extinction represents formation of a new trace, we have built a neural network model in which either simple retrieval, reconsolidation or extinction of a stored attractor can occur upon contextual reexposure, depending on the similarity between the representations of the original learning and reexposure sessions. This is achieved by assuming that independent mechanisms mediate Hebbian-like synaptic strengthening and mismatch-driven labilization of synaptic changes, with protein synthesis inhibition preferentially affecting the former. Our framework provides a unified mechanistic explanation for experimental data showing (a) the effect of reexposure duration on the occurrence of reconsolidation or extinction and (b) the requirement of memory updating during reexposure to drive reconsolidation

D -Serine is an endogenous co-agonist of the N-methyl-D: -aspartate (NMDA) receptor and has been suggested to improve cognitive deficits in schizophrenia.The present study investigates the effects of treatment with D -serine in mice on tasks that require recognition learning and working memory, two cognitive domains that are impaired in schizophrenia.We studied the effects of various regimens of systemic administration of D -serine (50 mg/kg/day) on BALB/c mice performing object recognition, T-maze alternation, and open-field exploration tasks. For the object recognition task, we also contrasted the effects of D -serine and D -cycloserine and investigated whether D -serine could reverse alterations induced by subchronic injections of the NMDA antagonist MK-801. D -Serine levels after injections were measured by high-performance liquid chromatography.In the object recognition task, pre-training treatment with D -serine or D -cycloserine significantly enhanced recognition memory 24 h after training. A single administration of D -serine 30 min (but not 6 h) after training produced similar enhancement, suggesting an effect on memory consolidation. Daily treatment with D: -serine enhanced both object recognition and T-maze performance over multiple days and improved short-term memory in MK-801-treated mice. D -Serine treatment did not alter open-field exploration. Behavioral effects were accompanied by increased levels of D -serine in the hippocampus of treated animals.Our results show that treatment with D -serine can improve performance in tasks related to recognition learning and working memory, suggesting that this agent can be useful for the treatment of disorders involving declines in these cognitive domains.

Environmental enrichment is known to induce plastic changes in the brain, including morphological changes in hippocampal neurons, with increases in synaptic and spine densities. In recent years, the evidence for a role of astrocytes in regulating synaptic transmission and plasticity has increased, and it is likely that morphological and functional changes in astrocytes play an important role in brain plasticity. Our study was designed to evaluate changes in astrocytes induced by environmental enrichment in the CA1 region of the hippocampus, focusing on astrocytic density and on morphological changes in astrocytic processes. After 8 weeks of environmental enrichment starting at weaning, male CF-1 mice presented no significant changes in astrocyte number or in the density of glial fibrillary acidic protein (GFAP) immunoreactivity in the stratum radiatum. However, they did present changes in astrocytic morphology in the same region, as expressed by a significant increase in the ramification of astrocytic processes measured by the Sholl concentric circles method, as well as by an increase in the number and length of primary processes extending in a parallel orientation to CA1 nerve fibers. This led astrocytes to acquire a more stellate morphology, a fact which could be related to the increase in hippocampal synaptic density observed in previous studies. These findings corroborate the idea that structural changes in astrocytic networks are an integral part of plasticity processes occurring in the brain.

The gap between basic neuroscience and clinical psychiatry in the treatment of anxiety disorders has been steadily diminishing over recent years. Among the leading advances in this field of translation research is the application of knowledge on the neurobiology of fear memory to the treatment of anxiety disorders in humans. Animal studies have identified N-methyl-D-aspartate (NMDA) receptors as crucial in fear memory acquisition and consolidation, as well as in its extinction and reconsolidation. Based on this, the NMDA receptor partial agonist D-cycloserine, which facilitates fear extinction in rodents, has been shown to increase the effect of exposure therapy in psychiatric patients for conditions such as phobias, social anxiety and obsessive-compulsive disorder. In this article, we review current strategies for targeting the NMDA receptor in the treatment of fear-related disorders, analyzing experimental results, clinical data, and recent patents in the field, while also addressing potential new approaches to explore this field of drug discovery.

The observation of memory recovery following post-training amnestic interventions has historically caused controversy over the meaning of this finding, leading some authors to question the paradigm of a consolidation period for memories. Similarly, recent demonstrations of transient amnesia caused by interventions following memory reactivation have been used to question the existence of a retrieval-driven reconsolidation process. The present work aims to approach the phenomenon of transient amnesia following disruptions of consolidation and reconsolidation, discussing how memory recovery might be explained within a framework of systems consolidation, persistent synaptic reinforcement, and multiple memory traces. With these concepts in mind, we propose that long-term consolidation processes can underlie recovery from amnesia, demonstrating the feasibility of such a hypothesis in a two-structure computational model of learning in which consolidation is dependent upon synaptic reentry reinforcement. On the basis of this, we suggest that prolonged consolidation can account for experimental findings of transient amnesia, in a way that explains differences between disruptions of consolidation and reconsolidation without the need to dwell into the discussion between storage- and retrieval-based explanations for memory impairment.

