Modest phenotypic improvements in ASA-deficient mice with only one UDP-galactose:ceramide-galactosyltransferase gene

BACKGROUND: Arylsulfatase A (ASA)-deficient mice are a model for the lysosomal storage disorder metachromatic leukodystrophy. This lipidosis is characterised by the lysosomal accumulation of the sphingolipid sulfatide. Storage of this lipid is associated with progressive demyelination. We have mated ASA-deficient mice with mice heterozygous for a non-functional allele of UDP-galactose:ceramide-galactosyltransferase (CGT). This deficiency is known to lead to a decreased synthesis of galactosylceramide and sulfatide, which should reduce sulfatide storage and improve pathology in ASA-deficient mice. RESULTS: ASA-/- CGT+/- mice, however, showed no detectable decrease in sulfatide storage. Neuronal degeneration of cells in the spiral ganglion of the inner ear, however, was decreased. Behavioural tests showed small but clear improvements of the phenotype in ASA-/- CGT+/- mice. CONCLUSION: Thus the reduction of galactosylceramide and sulfatide biosynthesis by genetic means overall causes modest improvements of pathology

Quinolinic acid injection in mouse medial prefrontal cortex affects reversal learning abilities, cortical connectivity and hippocampal synaptic plasticity.

Intracerebral injection of the excitotoxic, endogenous tryptophan metabolite, quinolinic acid (QA), constitutes a chemical model of neurodegenerative brain disease. Complementary techniques were combined to examine the consequences of QA injection into medial prefrontal cortex (mPFC) of C57BL6 mice. In accordance with the NMDAR-mediated synapto- and neurotoxic action of QA, we found an initial increase in excitability and an augmentation of hippocampal long-term potentiation, converting within two weeks into a reduction and impairment, respectively, of these processes. QA-induced mPFC excitotoxicity impaired behavioral flexibility in a reversal variant of the hidden-platform Morris water maze (MWM), whereas regular, extended MWM training was unaffected. QA-induced mPFC damage specifically affected the spatial-cognitive strategies that mice use to locate the platform during reversal learning. These behavioral and cognitive defects coincided with changes in cortical functional connectivity (FC) and hippocampal neuroplasticity. FC between various cortical regions was assessed by resting-state fMRI (rsfMRI) methodology, and mice that had received QA injection into mPFC showed increased FC between various cortical regions. mPFC and hippocampus (HC) are anatomically as well as functionally linked as part of a cortical network that controls higher-order cognitive functions. Together, these observations demonstrate the central functional importance of rodent mPFC as well as the validity of QA-induced mPFC damage as a preclinical rodent model of the early stages of neurodegeneration

Astrocyte calcium dysfunction causes early network hyperactivity in Alzheimer's disease

Dysfunctions of network activity and functional connectivity (FC) represent early events in Alzheimer's disease (AD), but the underlying mechanisms remain unclear. Astrocytes regulate local neuronal activity in the healthy brain, but their involvement in early network hyperactivity in AD is unknown. We show increased FC in the human cingulate cortex several years before amyloid deposition. We find the same early cingulate FC disruption and neuronal hyperactivity in AppNL-F mice. Crucially, these network disruptions are accompanied by decreased astrocyte calcium signaling. Recovery of astrocytic calcium activity normalizes neuronal hyperactivity and FC, as well as seizure susceptibility and day/night behavioral disruptions. In conclusion, we show that astrocytes mediate initial features of AD and drive clinically relevant phenotypes

DMRN+18: Digital Music Research Network One-day Workshop 2023

DMRN+18: Digital Music Research Network One-day Workshop 2023 Queen Mary University of London Tuesday 19th December 2023 • Keynote speaker: Stefan Bilbao The Digital Music Research Network (DMRN) aims to promote research in the area of digital music, by bringing together researchers from UK and overseas universities, as well as industry, for its annual workshop. The workshop will include invited and contributed talks and posters. The workshop will be an ideal opportunity for networking with other people working in the area. Keynote speakers: Stefan Bilbao Tittle: Physics-based Audio: Sound Synthesis and Virtual Acoustics. Abstract: Any acoustically-produced sound produced must be the result of physical laws that describe the dynamics of a given system---always at least partly mechanical, and sometimes with an electronic element as well. One approach to the synthesis of natural acoustic timbres, thus, is through simulation, often referred to in this context as physical modelling, or physics-based audio. In this talk, the principles of physics-based audio, and the various different approaches to simulation are described, followed by a set of examples covering: various musical instrument types; the important related problem of the emulation of room acoustics or “virtual acoustics”; the embedding of instruments in a 3D virtual space; electromechanical effects; and also new modular instrument designs based on physical laws, but without a counterpart in the real world. Some more technical details follow, including the strengths, weaknesses and limitations of such methods, and pointers to some links to data-centred black-box approaches to sound generation and effects processing. The talk concludes with some musical examples and recent work on moving such algorithms to a real-time setting.. Bio: Stefan is a Professor (full) at Reid School of Music, University of Edinburgh, he is the Personal Chair of Acoustics and Audio Signal Processing, Music. He currently works on computational acoustics, for applications in sound synthesis and virtual acoustics. Special topics of interest include: Finite difference time domain methods, distributed nonlinear systems such as strings and plates, architectural acoustics, spatial audio in simulation, multichannel sound synthesis, and hardware and software realizations. More information on: https://www.acoustics.ed.ac.uk/group-members/dr-stefan-bilbao/ DMRN+18 is sponsored by The UKRI Centre for Doctoral Training in Artificial Intelligence and Music (AIM); a leading PhD research programme aimed at the Music/Audio Technology and Creative Industries, based at Queen Mary University of London

