ARE THERE DISCRETE GAMMA SUB-BANDS IN HIPPOCAMPAL NETWORKS DURING SPATIAL LEARNING ?

International audienc

Differential contribution of APP metabolites to early cognitive deficits in a TgCRND8 mouse model of Alzheimer’s disease

International audienceAlzheimer's disease (AD) is a neurodegenerative pathology commonly characterized by a progressive and irreversible deterioration of cognitive functions, especially memory. Although the etiology of AD remains unknown , a consensus has emerged on the amyloid hypothesis, which posits that increased production of soluble amyloid b (Ab) peptide induces neuronal network dysfunctions and cognitive deficits. However, the relative failures of Ab-centric therapeutics suggest that the amyloid hypothesis is incomplete and/or that the treatments were given too late in the course of AD, when neuronal damages were already too extensive. Hence, it is striking to see that very few studies have extensively characterized, from anatomy to behavior, the alterations associated with pre-amyloid stages in mouse models of AD amyloid pathology. To fulfill this gap, we examined memory capacities as well as hippocampal network anatomy and dynamics in young adult pre-plaque TgCRND8 mice when hippocampal Ab levels are still low. We showed that TgCRND8 mice present alterations in hippocampal inhibitory networks and g oscillations at this stage. Further, these mice exhibited deficits only in a subset of hippocampal-dependent memory tasks, which are all affected at later stages. Last, using a pharmacological approach, we showed that some of these early memory deficits were Ab-independent. Our results could partly explain the limited efficacy of Ab-directed treatments and favor multitherapy approaches for early symptomatic treatment for AD

A role of melanin-concentrating hormone producing neurons in the central regulation of paradoxical sleep

BACKGROUND: Peptidergic neurons containing the melanin-concentrating hormone (MCH) and the hypocretins (or orexins) are intermingled in the zona incerta, perifornical nucleus and lateral hypothalamic area. Both types of neurons have been implicated in the integrated regulation of energy homeostasis and body weight. Hypocretin neurons have also been involved in sleep-wake regulation and narcolepsy. We therefore sought to determine whether hypocretin and MCH neurons express Fos in association with enhanced paradoxical sleep (PS or REM sleep) during the rebound following PS deprivation. Next, we compared the effect of MCH and NaCl intracerebroventricular (ICV) administrations on sleep stage quantities to further determine whether MCH neurons play an active role in PS regulation. RESULTS: Here we show that the MCH but not the hypocretin neurons are strongly active during PS, evidenced through combined hypocretin, MCH, and Fos immunostainings in three groups of rats (PS Control, PS Deprived and PS Recovery rats). Further, we show that ICV administration of MCH induces a dose-dependant increase in PS (up to 200%) and slow wave sleep (up to 70%) quantities. CONCLUSION: These results indicate that MCH is a powerful hypnogenic factor. MCH neurons might play a key role in the state of PS via their widespread projections in the central nervous system

Monocyte derived dendritic cells retain their functional capacity in patients following infection with hepatitis C virus

Studies assessing the function of monocyte derived dendritic cells (MD-DC) in individuals with hepatitis C virus (HCV) infection have shown conflicting results. Impaired MD-DC function in chronic HCV infection would have important implications both for understanding the pathogenesis of HCV infection and in the use of autologous MD-DC in vaccination strategies. We determined the allostimulatory capacity of MD-DC in the same patient before and after HCV infection. Next, the phenotype, cytokine production and allostimulatory function of immature and mature MD-DC in individuals with persistent HCV infection were compared directly with MD-DC from healthy individuals. Finally, we assessed the ability of MD-DC to prime autologous naïve peptide specific CD8+ T cells using HLA-A2 class-I tetramers. DCs retained the same allostimulatory capacity before and following the establishment of persistent HCV infection. The surface phenotype and the amount of interleukin (IL)-10 and IL-12(p70) produced during DC maturation did not differ between HCV-infected individuals and healthy controls. Mature DCs from HCV-infected individuals performed comparably in an allogeneic MLR compared with healthy individuals. Mature MD-DC from HCV-infected individuals stimulated the expansion of peptide specific naïve CD8+ T cells. MD-DC from HCV-infected and healthy individuals are phenotypically indistinguishable and perform comparably in functional assays