The series of disease mongering articles in the April 2006 issue of PLoS Medicine overall seem to define the term as “widening the boundaries of illness” [ 1] by “taking a normal function and implying that there's something wrong with it and that it should be treated” [ 2]. While there is undoubtedly a strong case to be made for this sort of practice by pharmaceutical companies, perhaps we should also question ourselves on what we mean by “disease boundaries.” All of the conditions touched on by the disease mongering series (e.g., bipolar disease, attention deficit hyperactivity disorder, restless legs syndrome, and sexual dysfunctions) share the fact that they represent spectra of symptoms felt by virtually everyone, but which for some people can reach a point at which they become disturbing. However, since the benefit of treating these symptoms is ultimately dependent on their significance in a patient's life, it seems doubtful that anyone but the patient can adequately define the “boundaries” of illness for these conditions. The existence of these large “grey zones” between disease and normality (as well as the difficulty of doctors in dealing with them) might help to explain the increase in “lifestyle drug use” and self-prescription of psychiatric medication [ 3]. While these behaviors undoubtedly carry risks, they might well be an inevitable development in an age where information on anything (including drugs) is so widely available. Moreover, tampering with body chemistry is nothing new (alcohol, coffee, chocolate, and sunlight come to mind as examples), and it is hard to expect people will not do it because of pharmaceutical labels. Therefore, complain as we may, it is unlikely that this trend can be feasibly prevented. Therefore, if we want to prevent disease mongering, perhaps we should start by focusing on our own concept of “disease.” Maybe it is time we start to loosen the grip on our powers to define disease and start working less as diagnosing machines and more as decision facilitators for patients. It seems quite absurd to decide on a “concept” of erectile dysfunction or depression that can define who should be treated. On the contrary, our role should be to inform patients of the benefits and risks of treatment (or nontreatment) for their particular condition. This also means being comfortable with the fact that, no matter which criteria one uses to define disease, there will always be “normal” people who will want treatment as well as “sick” people who will refuse it. And in both cases they are probably entitled to do so, without necessarily receiving a diagnosis of “normal” or “sick.” Moreover, since the trend for self-prescription is not likely to be prevented, and since the pharmaceutical industry will surely try to capitalize on it, perhaps we should also worry about making nonprofit, unbiased scientific information more available to the public. Education on health matters is an important responsibility that traditionally has been overlooked by doctors in most countries. Now, if ever, seems to be the time to change that, because if physicians do not concentrate on it, drug companies will be happy to do it for them. It is obvious that medicine cannot abandon the concept of disease boundaries, since most of our medical knowledge and research is still based on it. Moreover, there are fields in which medical responsibility is sure to remain important in defining these boundaries (e.g., attribution of public funds, research studies, and treatment of children). But after reading so much on disease mongering, it seems to me that if we become a little more flexible in admitting that “disease boundaries” for many conditions are an oxymoron, perhaps the pharmaceutical industry will make less of a fuss in trying to convince people they are ill. My guess is that this would do everybody a favor.

We hereby describe a simple and inexpensive approach to evaluate the position and locomotion of rodents in an arena. The system is based on webcam registering of animal behaviour with subsequent analysis on customized software. Based on black/white differentiation, it provides rapid evaluation of animal position over a period of time, and can be used in a myriad of behavioural tasks in which locomotion, velocity or place preference are variables of interest. A brief review of the results obtained so far with this system and a discussion of other possible applications in behavioural neuroscience are also included. Such a system can be easily implemented in most laboratories and can significantly reduce the time and costs involved in behavioural analysis, especially in developing countries.

