Astrocyte-neuron lactate transport is required for long-term memory formation.

We report that, in the rat hippocampus, learning leads to a significant increase in extracellular lactate levels that derive from glycogen, an energy reserve selectively localized in astrocytes. Astrocytic glycogen breakdown and lactate release are essential for long-term but not short-term memory formation, and for the maintenance of long-term potentiation (LTP) of synaptic strength elicited in vivo. Disrupting the expression of the astrocytic lactate transporters monocarboxylate transporter 4 (MCT4) or MCT1 causes amnesia, which, like LTP impairment, is rescued by L-lactate but not equicaloric glucose. Disrupting the expression of the neuronal lactate transporter MCT2 also leads to amnesia that is unaffected by either L-lactate or glucose, suggesting that lactate import into neurons is necessary for long-term memory. Glycogenolysis and astrocytic lactate transporters are also critical for the induction of molecular changes required for memory formation, including the induction of phospho-CREB, Arc, and phospho-cofilin. We conclude that astrocyte-neuron lactate transport is required for long-term memory formation.

Macrophage migration inhibitory factor is critically involved in basal and fluoxetine-stimulated adult hippocampal cell proliferation and in anxiety, depression, and memory-related behaviors.

Intensive research is devoted to unravel the neurobiological mechanisms mediating adult hippocampal neurogenesis, its regulation by antidepressants, and its behavioral consequences. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that is expressed in the CNS, where its function is unknown. Here, we show, for the first time, the relevance of MIF expression for adult hippocampal neurogenesis. We identify MIF expression in neurogenic cells (in stem cells, cells undergoing proliferation, and in newly proliferated cells undergoing maturation) in the subgranular zone of the rodent dentate gyrus. A causal function for MIF in cell proliferation was shown using genetic (MIF gene deletion) and pharmacological (treatment with the MIF antagonist Iso-1) approaches. Behaviorally, genetic deletion of MIF resulted in increased anxiety- and depression-like behaviors, as well as of impaired hippocampus-dependent memory. Together, our studies provide evidence supporting a pivotal function for MIF in both basal and antidepressant-stimulated adult hippocampal cell proliferation. Moreover, loss of MIF results in a behavioral phenotype that, to a large extent, corresponds with alterations predicted to arise from reduced hippocampal neurogenesis. These findings underscore MIF as a potentially relevant molecular target for the development of treatments linked to deficits in neurogenesis, as well as to problems related to anxiety, depression, and cognition.

Motility tests for drugs preventing PolyQ aggregation in recombinant Caenorhabditis elegans.

The pathological formation of proteinaceous aggregates that accumulate into the brain cells of patients are hallmarks of neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral sclerosis and the heterogeneous group of polyglutamine (polyQ) diseases. In the polyQ diseases, the most upstream events of the pathogenic cascade are the misfolding and aggregation of proteins, such as huntingtin in Huntington's disease, that contain expanded stretch of glutamine residues above 35--‐40 repeats. This expanded polyQ stretch triggers the misfolding and aggregation of cytotoxic polyQ proteins in the neurons that cause cell death through different processes, like apoptosis, excessive inflammation, formation of free radicals, eventually leading to neuronal loss and neurodegeneration. This study focuses on the cellular network of chaperone proteins that can prevent protein aggregation by binding misfolding intermediates and may, as in the case of HSP70, actively unfold misfolded proteins into refoldable non--‐toxic ones (Hinault et al., 2010; Sharma et al., 2011). The chaperones can also collaborate with the proteasome to convert stable harmful proteins into harmless amino acids. Thus, the chaperone proteins that are the most important cellular factors of prevention and curing of protein misfolding, are negatively affected by aging (Morley et al., 2002) and fail to act properly in the neurons of aged persons, which eventually may lead to neurodegenerative pathologies. The general aim of this research was to identify least toxic drugs that can upregulate the expression of chaperone genes in cells suffering from polyQ--‐ mediated protein aggregation and degeneration. The specific aim of this study was to observe the effect of ten drugs on polyQ aggregation in a recombinant nematode Caenorhabditis elegans expressing a chimeric protein containing a sequence of 35 glutamines (Q35) fused to the green fluorescent protein in muscle cells, which causes an age--‐ and temperature--‐ dependent phenotype of accelerated paralysis. The drugs were selected after having proven their causing the overexpression of chaperone proteins in a previous wide screening of 2000 drugs on the moss plant Physcomitrella patens. The screening that we performed in this study was on these ten drugs. It suggested that piroxicam and anisindione were good reducers of polyglutamine disease mediated paralysis. A hypothesis can be made that they may act as good enhancers of the heat shock response, which causes the overexpression of many HSP chaperones and thus reduce motility impairment of polyQ disease expressing nematodes. Piroxicam was found to have the greatest effect on reducing polyQ35 proteins aggregates mediated paralysis in a dose--‐dependent manner but was also found to either have a toxic effect on wild type C.elegans, either to change its natural motility behavior, eventually reducing its motility in both cases. Chloroform should be preferred over DMSO as a drug solvent as it appears to be less toxic to C.elegans.