Subtle behavioral changes and increased prefrontal-hippocampal network synchronicity in APPNL-G-F mice before prominent plaque deposition

Amyloid-β (Aβ) peptides occur in the brains of patients with Alzheimer's disease (AD), but their role in functional impairment is still debated. High levels of APP and APP fragments in mice that overexpress APP might confound their use in preclinical research. We examined the occurrence of behavioral, cognitive and neuroimaging changes in APPNL-G-F knock-in mice that display Aβ42 amyloidosis in the absence of APP overexpression. Female APPNL-G-F mice (carrying Swedish, Iberian and Arctic APP mutations) were compared to APPNL mice (APP Swedish) at 3, 7 and 10 months. Mice were subjected to a test battery that referred to clinical AD symptoms, comprising cage activity, open field, elevated plus maze, social preference and novelty test, and spatial learning, reversal learning and spatial reference memory performance. Our assessment confirmed that behavior at these early ages was largely unaffected in these mice in accordance with previous reports, with some subtle behavioral changes, mainly in social and anxiety-related test performance. Resting-state functional MRI (rsfMRI) assessed connectivity between hippocampal and prefrontal regions with an established role in flexibility, learning and memory. Increased prefrontal-hippocampal network synchronicity was found in 3-month-old APPNL-G-F mice. These functional changes occurred before prominent amyloid plaque deposition

High fat diet treatment impairs hippocampal long-term potentiation without alterations of the core neuropathological features of Alzheimer disease

Type 2 diabetes (T2DM) and obesity might increase the risk for AD by 2-fold. Different attempts to model the effect of diet-induced diabetes on AD pathology in transgenic animal models, resulted in opposite conclusions. Here, we used a novel knock-in mouse model for AD, which, differently from other models, does not overexpress any proteins. Long-term high fat diet treatment triggers a reduction in hippocampal N-acetyl-aspartate/myo-inositol metabolites ratio and impairs long term potentiation in hippocampal acute slices. Interestingly, these alterations do not correlate with changes in the core neuropathological features of AD, i.e. amyloidosis and Tau hyperphosphorylation. The data suggest that AD phenotypes associated with high fat diet treatment seen in other models for AD might be exacerbated because of the overexpressing systems used to study the effects of familial AD mutations. Our work supports the increasing insight that knock-in mice might be more relevant models to study the link between metabolic disorders and AD

Progressive leukoencephalopathy impairs neurobehavioral development in sialin-deficient mice

Slc17a5−/− mice represent an animal model for the infantile form of sialic acid storage disease (SASD). We analyzed genetic and histological time-course expression of myelin and oligodendrocyte (OL) lineage markers in different parts of the CNS, and related this to postnatal neurobehavioral development in these mice. Sialin-deficient mice display a distinct spatiotemporal pattern of sialic acid storage, CNS hypomyelination and leukoencephalopathy. Whereas few genes are differentially expressed in the perinatal stage (p0), microarray analysis revealed increased differential gene expression in later postnatal stages (p10–p18). This included progressive upregulation of neuroinflammatory genes, as well as continuous down-regulation of genes that encode myelin constituents and typical OL lineage markers. Age-related histopathological analysis indicates that initial myelination occurs normally in hindbrain regions, but progression to more frontal areas is affected in Slc17a5−/− mice. This course of progressive leukoencephalopathy and CNS hypomyelination delays neurobehavioral development in sialin-deficient mice. Slc17a5−/− mice successfully achieve early neurobehavioral milestones, but exhibit progressive delay of later-stage sensory and motor milestones. The present findings may contribute to further understanding of the processes of CNS myelination as well as help to develop therapeutic strategies for SASD and other myelination disorders