There is growing pharmacological evidence from several animal models of seizure disorders that adenosine possesses endogenous anticonvulsant activity. Apart from being released from cells, adenosine can be produced by the degradation of adenine nucleotides by ectoenzymes or soluble nucleotidases. These enzymes constitute an important mechanism in synaptic modulation, as they hydrolyze ATP, an excitatory neurotransmitter, to adenosine, a neuroprotective compound. We recently demonstrated an increase in ectoenzyme activity in rat brain synaptosomes after pentylenetetrazol-kindling in rats resistant to kindling, suggesting a role for ectonucleotidases in the seizure control. The present work investigates the effect of seizures induced by pentylenetetrazol kindling on the enzymes that could be playing a role in ATP, ADP and AMP hydrolysis to adenosine in rat blood serum. Animals received injections of PTZ (30 mg/kg, i.p., dissolved in 0.9% saline) once every 48 h, totaling 10 stimulations and the controls animals were injected with saline. The hydrolysis of ATP, ADP and AMP were significantly increased (42, 40, and 45%, respectively), while phosphodiesterase activity was unchanged. These results suggest once more that an increase in the ATP diphosphohydrolase and 5'-nucleotidase activities and, possibly, in adenosine levels, could represent an important compensatory mechanism in the development of chronic epilepsy. Moreover, the fact that this increase can also be measured in serum could mean that these enzymes might be useful as plasma markers of seizures in epilepsy.

Background: Visual evoked potentials (VEPs) and brain stem auditory evoked potentials (BAEPs) have been proposed as tools in the diagnosis of subclinical hepatic encephalopathy (HE). However, little information exists to determine their usefulness in pediatric patients. This study was undertaken to evaluate both methods in the detection of subclinical HE in pediatric liver transplant candidates. Methods: VEPs and BAEPs were recorded in 15 pediatric liver transplant candidates with no clinical signs of HE. The wave latencies found in these examinations were then compared with those in 16 healthy controls of similar age. Laboratory data on liver function and electroencephalographic data from the patients were also recorded to examine their correlation with the evoked potentials results. Results: No differences were found in the BAEP results between patients and controls. However, in the VEPs, the liver transplant candidates had significantly prolonged N1 (N75) latencies when compared with controls; no significant delay was found in the other waves. In contrast, among the children with liver disease, higher BAEP peak latencies correlated positively with electroencephalographic abnormalities, but this correlation was not observed in VEPs. Conclusions: Evoked potentials might be of use in detecting alterations related to HE in children. However, further studies are necessary to determine their sensitivity and specificity in this situation.

Submitted by Biblioteca Suporte PUCRS (biblioteca.suporte@pucrs.br) on 2022-10-13T12:38:13Z No. of bitstreams: 2 Altered_ATP_hydrolysis_by_pentylenetetrazolkindling_in_rat_brain_synaptosomes.pdf: 23036 bytes, checksum: 83992a79e15d066cbb23a8ea9cfdc1d2 (MD5) Altered_ATP_hydrolysis_by_pentylenetetrazolkindling_in_rat_brain_synaptosomes.pdf: 23036 bytes, checksum: 83992a79e15d066cbb23a8ea9cfdc1d2 (MD5) Made available in DSpace on 2022-10-13T12:38:13Z (GMT). No. of bitstreams: 2 Altered_ATP_hydrolysis_by_pentylenetetrazolkindling_in_rat_brain_synaptosomes.pdf: 23036 bytes, checksum: 83992a79e15d066cbb23a8ea9cfdc1d2 (MD5) Altered_ATP_hydrolysis_by_pentylenetetrazolkindling_in_rat_brain_synaptosomes.pdf: 23036 bytes, checksum: 83992a79e15d066cbb23a8ea9cfdc1d2 (MD5) Previous issue date: 2000

Purpose: the physiologic role of the cellular prion protein (PrPc) is unknown. Mice devoid of PrPc develop normally and show only minor deficits. However, electrophysiologic and histologic alterations found in these mice suggest a possible:role fur PrPc in seizure threshold and/or epilepsy.Methods: We tested the sensitivity of PrPc knockout mice to seizures induced by single convulsant or repeated subconvulsant (kindling) doses of pentylenetetrazol (PTZ), and to status epilepticus (SE) induced by kainic acid or pilocarpine.Results. in PTZ kindling, seizure severity progressed faster in the PrPc knockout group, in which 92.8% reached stage 5 or death after 4 days of stimulation, as opposed to 38.4% in wildtype animals: After 10 injections, mortality was 85.7% among knockouts and 15.3% among controls. After a single PTZ injection (60 mg/kg), overall mortality due to seizures was 91% in knockout mice, but only 33% among wild-type animals. Pilocarpine-induced SE (320 mg/kg) caused an 86.7% mortality in knockouts, as opposed to 40% in wild-type animals. Finally, after kainic acid injections (10 mg/kg), 70% of the knockouts developed at least one severe seizure, and 50% showed repetitive seizures, whereas no wild-type animal exhibited observable seizures.Conclusions: Animals lacking cellular prion protein expression are more susceptible to seizures induced by various convulsant agents. This is perhaps the most striking alteration yet found in PrPc-null mice, who at first analysis appeared to be completely normal. A possible role for PrPc in chronic and idiopathic (familial), secondary, or cryptogenic epilepsies in humans remains to be investigated. Univ Fed Rio Grande Sul, ICBS, Dept Bioquim, Ctr Memoria, BR-90035003 Porto Alegre, RS, Brazil UNIFESP, EPM, Dept Expt Neurol, São Paulo, Brazil Ludwig Inst Canc Res, São Paulo, Brazil UNIFESP, EPM, Dept Expt Neurol, São Paulo, Brazil Web of Science

