Increased numbers of oligodendrocyte lineage cells in the optic nerves of cerebroside sulfotransferase knockout mice

Sulfatide is a myelin glycolipid that functions in the formation of paranodal axo-glial junctions in vivo and in the regulation of oligodendrocyte differentiation in vitro. Cerebroside sulfotransferase (CST) catalyzes the production of two sulfated glycolipids, sulfatide and proligodendroblast antigen, in oligodendrocyte lineage cells. Recent studies have demonstrated significant increases in oligodendrocytes from the myelination stage through adulthood in brain and spinal cord under CST-deficient conditions. However, whether these result from excess migration or in situ proliferation during development is undetermined. In the present study, CST-deficient optic nerves were used to examine migration and proliferation of oligodendrocyte precursor cells (OPCs) under sulfated glycolipid-deficient conditions. In adults, more NG2-positive OPCs and fully differentiated cells were observed. In developing optic nerves, the number of cells at the leading edge of migration was similar in CST-deficient and wild-type mice. However, BrdU+ proliferating OPCs were more abundant in CST-deficient mice. These results suggest that sulfated glycolipids may be involved in proliferation of OPCs in vivo

The intellectual disability risk gene Kdm5b regulates long term memory consolidation in the hippocampus

This is the author accepted manuscript. the final version is available from the Society for Neuroscience via the DOI in this recordData availability: RNAseq data (fastq files) were deposited at the Gene Expression Omnibus (GEO) archive under the accession number GSE240887 and made freely available upon publicationThe histone lysine demethylase KDM5B is implicated in recessive intellectual disability disorders and heterozygous, protein truncating variants in KDM5B are associated with reduced cognitive function in the population. The KDM5 family of lysine demethylases has developmental and homeostatic functions in the brain, some of which appear to be independent of lysine demethylase activity. To determine the functions of KDM5B in hippocampus-dependent learning and memory, we first studied male and female mice homozygous for a Kdm5b ΔARID allele that lacks demethylase activity. Kdm5b ΔARID/ΔARID mice exhibited hyperactivity and long-term memory deficits in hippocampus-dependent learning tasks. The expression of immediate early, activity-dependent genes was downregulated in these mice and hyperactivated upon learning stimulus compared to wildtype mice. A number of other learning-associated genes was also significantly dysregulated in the Kdm5b ΔARID/ΔARID hippocampus. Next, we knocked down Kdm5b specifically in the adult, wildtype mouse hippocampus with shRNA. Kdm5b knockdown resulted in spontaneous seizures, hyperactivity and hippocampus-dependent long-term memory and long-term potentiation deficits. These findings identify KDM5B as a critical regulator of gene expression and synaptic plasticity in the adult hippocampus and suggest that at least some of the cognitive phenotypes associated with KDM5B gene variants are caused by direct effects on memory consolidation mechanisms. Significance statement The histone lysine demethylase KDM5B has been implicated in cognitive performance and intellectual disability conditions in the human population. In the present manuscript we show that mice expressing a demethylase-deficient KDM5B and mice with a specific knockdown of KDM5B in the adult hippocampus exhibit hippocampus-dependent learning and memory phenotypes. Molecular analyses suggest a key role for KDM5B in regulating the dynamic expression of activity-regulated genes during memory consolidation. Deficits in LTP are present in mice with KDM5B knockdown. Together, these findings provide the first evidence for a direct function for KDM5B in memory consolidation in the hippocampus.Medical Research Council (MRC)National Institute of AgingWellcome Trus

The intellectual disability risk gene Kdm5b regulates long term memory consolidation in the hippocampus