How do the different components of episodic memory develop? Role of executive functions and short-term feature-binding abilities.

This study investigated the development of all 3 components of episodic memory (EM), as defined by Tulving, namely, core factual content, spatial context, and temporal context. To this end, a novel, ecologically valid test was administered to 109 participants aged 4-16 years. Results showed that each EM component develops at a different rate. Ability to memorize factual content emerges early, whereas context retrieval abilities continue to improve until adolescence, due to persistent encoding difficulties (isolated by comparing results on free recall and recognition tasks). Exploration of links with other cognitive functions revealed that short-term feature-binding abilities contribute to all EM components, and executive functions to temporal and spatial context, although ability to memorize temporal context is predicted mainly by age.

Tests diagnostiques rapides (TDR): la panacée pour le praticien [Rapid diagnostic tests (RDT): the cure-all for the practitioner?].

Many rapid diagnostic tests (RDT) for the diagnosis of infectious diseases have been developed over the last 20 years. These allow (1) administering a treatment immediately in case of a potentially fatal disease, (2) prescribing a specific rather than presumptive treatment, (3) quickly introducing measures aimed at interrupting the transmission of the disease, (4) avoiding useless antibiotic treatments and (5) implementing a sequential diagnostic strategy to avoid extensive investigations. Using the example of malaria, a new strategy that includes a RDT as first-line emergency diagnostic tool and, when negative, delayed microscopy at the laboratory opening time is implemented in Lausanne since 1999. This strategy has been shown to be safe. Each TDR has its own characteristics that imperatively need to be known by the practitioner if he/she wants to use it in a rational way.

Astrocytes: powering memory.

Creating long-term memory requires a cellular program in neurons involving gene expression, protein synthesis, and formation of new synaptic connections. Suzuki et al. (2011) show that astrocytes, glial cells of the brain, play a necessary role in this program by converting glycogen to lactate and transporting it to neurons.

Age-related differences on event-related potentials and brain rhythm oscillations during working memory activation.

Previous functional imaging studies have pointed to the compensatory recruitment of cortical circuits in old age in order to counterbalance the loss of neural efficiency and preserve cognitive performance. Recent electroencephalographic (EEG) analyses reported age-related deficits in the amplitude of an early positive-negative working memory (PN(wm)) component as well as changes in working memory (WM)-load related brain oscillations during the successful performance of the n-back task. To explore the age-related differences of EEG activation in the face of increasing WM demands, we assessed the PN(wm) component area, parietal alpha event-related synchronization (ERS) as well as frontal theta ERS in 32 young and 32 elderly healthy individuals who successfully performed a highly WM demanding 3-back task. PN(wm) area increased with higher memory loads (3- and 2-back > 0-back tasks) in younger subjects. Older subjects reached the maximal values for this EEG parameter during the less WM demanding 0-back task. They showed a rapid development of an alpha ERS that reached its maximal amplitude at around 800 ms after stimulus onset. In younger subjects, the late alpha ERS occurred between 1,200 and 2,000 ms and its amplitude was significantly higher compared with elders. Frontal theta ERS culmination peak decreased in a task-independent manner in older compared with younger cases. Only in younger individuals, there was a significant decrease in the phasic frontal theta ERS amplitude in the 2- and 3-back tasks compared with the detection and 0-back tasks. These observations suggest that older adults display a rapid mobilization of their neural generators within the parietal cortex to manage very low demanding WM tasks. Moreover, they are less able to activate frontal theta generators during attentional tasks compared with younger persons.