Mitogen-activated protein kinase (MAPK) is a serine/threonine protein kinase abundantly expressed in postmitotic neurons of the developed nervous system. MAPK is activated in and required for both the induction of long-term potentiation (LTP) in hippocampal slices and the acquisition of fear conditioning training in rats. The present work was performed in order to test the effect of the specific inhibitor of MAPK kinase (MAPKK), PD 098059, on retention of a step-down inhibitory avoidance (IA). Adult male Wistar rats were bilaterally injected (0.5 microl/side) with PD 098059 (at 0.5, 5, or 50 microM) or vehicle into the entorhinal cortex or into the parietal cortex immediately after IA training using a 0.4 mA footshock. Retention testing was carried out 24 h after training. PD 098059 impaired retention when injected into the entorhinal cortex at the dose of 50 microM, but not at the doses of 5 or 0.5 microM. When infused into the parietal cortex, PD 098059 was amnestic at the doses of 5 and 50 microM. The drug had no effect when infused at the highest dose in either structure 6 h after training. Our results suggest that the MAPKK inhibitor impairs IA retention memory in a dose-dependent manner when injected immediately after training into entorhinal cortex or parietal cortex. The effective dose is variable according to the neocortical structure studied.

The comments voiced by some scientists in response to Brian Nosek's project to systematically replicate studies in social psychology (“Psychology's bold initiative,” S. Carpenter, News Focus, 30 March, p. [1558][1]) are deeply worrisome. Reluctance to replicate data in a given field of science because it might harm the field's public image among other disciplines is symptomatic of a very dangerous logic. If such concerns are deemed valid, it seems natural to assume that scientists should also be worried about replicating their own labs' findings because of their standing among other laboratories, or that postdocs should not try to repeat experiments because it will make them look bad among their lab colleagues. The fact that this logic has spread among scientists is probably a large part of the reason why systematic replication studies have become so urgent in the first place. When the public image of a given field of science (or of science as a whole) becomes more important than establishing the truth of its findings in its value scale, one must conclude that something has gone awry along the way. [1]: pending:yes

