NIHRDataInsights/HRCSData huggingface dataset:
Title: Understanding the contribution of cortical interneuron dysfunction to schizophrenia
Funder: Medical Research Council

Abstract: The pathophysiology of schizophrenia remains poorly understood, but defects in cortical interneurons -primarily in Parvalbumin-expressing (PV+) interneurons- are among the most replicated neuropathological findings. In addition, functional studies in humans have shown gamma oscillatory activity is abnormal in schizophrenia patients. Since work in rodents have demonstrated that PV+ interneurons are required for gamma oscillations, these findings reinforce the notion that PV+ interneurons are central to the disease process in schizophrenia. We aim to understand how pathological genetic variation and environmental risk factors converge during brain development to disrupt the function of cortical inhibitory neurons in at least a fraction of schizophrenia patients. We will use mice in this research programme because this is the animal model most amenable to genetic manipulation with brain circuits resembling those found in humans. The proposed research programme has three objectives: (1) To analyse the neural circuit mechanisms linking PV+ interneuron dysfunction to striatal hyperdopaminergia, (2) To investigate the neural circuit mechanisms through which genetic risk and adverse environmental factors may interact to disrupt cortical inhibitory circuits, and (3) To determine how gene networks linked to schizophrenia influence the development and function of PV+ interneurons in the cerebral cortex. Our proposed research builds on recent findings from our laboratories and capitalises on recent human genetic and epidemiological studies to bridge the gap between causes and mechanisms in schizophrenia. Successful execution of this research programme may lead to novel strategies for the development of new pharmacological treatments for schizophrenia.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: NEUROLOGICAL
Title: EnCRISPrx - A Permanent CRISPR-based Approach To Rescue Dravet Syndrome By Enhancing Scn1a Promoter Activity
Funder: Medical Research Council

Abstract: Dravet Syndrome is a severe childhood epilepsy affecting 1:15000 live births, and is characterized by prolonged seizures, autistic features, movement disorders and sleep deficits. 80% of the mutations causing Dravet are in the sodium channel gene SCN1A, which codes for Nav1.1. These are mainly nonsense mutations leading to SCN1A haploinsufficiency. Dravet syndrome is resistant to anti-epileptic medication, and sodium channel targeting drugs may even worsen it, probably because inhibitory neurons do not tolerate SCN1A haploinsufficiency as well as principal neurons. At the moment gene therapy is not realistic because the gene is too big for Adeno-Associated viral vectors that have been used in clinical trials for widespread CNS transduction. We aim to find a general approach to rescue haploinsufficient mutations in SCN1A. We will increase the activity of the endogenous SCN1A promoter. Using this strategy, our goal is to increase the transcription of both the wild type and the mutant alleles, thus restoring Nav1.1 expression to a normal level. We will test the therapy in an animal model of Dravet Syndrome at different developmental stages, examining their efficiency in suppressing spontaneous and febrile seizures, and correcting behavioural deficits such as social interactions. This proposal will be useful not only to understand if and when we can rescue Dravet syndrome, but will yield proof of principle of a generalizable method for treating other CNS diseases arising from haploinsufficiency. We think this approach will help to take gene editing closer to clinical translation for neurological diseases. Moreover, it will have an impact for basic neuroscience because, for the first time, we will be able to study the consequences of modifying genes in vivo.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL
Title: Roles of ER in distal axon pathologies
Funder: Medical Research Council