Allergy to betalactam antibiotics in children: results of a 20-year study based on clinical history, skin and challenge tests.

To cite this article: Ponvert C, Perrin Y, Bados-Albiero A, Le Bourgeois M, Karila C, Delacourt C, Scheinmann P, De Blic J. Allergy to betalactam antibiotics in children: results of a 20-year study based on clinical history, skin and challenge tests. Pediatr Allergy Immunol 2011; 22: 411-418. ABSTRACT: Studies based on skin and challenge tests have shown that 12-60% of children with suspected betalactam hypersensitivity were allergic to betalactams. Responses in skin and challenge tests were studied in 1865 children with suspected betalactam allergy (i) to confirm or rule out the suspected diagnosis; (ii) to evaluate diagnostic value of immediate and non-immediate responses in skin and challenge tests; (iii) to determine frequency of betalactam allergy in those children, and (iv) to determine potential risk factors for betalactam allergy. The work-up was completed in 1431 children, of whom 227 (15.9%) were diagnosed allergic to betalactams. Betalactam hypersensitivity was diagnosed in 50 of the 162 (30.9%) children reporting immediate reactions and in 177 of the 1087 (16.7%) children reporting non-immediate reactions (p < 0.001). The likelihood of betalactam hypersensitivity was also significantly higher in children reporting anaphylaxis, serum sickness-like reactions, and (potentially) severe skin reactions such as acute generalized exanthematic pustulosis, Stevens-Johnson syndrome, and drug reaction with systemic symptoms than in other children (p < 0.001). Skin tests diagnosed 86% of immediate and 31.6% of non-immediate sensitizations. Cross-reactivity and/or cosensitization among betalactams was diagnosed in 76% and 14.7% of the children with immediate and non-immediate hypersensitivity, respectively. The number of children diagnosed allergic to betalactams decreased with time between the reaction and the work-up, probably because the majority of children with severe and worrying reactions were referred for allergological work-up more promptly than the other children. Sex, age, and atopy were not risk factors for betalactam hypersensitivity. In conclusion, we confirm in numerous children that (i) only a few children with suspected betalactam hypersensitivity are allergic to betalactams; (ii) the likelihood of betalactam allergy increases with earliness and/or severity of the reactions; (iii) although non-immediate-reading skin tests (intradermal and patch tests) may diagnose non-immediate sensitizations in children with non-immediate reactions to betalactams (maculopapular rashes and potentially severe skin reactions especially), the diagnostic value of non-immediate-reading skin tests is far lower than the diagnostic value of immediate-reading skin tests, most non-immediate sensitizations to betalactams being diagnosed by means of challenge tests; (iv) cross-reactivity and/or cosensitizations among betalactams are much more frequent in children reporting immediate and/or anaphylactic reactions than in the other children; (v) age, sex and personal atopy are not significant risk factors for betalactam hypersensitivity; and (vi) the number of children with diagnosed allergy to betalactams (of the immediate-type hypersensitivity especially) decreases with time between the reaction and allergological work-up. Finally, based on our experience, we also propose a practical diagnostic approach in children with suspected betalactam hypersensitivity.

NLRC4 inflammasomes in dendritic cells regulate noncognate effector function by memory CD8⁺ T cells.

Memory T cells exert antigen-independent effector functions, but how these responses are regulated is unclear. We discovered an in vivo link between flagellin-induced NLRC4 inflammasome activation in splenic dendritic cells (DCs) and host protective interferon-γ (IFN-γ) secretion by noncognate memory CD8(+) T cells, which could be activated by Salmonella enterica serovar Typhimurium, Yersinia pseudotuberculosis and Pseudomonas aeruginosa. We show that CD8α(+) DCs were particularly efficient at sensing bacterial flagellin through NLRC4 inflammasomes. Although this activation released interleukin 18 (IL-18) and IL-1β, only IL-18 was required for IFN-γ production by memory CD8(+) T cells. Conversely, only the release of IL-1β, but not IL-18, depended on priming signals mediated by Toll-like receptors. These findings provide a comprehensive mechanistic framework for the regulation of noncognate memory T cell responses during bacterial immunity.