Development of calcium phosphate suspensions suitable for the stereolithography process

peer reviewedWith the median age of the population steadily rising, the rate of bone disorders increases as well, making the need of bone implants more and more urgent in our society. However, manufacturing of synthetic bioimplants requires high flexibility of the process and materials with sufficient mechanical strength and biocompatible properties. This paper is devoted to the printing of β-tricalcium phosphate (β-TCP) by stereolithography. The suspensions or pastes containing the photosensitive-resin mixed with β-TCP powder were assessed for the following parameters: rheological behaviour, thermal degradation of photo-cured samples, quality of green and sintered parts. It appeared that the composition of the photo-sensitive resin influences the viscosity of the paste. However, no direct correlation could be drawn between the viscosity of the photo-sensitive resins and the viscosity of the whole paste. A hypothesis is that the chemical structure of the monomers composing the photo-sensitive resin also impacts the viscosity of the paste. A thermal debinding cycle was built from the thermogravimetric analysis of the photo-cured samples. The structure of the post printed (green) parts and final parts (parts after debinding and sintering) was evaluated. It appeared that the pastes with the lowest viscosity were the easiest to process, and that the green parts made with these pastes were the easiest to clean, reducing the number of defects in the sintered parts. Process optimisation was also assessed. Different light parameters were evaluated, and it appeared that reducing the light power during the printing improved the resolution as well as the quality of the sintered parts

Surface reconstruction from routine CT-scan shows large anatomical variations of falx cerebri and tentorium cerebelli

Background: Finite element modeling of the human head offers an alternative to experimental methods in understanding the biomechanical response of the head in trauma brain injuries. Falx, tentorium, and their notches are important structures surrounding the brain, and data about their anatomical variations are sparse. Objective: To describe and quantify anatomical variations of falx cerebri, tentorium cerebelli, and their notches. Methods: 3D reconstruction of falx and tentorium was performed by points identification on 40 brain CT-scans in a tailored Matlab program. A scatter plot was obtained for each subject, and 8 anatomical landmarks were selected. A reference frame was defined to determine the coordinates of landmarks. Segments and areas were computed. A reproducibility study was done. Results: The height of falx was 34.9 ± 3.9 mm and its surface area 56.5 ± 7.7 cm2. The width of tentorium was 99.64 ± 4.79 mm and its surface area 57.6 ± 5.8 cm2. The mean length, height, and surface area of falx notch were respectively 96.9 ± 8 mm, 41.8 ± 5.9 mm, and 28.8 ± 5.8 cm2 (range 15.8-40.5 cm2). The anterior and maximal widths of tentorial notch were 25.5 ± 3.5 mm and 30.9 ± 2.5 mm; its length 54.9 ± 5.2 mm and its surface area 13.26 ± 1.6 cm2. The length of falx notch correlated with the length of tentorial notch (r = 0.62, P < 0.05). Conclusion: We observe large anatomical variations of falx, tentorium, and notches, crucial to better understand the biomechanics of brain injury, in personalized finite element models

Serine/threonine acetylation of TGFbeta-activated kinase (TAK1) by Yersinia pestis YopJ inhibits innate immune signaling