Abstract: Endoplasmic reticulum (ER) forms a dynamic network of sheets and tubules. It is central to Ca2+ and lipid homeostasis, and forms close contacts with other organelles. In neurons, it appears continuous through dendrites, cell body and axon, and is therefore termed a "neuron within a neuron" - potentially carrying local, regional, or long-range signals, independent of action potentials or physical transport, up to 1m in humans. An important role for it is supported by the finding that several axon degeneration genes, for the condition Hereditary Spastic Paraplegia (HSP) encode ER modelling proteins. In Drosophila we have developed tools to visualise axon ER, and shown that some ER-modelling proteins can affect the amount, continuity, or tubule dimensions of axon ER. Our aim is to understand the physiological phenotypes in axons and synapses that result from the structural ER changes that we see in Drosophila HSP mutants - local loss of ER in synapses, local increase in ER in axons, disrupted continuity, and increased tubule diameter. We will test local Ca2+ handling, synaptic transmission, ER-plasma membrane lipid exchange, mitochondrial function, and longer range propagation of Ca2+ flows in cytosol and ER lumen. By understanding the physiological consequences of ER structural changes for synapses and distal axons in Drosophila, we will be able to build models of the pathophysiology of HSP that can inform further work in both Drosophila and mammalian models. Our findings will also inform models of other distal neuropathies where ER plays a role.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: LonDownsPREVENT: A longitudinal study of the mechanisms of cerebral amyloid angiopathy and neurodegeneration in Down syndrome to inform AD prevention
Funder: Medical Research Council

Abstract: The proposed research focuses uniquely on the earliest stages of AD in DS, a population with ultra-high genetic risk for dementia (>90% at age 65), to understand the mechanisms leading to CAA and neurodegeneration in patients with "pure" amyloid-driven pathology. We will conduct a longitudinal study with sequential MRI imaging (3 timepoints 12 months apart) in 80 DS participants with AD pathology but without dementia diagnoses aged 35 - 54 years (i.e. in preclinical and prodromal stages of AD), as well as baseline assessments in a younger, healthy DS group aged 18-30 (n = 40). Participants will complete clinical assessments using our validated, sensitive tools and donate blood samples for DNA analysis (APOE and DS subtype) and plasma biomarkers (Neurofilament light (NfL), Abeta-42,40 and Tau using ultrasensitive SIMOA assays). Using MRI, we aim to deliver critical data on 1) cerebrovascular alterations using structural MRI markers of CAA (e.g. cerebral microbleeds, cSS) and to quantify cerebral blood flow (arterial spin labeling), and 2) AD progression using both diffusion MRI (microstructural changes) as early marker of AD, and structural MRI (macroscopic changes and cortical atrophy). At the plasma biomarker level, this will allow us to explore hypotheses related to the sequence of events leading to amyloid-induced CAA, using Abeta 42/40 ratio as marker of amyloid deposition, Tau for neuronal response and NfL as marker of neurodegeneration. At the imaging level, we will consider the role of cerebral blood flow alterations and changes in MRI diffusion as early surrogate markers for cognitive decline, with atrophy developing subsequently. DS individuals are typically excluded from clinical trials of new amyloid-targeting treatment to prevent or delay AD because of a lack of biomarker and progression data and concern about safety. We will deliver longitudinal, multimodal data to describe the parameters of AD progression which can then be used to plan such trials.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Local sleep homeostasis and single cell rest
Funder: Medical Research Council

Abstract: Sleep is of vital importance for health, and insufficient or disrupted sleep has been linked to a broad range of neurological disorders. Crucially, despite decades of research many fundamental questions remain, such as why sleep deprivation impacts brain function and what are the specific mechanisms that convey the benefits of sleep to the brain. We propose that the most important role of sleep is to provide individual neurons with a period in which to perform processes of cellular maintenance that are required after periods of elevated synaptic activity. In particular, we hypothesise that sleep enables neurons to deal with cellular stress associated with the accumulation of misfolded proteins in the lumen of the endoplasmic reticulum - so called "ER stress". Whilst most cells in the body can presumably undergo rest relatively independently, we propose that neurons must rest together due to their extensive interconnectivity. Thus, rest at the single neuron level requires both synchronised network activity and withdrawal from the environment. In this project we will test this hypothesis for the first time using a combination of electrophysiological, molecular and pharmacological techniques. First, we will investigate whether elevated synaptic activity during waking is associated with both an increased local sleep drive and naturally induced cellular stress. Second, we will induce cellular stress directly using local application of drugs, or by manipulating proteins, which lead to enhanced protein misfolding and accumulation. Finally, we will investigate whether sleep is necessary for the local recovery from ER stress and elucidate the time scale of this recovery. This project will address the function of sleep from the molecular to the behavioural level, it will develop novel tools and concepts for understanding sleep regulation and it will inform future studies that aim to target sleep as a means of preventing cognitive decline and neurodegenerative disorders.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: The neural correlates of personal semantic memory across the lifecourse
Funder: Medical Research Council