MP2RAGE provides new clinically-compatible correlates of mild cognitive deficits in relapsing-remitting multiple sclerosis.

Despite that cognitive impairment is a known early feature present in multiple sclerosis (MS) patients, the biological substrate of cognitive deficits in MS remains elusive. In this study, we assessed whether T1 relaxometry, as obtained in clinically acceptable scan times by the recent Magnetization Prepared 2 Rapid Acquisition Gradient Echoes (MP2RAGE) sequence, may help identifying the structural correlate of cognitive deficits in relapsing-remitting MS patients (RRMS). Twenty-nine healthy controls (HC) and forty-nine RRMS patients underwent high-resolution 3T magnetic resonance imaging to obtain optimal cortical lesion (CL) and white matter lesion (WML) count/volume and T1 relaxation times. T1 z scores were then obtained between T1 relaxation times in lesion and the corresponding HC tissue. Patient cognitive performance was tested using the Brief Repeatable Battery of Neuro-psychological Tests. Multivariate analysis was applied to assess the contribution of MRI variables (T1 z scores, lesion count/volume) to cognition in patients and Bonferroni correction was applied for multiple comparison. T1 z scores were higher in WML (p < 0.001) and CL-I (p < 0.01) than in the corresponding normal-appearing tissue in patients, indicating relative microstructural loss. (1) T1 z scores in CL-I (p = 0.01) and the number of CL-II (p = 0.04) were predictors of long-term memory; (2) T1 z scores in CL-I (β = 0.3; p = 0.03) were independent determinants of long-term memory storage, and (3) lesion volume did not significantly influenced cognitive performances in patients. Our study supports evidence that T1 relaxometry from MP2RAGE provides information about microstructural properties in CL and WML and improves correlation with cognition in RRMS patients, compared to conventional measures of disease burden.

The neuronal monocarboxylate transporter MCT2: its regulation by BDNF and its role in learning and memory