We read with great interest the article by Orban et al.1xOrban, P.C., Chapman, P.F., and Brambilla, R. Trends Neurosci. 1999; 22: 38–44Abstract | Full Text | Full Text PDF | PubMed | Scopus (161)See all References1 because we too have recently found that the mitogen-activated protein kinase (MAPK) cascade is involved in the long-term memory of an inhibitory avoidance task (IA). The infusion of a specific MAPK kinase inhibitor, PD 098059, into the amygdala 3 h after training impaired IA retention in rats2xSee all References2. These data, together with the discovery that Ras–GRF (guanine-releasing factor)-null mice show impairment in plasticity in the amygdala and in an aversive learning task3xBrambilla, R. et al. Nature. 1997; 390: 281–286Crossref | PubMedSee all References3, suggests that the MAPK cascade has a crucial role both in the physiology and the development of the amygdala. We also found that, in the CA1 region of the hippocampus, the inhibition of MAPK kinase 3 h after training2xSee all References2, like that of protein kinase A (PKA)4xIzquierdo, I. and Medina, J.H. Neurobiol. Learn. Mem. 1997; 68: 285–316Crossref | PubMed | Scopus (612)See all References4, also impaired long-term IA retention. Meanwhile, Atkins et al. have demonstrated a requirement for MAPK activation in the hippocampus during fear-conditioning5xAtkins, C.M. et al. Nat. Neurosci. 1998; 1: 602–609Crossref | PubMedSee all References5, and MAPK activation is also required for the induction of LTP in the hippocampus6xEnglish, J.D. and Sweat, J.D. J. Biol. Chem. 1997; 272: 19103–19106Crossref | PubMed | Scopus (620)See all References6. As was indicated by Orban et al.1xOrban, P.C., Chapman, P.F., and Brambilla, R. Trends Neurosci. 1999; 22: 38–44Abstract | Full Text | Full Text PDF | PubMed | Scopus (161)See all References, 3xBrambilla, R. et al. Nature. 1997; 390: 281–286Crossref | PubMedSee all References, Ras–GRF-null mice have no impairment of LTP in the hippocampus and show normal behavior during spatial learning tasks; these animals, therefore, seem to be able to compensate the eventual MAPK cascade dysfunction in the hippocampus.When infused into the entorhinal cortex immediately or 3 h after training, PD 098059 (Ref. 2xSee all ReferencesRef. 2), like the PKA inhibitor4xIzquierdo, I. and Medina, J.H. Neurobiol. Learn. Mem. 1997; 68: 285–316Crossref | PubMed | Scopus (612)See all References4, also impaired IA. The similar post-training time window of effectiveness of the MAPK (Ref. 2xSee all ReferencesRef. 2) and PKA (Ref. 4xIzquierdo, I. and Medina, J.H. Neurobiol. Learn. Mem. 1997; 68: 285–316Crossref | PubMed | Scopus (612)See all ReferencesRef. 4) inhibitors in the CA1 region and the entorhinal cortex is coincident with the rise in cAMP levels, PKA activity and FOS levels4xIzquierdo, I. and Medina, J.H. Neurobiol. Learn. Mem. 1997; 68: 285–316Crossref | PubMed | Scopus (612)See all References4, which raises the possibility of crosstalk between the MAPK and PKA cascades in these structures. In fact, MAPK activation by the cAMP–PKA pathway has been demonstrated in PC12 cells7xVossler, M.R. et al. Cell. 1997; 89: 73–82Abstract | Full Text | Full Text PDF | PubMedSee all References7, while cAMP can stimulate neuronal MAPK through a PKA-independent mechanism8xKawasaki, H. et al. Science. 1998; 282: 2275–2279Crossref | PubMed | Scopus (905)See all References8.Other kinases can interact either directly or indirectly with the MAPK cascade, including protein kinase C (PKC)9xSeger, R. and Krebs, E.G. FASEB J. 1995; 9: 726–735PubMedSee all References9 and Ca2+/calmodulin-dependent protein kinases II (CaMKII)10xChen, H.J. et al. Neuron. 1998; 20: 895–904Abstract | Full Text | Full Text PDF | PubMed | Scopus (394)See all References10 and IV (CaMKIV)8xKawasaki, H. et al. Science. 1998; 282: 2275–2279Crossref | PubMed | Scopus (905)See all References, 11xSahyoun, N. et al. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 2643–2647Crossref | PubMedSee all References. Some of these kinses (PKC, CaMKII) have also been shown to be involved in the IA processing at different post-training times, depending on the brain structure studied4xIzquierdo, I. and Medina, J.H. Neurobiol. Learn. Mem. 1997; 68: 285–316Crossref | PubMed | Scopus (612)See all References4. It has been estimated that humans have as many as 2000 genes encoding protein kinases and 1000 genes encoding phosphatases12xHunter, T. Cell. 1995; 80: 225–236Abstract | Full Text PDF | PubMed | Scopus (2149)See all References12. This extensive repertoire of kinases and phosphatases forms a complex network of biological signaling pathways13xBhalla, U.S. and Iyengar, R. Science. 1999; 283: 381–387Crossref | PubMed | Scopus (1018)See all References13, which can contribute to the specific response of distinct brain regions during physiological processes (for example, memory), as well as in genetic (for example, inborn errors of metabolism) or acquired pathologies (for example, stroke, secondary epilepsy).

SummaryAlzheimer’s disease (AD) and type 2 diabetes appear to share similar pathogenic mechanisms. dsRNA-dependent protein kinase (PKR) underlies peripheral insulin resistance in metabolic disorders. PKR phosphorylates eukaryotic translation initiation factor 2α (eIF2α-P), and AD brains exhibit elevated phospho-PKR and eIF2α-P levels. Whether and how PKR and eIF2α-P participate in defective brain insulin signaling and cognitive impairment in AD are unknown. We report that β-amyloid oligomers, AD-associated toxins, activate PKR in a tumor necrosis factor α (TNF-α)-dependent manner, resulting in eIF2α-P, neuronal insulin receptor substrate (IRS-1) inhibition, synapse loss, and memory impairment. Brain phospho-PKR and eIF2α-P were elevated in AD animal models, including monkeys given intracerebroventricular oligomer infusions. Oligomers failed to trigger eIF2α-P and cognitive impairment in PKR−/− and TNFR1−/− mice. Bolstering insulin signaling rescued phospho-PKR and eIF2α-P. Results reveal pathogenic mechanisms shared by AD and diabetes and establish that proinflammatory signaling mediates oligomer-induced IRS-1 inhibition and PKR-dependent synapse and memory loss.