The histone lysine demethylase KDM5B is implicated in recessive intellectual disability disorders and heterozygous, protein truncating variants in KDM5B are associated with reduced cognitive function in the population. The KDM5 family of lysine demethylases has developmental and homeostatic functions in the brain, some of which appear to be independent of lysine demethylase activity. To determine the functions of KDM5B in hippocampus-dependent learning and memory, we first studied male and female mice homozygous for a Kdm5bΔARID allele that lacks demethylase activity. Kdm5bΔARID/ΔARID mice exhibited hyperactivity and long-term memory deficits in hippocampus-dependent learning tasks. The expression of immediate early, activity-dependent genes was downregulated in these mice and hyperactivated upon learning stimulus compared to wildtype mice. A number of other learning-associated genes was also significantly dysregulated in the Kdm5bΔARID/ΔARID hippocampus. Next, we knocked down Kdm5b specifically in the adult, wildtype mouse hippocampus with shRNA. Kdm5b knockdown resulted in spontaneous seizures, hyperactivity and hippocampus-dependent long-term memory and long-term potentiation deficits. These findings identify KDM5B as a critical regulator of gene expression and synaptic plasticity in the adult hippocampus and suggest that at least some of the cognitive phenotypes associated with KDM5B gene variants are caused by direct effects on memory consolidation mechanisms. Significance statement The histone lysine demethylase KDM5B has been implicated in cognitive performance and intellectual disability conditions in the human population. In the present manuscript we show that mice expressing a demethylase-deficient KDM5B and mice with a specific knockdown of KDM5B in the adult hippocampus exhibit hippocampus-dependent learning and memory phenotypes. Molecular analyses suggest a key role for KDM5B in regulating the dynamic expression of activity-regulated genes during memory consolidation. Deficits in LTP are present in mice with KDM5B knockdown. Together, these findings provide the first evidence for a direct function for KDM5B in memory consolidation in the hippocampus

Automated Home-Cage Behavioural Phenotyping of Mice

Neurobehavioral analysis of mouse phenotypes requires the monitoring of mouse behavior over long periods of time. Here, we describe a trainable computer vision system enabling the automated analysis of complex mouse behaviors. We provide software and an extensive manually annotated video database used for training and testing the system. Our system performs on par with human scoring, as measured from ground-truth manual annotations of thousands of clips of freely behaving mice. As a validation of the system, we characterized the home-cage behaviors of two standard inbred and two non-standard mouse strains. From this data we were able to predict in a blind test the strain identity of individual animals with high accuracy. Our video-based software will complement existing sensor based automated approaches and enable an adaptable, comprehensive, high-throughput, fine-grained, automated analysis of mouse behavior.McGovern Institute for Brain ResearchCalifornia Institute of Technology. Broad Fellows Program in Brain CircuitryNational Science Council (China) (TMS-094-1-A032

False discovery rate estimation and heterobifunctional cross-linkers

<div><p>False discovery rate (FDR) estimation is a cornerstone of proteomics that has recently been adapted to cross-linking/mass spectrometry. Here we demonstrate that heterobifunctional cross-linkers, while theoretically different from homobifunctional cross-linkers, need not be considered separately in practice. We develop and then evaluate the impact of applying a correct FDR formula for use of heterobifunctional cross-linkers and conclude that there are minimal practical advantages. Hence a single formula can be applied to data generated from the many different non-cleavable cross-linkers.</p></div

Enhanced warming over the global subtropical western boundary currents

Author Posting. © The Author(s), 2011. This is the author's version of the work. It is posted here by permission of Nature Publishing Group for personal use, not for redistribution. The definitive version was published in Nature Climate Change 2 (2012): 161-166, doi:10.1038/nclimate1353.Subtropical western boundary currents are warm, fast flowing currents that form on the western side of ocean basins. They carry warm tropical water to the mid-latitudes and vent large amounts of heat and moisture to the atmosphere along their paths, affecting atmospheric jet streams and mid-latitude storms, as well as ocean carbon uptake. The possibility that these highly energetic and nonlinear currents might change under greenhouse gas forcing has raised significant concerns, but detecting such changes is challenging owing to limited observations. Here, using reconstructed sea surface temperature datasets and newly developed century-long ocean and atmosphere reanalysis products, we find that the post-1900 surface ocean warming rate over the path of these currents is two to three times faster than the global mean surface ocean warming rate. The accelerated warming is associated with a synchronous poleward shift and/or intensification of global subtropical western boundary currents in conjunction with a systematic change in winds over both hemispheres. This enhanced warming may reduce ocean's ability to absorb anthropogenic carbon dioxide over these regions. However, uncertainties in detection and attribution of these warming trends remain, pointing to a need for a long-term monitoring network of the global western boundary currents and their extensions.This work is supported by China National Key Basic Research Project (2007CB411800) and National Natural Science Foundation Projects (40788002, 40921004). WC is supported by the Australian Climate Change Science program and the Southeast Australia Climate Initiative. HN is supported in part by the Japanese Ministry of Education, Culture, Sports, Science and Technology through Grant-in-Aid for Scientific Research on Innovative Areas #2205 and by the Japanese Ministry of Environment through Global Environment Research Fund (S-5). MJM is supported by NOAA’s Climate Program Office.2012-07-2