Glucose has been considered the major, if not the exclusive, energy substrate for the brain. But under certain physiological and pathological conditions other substrates, namely monocarboxylates (lactate, pyruvate and ketone bodies), can contribute significantly to satisfy brain energy demands. These monocarboxylates need to be transported across the blood-brain barrier or out of astrocytes into the extracellular space and taken up into neurons. It has been shown that monocarboxylates are transported by a family of proton-linked transporters called monocarboxylate transporters (MCTs). In the central nervous system, MCT2 is the predominant neuronal isoform and little is known about the regulation of its expression. Noradrenaline (NA), insulin and IGF-1 were previously shown to enhance the expression of MCT2 in cultured cortical neurons via a translational mechanism. Here we demonstrate that the well known brain neurotrophic factor BDNF enhances MCT2 protein expression in cultured cortical neurons and in synaptoneurosome preparations in a time- and concentrationdependent manner without affecting MCT2 mRNA levels. We observed that BDNF induced MCT2 expression by activation of MAPK as well as PI3K/Akt/mTOR signaling pathways. Furthermore, we investigated the possible post-transcriptional regulation of MCT2 expression by a neuronal miRNA. Then, we demonstrated that BDNF enhanced MCT2 expression in the hippocampus in vivo, in parallel with some post-synaptic proteins such as PSD95 and AMPA receptor GluR2/3 subunits, and two immediate early genes Arc and Zif268 known to be expressed in conditions related to synaptic plasticity. In the last part, we demonstrated in vivo that a downregulation of hippocampal MCT2 via silencing with an appropriate lentiviral vector in mice caused an impairment of working memory without reference memory deficit. In conclusion, these results suggest that regulation of neuronal monocarboxylate transporter MCT2 expression could be a key event in the context of synaptic plasticity, allowing an adequate energy substrate supply in situations of altered synaptic efficacy. - Le glucose représente le substrat énergétique majeur pour le cerveau. Cependant, dans certaines conditions physiologiques ou pathologiques, le cerveau a la capacité d'utiliser des substrats énergéiques appartenant à la classe des monocarboxylates (lactate, pyruvate et corps cétoniques) afin de satisfaire ses besoins énergétiques. Ces monocarboxylates doivent être transportés à travers la barrière hématoencéphalique mais aussi hors des astrocytes vers l'espace extracellulaire puis re-captés par les neurones. Leur transport est assuré par une famillle de transporteurs aux monocarboxylates (MCTs). Dans le système nerveux central, les neurones expriment principalement l'isoforme MCT2 mais peu d'informations sont disponibles concernant la régulation de son expression. Il a été montré que la noradrénaline, l'insuline et l'IGF-1 induisent l'expression de MCT2 dans des cultures de neurones corticaux par un mécanisme traductionnel. Dans cette étude nous démontrons dans un premier temps que le facteur neurotrophique BDNF augmente l'expression de MCT2 à la fois dans des cultures de neurones corticaux et dans les préparations synaptoneurosomales selon un décours temporel et une gamme de concentrations propre. Aucun changement n'a été observé concernant les niveaux d'ARNm de MCT2. Nous avons observé que le BDNF induisait l'expression de MCT2 par l'activation simultanée des voies de signalisation MAPK et PI3K/Akt/mTOR. De plus, nous nous sommes intéressés à une potentielle régulation par les micro-ARNs de la synthèse de MCT2. Ensuite, nous avons démontré que le BDNF induit aussi l'expression de MCT2 dans l'hippocampe de la souris en parallèle avec d'autres protéines post-synaptiques telles que PSD95 et GluR2/3 et avec deux « immediate early genes » tels que Arc et Zif268 connus pour être exprimés dans des conditions de plasticité synaptique. Dans un dernier temps, nous avons démontré qu'une diminution d'expression de MCT2 induite par le biais d'un siRNA exprimé via un vecteur lentiviral dans l'hippocampe de souris générait des déficits de mémoire de travail sans affecter la mémoire de référence. En conclusion, ces résultats nous suggèrent que le transporteur aux monocarboxylates neuronal MCT2 serait essentiel pour l'apport énergétique du lactate pour les neurones dans des conditions de haute activité neuronale comme c'est le cas pendant les processus de plasticité synaptique.

Rivastigmine for HIV-associated neurocognitive disorders: A randomized crossover pilot study.

OBJECTIVE: To assess the efficacy and safety of rivastigmine for the treatment of HIV-associated neurocognitive disorders (HAND) in a cohort of long-lasting aviremic HIV+ patients. METHODS: Seventeen aviremic HIV+ patients with HAND were enrolled in a randomized, double-blind, placebo-controlled, crossover study to receive either oral rivastigmine (up to 12 mg/day for 20 weeks) followed by placebo (20 weeks) or placebo followed by rivastigmine. Efficacy endpoints were improvement on rivastigmine in the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and individual neuropsychological scores of information processing speed, attention/working memory, executive functioning, and motor skills. Measures of safety included frequency and nature of adverse events and abnormalities on laboratory tests and on plasma concentrations of antiretroviral drugs. Analyses of variance with repeated measures were computed to look for treatment effects. RESULTS: There was no change on the primary outcome ADAS-Cog on drug. For secondary outcomes, processing speed improved on rivastigmine (Trail Making Test A: F(1,13) = 5.57, p = 0.03). One measure of executive functioning just failed to reach significance (CANTAB Spatial Working Memory [strategy]: F(1,13) = 3.94, p = 0.069). No other change was observed. Adverse events were frequent, but not different from those observed in other populations treated with rivastigmine. No safety issues were recorded. CONCLUSIONS: Rivastigmine in aviremic HIV+ patients with HAND seemed to improve psychomotor speed. A larger trial with the better tolerated transdermal form of rivastigmine is warranted. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that rivastigmine is ineffective for improving ADAS-Cog scores, but is effective in improving some secondary outcome measures in aviremic HIV+ patients with HAND.