The Gram-negative bacteria Yersinia pestis, causative agent of plague, is extremely virulent. One mechanism contributing to Y. pestis virulence is the presence of a type-three secretion system, which injects effector proteins, Yops, directly into immune cells of the infected host. One of these Yop proteins, YopJ, is proapoptotic and inhibits mammalian NF-kappaB and MAP-kinase signal transduction pathways. Although the molecular mechanism remained elusive for some time, recent work has shown that YopJ acts as a serine/threonine acetyl-transferase targeting MAP2 kinases. Using Drosophila as a model system, we find that YopJ inhibits one innate immune NF-kappaB signaling pathway (IMD) but not the other (Toll). In fact, we show YopJ mediated serine/threonine acetylation and inhibition of dTAK1, the critical MAP3 kinase in the IMD pathway. Acetylation of critical serine/threonine residues in the activation loop of Drosophila TAK1 blocks phosphorylation of the protein and subsequent kinase activation. In addition, studies in mammalian cells show similar modification and inhibition of hTAK1. These data present evidence that TAK1 is a target for YopJ-mediated inhibition

Stabilized low-n amyloid-ß oligomers induce robust novel object recognition deficits associated with inflammatory, synaptic, and GABAergic dysfunction in the rat

YesBackground:With current treatments for Alzheimer’s disease (AD) only providing temporary symptomatic benefits, disease modifying drugs are urgently required. This approach relies on improved understanding of the early pathophysiology of AD. A new hypothesis has emerged, in which early memory loss is considered a synapse failure caused by soluble amyloid-β oligomers (Aβo). These small soluble Aβo, which precede the formation of larger fibrillar assemblies, may be the main cause of early AD pathologies. Objective:The aim of the current study was to investigate the effect of acute administration of stabilized low-n amyloid-β1-42 oligomers (Aβo1-42) on cognitive, inflammatory, synaptic, and neuronal markers in the rat. Methods:Female and male Lister Hooded rats received acute intracerebroventricular (ICV) administration of either vehicle or 5 nmol of Aβo1-42 (10μL). Cognition was assessed in the novel object recognition (NOR) paradigm at different time points. Levels of inflammatory (IL-1β, IL-6, TNF-α), synaptic (PSD-95, SNAP-25), and neuronal (n-acetylaspartate, parvalbumin-positive cells) markers were investigated in different brain regions (prefrontal and frontal cortex, striatum, dorsal and ventral hippocampus). Results:Acute ICV administration of Aβo1-42 induced robust and enduring NOR deficits. These deficits were reversed by acute administration of donepezil and rolipram but not risperidone. Postmortem analysis revealed an increase in inflammatory markers, a decrease in synaptic markers and parvalbumin containing interneurons in the frontal cortex, with no evidence of widespread neuronal loss. Conclusion:Taken together the results suggest that acute administration of soluble low-n Aβo may be a useful model to study the early mechanisms involved in AD and provide us with a platform for testing novel therapeutic approaches that target the early underlying synaptic pathology

A class C CpG toll-like receptor 9 agonist successfully induces robust interferon-alpha production by plasmacytoid dendritic cells from patients chronically infected with hepatitis C

Immunomodulators that induce local endogenous interferon-alpha (IFN-α) production by plasmacytoid dendritic cells (pDCs) may offer new strategies for the treatment of patients chronically infected with the hepatitis C virus (HCV). However, such an approach may be compromised if reports are true that IFN-α production by pDCs from patients with chronic HCV (cHCV) is profoundly impaired. To address the question of pDC dysfunction in cHCV more definitively, in the present study a panel of four prototypic synthetic agonists of toll-like receptor 7 (TLR7) or TLR9 were administered in vitro to pDCs purified from cHCV patients and from normal uninfected donors and their responses compared in terms of not only IFN-α production but also the global expression of other cytokines and phenotypic maturation. Plasmacytoid DCs from uninfected donors produced substantial levels of IFN-α in response to three of the four agonists and yet only one TLR9 agonist, a class C CpG oligodeoxynucleotide (ODN), induced robust IFN-α production by pDCs from cHCV patients. Proinflammatory cytokine production and phenotypic maturation in response to all four agonists was equivalent in infected and uninfected pDCs. These data point to a profound but selective defect in IFN-α production by pDCs from cHCV donors. Nonetheless, a class C CpG ODN successfully induced robust IFN-α production, suggesting that this class of TLR9 agonist may have utility as a future immunotherapeutic for the treatment of chronic HCV infection