Abstract: Declarative memory is typically defined as consisting of two independent systems: episodic and semantic. However, since this dichotomy was established, additional aspects of declarative memory have been described, which appear to share some features with episodic and semantic memory, but are also dissociable from them. These aspects of memory are commonly referred to as personal semantics (or semantic autobiographical memory). Despite offering high potential for more accurate models of memory and new diagnostic and rehabilitation pathways, personal semantics is not integrated into current models of declarative memory and knowledge, as it remains poorly studied. I have recently introduced a new framework to operationalise personal semantics according to 4 main types and their distinct neural correlates (Renoult et al., 2012). In the proposed research project, we will study these 4 types of personal semantics and examine how they relate to semantic and episodic memory in 60 younger (18-30) and 100 older (65-80) adults and in relation with genetic risk (APOE4 carriers) for Alzheimer's disease (AD). We will measure their corresponding neural correlates using event-related potentials (ERPs), multi-variate statistics and dipole source modelling using each participant's MRI. It is well established that semantic memory tends to be well-preserved in ageing and in early AD, while episodic memory performance tends to decrease with advancing age and to be impaired in AD. However, very little is known about personal semantics in ageing and AD. It is thus still unclear which types of personal semantics are modified in healthy ageing and in individuals at genetic risk for AD. By studying personal semantics alongside episodic and semantic memory in relation to age and genetic risk for AD, this project will contribute more accurate models of declarative memory, new memory tests, and will provide avenues for new rehabilitation approaches in memory-impaired individuals.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Characterisation of oligodendrocyte plasticity in the adult median eminence and its role in the regulation of energy balance
Funder: Medical Research Council

Abstract: The median eminence (ME) of the hypothalamus serves as an interface between peripheral and hypothalamic neuroendocrine circuits. It undergoes rapid structural remodelling in response to changes in peripheral energy availability and this plasticity determines how nearby neurons access and respond to blood-borne fuel-related signals. Its unique vasculature lacks a blood-brain-barrier, suggesting other specialized roles for local glia. Our pilot data indicate that new oligodendrocytes (OLs) are continuously formed in the adult ME and that OL production and differentiation in the ME are regulated by nutritional signals. We hypothesize that this adaptive OL-encoded response is required for the maintenance of energy homeostasis and impaired in obesity. Accordingly, our aims in this proposal are to determine how nutritional signals regulate OL differentiation, to determine how obesity affects OL plasticity in the human and murine ME, and to directly test the role of OL plasticity in the regulation of energy balance in mice. This research will increase our understanding of the role of glial cells in metabolic sensing and the regulation of neurocircuits controlling appetite and metabolism. It will also test a novel role for nutritional signals in the control of OL differentiation. Collectively, this research will promote important novel conceptual advances in the fields of obesity and adult brain plasticity, with potential implications for the treatment of metabolic and demyelinating diseases.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: NEUROLOGICAL
Title: The role of microRNA regulation in a Drosophila model of Huntington disease
Funder: Medical Research Council

Abstract: Huntington Disease (HD) is an incurable disease that causes a combination of motor, cognitive and behavioural features which deteriorate the patient's physical and mental abilities, ultimately leading to death. Recent studies in humans revealed that several small non-coding RNAs (microRNAs) show differential expression in HD brains suggesting that microRNAs may be involved in the development of HD pathology or constitute a compensatory mechanism by the patient. This project investigates these important and timely questions using a Drosophila model of HD. In preliminary work to this application we discovered that induction of HD in Drosophila leads to dysregulation of a common minimal microRNA "signature" associated to HD in both humans and flies. In addition, overexpression of one signature HD-microRNA upregulated in HD (miR-10) in a non-HD background is sufficient to trigger severe locomotor defects in adult flies, while attenuation of miR-10 function in HD flies significantly improves locomotor defects. These observations show that Drosophila is an excellent genetically-tractable system where to study the mechanisms that link microRNA dysregulation to HD. This proposal builds on this and investigates (i) the mechanisms that link HD to microRNA dysregulation, and (ii) the neural cellular basis underlying microRNA effects on motor dysfunction. The project will be developed as a novel collaboration between the labs of Professor Claudio Alonso (an international expert in microRNA neurobiology at the University of Sussex) and Professor Gillian Bates FRS, a world leader in the molecular and cellular biology of Huntington Disease from UCL. The work will thus contribute to two MRC core objectives in relation to neuroscience research: (i) fundamental discovery research relating to the development, function and disorders of the human nervous system, and (ii) research to inform novel strategies for preventing and treating disorders of the nervous system.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Elucidating the role of DNA methylation in the pathophysiology of lewy body diseases.
Funder: Medical Research Council

Abstract: Parkinson's disease (PD), PD dementia (PDD) and Dementia with Lewy bodies (DLB) are Lewy body (LB) diseases, which are characterised by the cytoplasmic accumulation of a-synuclein in neurons, forming Lewy bodies (LBs). At present we do not know what molecular changes may be driving disease onset and progression and there are currently no disease-modifying treatments for these diseases. This study will represent the first systematic, epigenome-wide association study (EWAS) of DNA methylation across multiple diseases characterised by synucleinopathy. We propose to analyse DNA methylation patterns using the Illumina EPIC array in 100 PD, 100 PDD, 100 DLB and 100 control donors in the substantia nigra (SN) as this is affected in the middle stages of disease, and the prefrontal cortex (PFC) as this is affected in the later stages of disease. We will identify DNA methylation signatures that can stratify individuals based on their diagnosis, genotype, pathology, symptoms and, in the case of PD, the presence of PDD. We will validate these patterns, and determine their cellular specificity using pyrosequencing and qRT-PCR on nucleic acid extracted from neurons and glia isolated from SN and PFC samples using fluorescence-activated cell sorting (FACS). Loci that appear to be neuronal we will investigate further using laser capture microdissection (LCM) in PFC samples. We will collect LB-bearing neurons and neurons free of pathology and use pyrosequencing to determine which loci are specifically altered in LB-bearing neurons. These loci will be the focus of our functional characterisation experiments, where we propose to use CRISPR/Cas9 technology to alter DNA methylation at these loci, and establish the downstream consequence on cell phenotype. Taken together, we will be able to identify differentially methylated loci that are causal in LB disease pathology, which could ultimately deliver new pharmacological targets, potentially improving the lives of sufferers.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Leveraging the power of genomics and transcriptomics to revolutionise the diagnosis and understanding of neurological disorders
Funder: Medical Research Council

Abstract: The primary challenge of genome analysis is that the capacity of genome sequencing to discover genetic variants substantially exceeds our ability to interpret their functional and clinical impact. We are uniquely placed to make use of the opportunities provided by the 100K to investigate neurodegenerative disorders, due to the large number of families, extensive clinical data and the 100K collection of biosamples. We will apply an integrated analytical approach in this proposal to; (a) Investigate and identify genomic abnormalities in the undiagnosed neurological disorders in the 100K using bioinformatic techniques, focusing on inherited neurodegenerative disorders and combining this with the extensive clinical data collected. Primarily we will find new disease genes and mosaic base substitutions, mutations in noncoding regions including potential novel exons currently annotated as intronic regions or conserved/constrained elements, mitochondrial DNA and nuclear mitochondrial mutations, (iv) cryptic splicing, (v) deletions, insertions, inversions and (vi) new repeat expansion disorders. (b) We will identify a large number of potentially pathogenic variants and optimise variant annotation and prioritisation using transcriptome data to improve diagnostic yield. (c) We will use RNA sequencing to further increase the diagnosis, and the availability of additional sequenced diseased cohorts through our research and collaborations, will increase our ability to validate pathogenicity of new disease genes. Using this approach, we will identify common mechanisms responsible for specific phenotypes that have an impact across the spectrum of Mendelian and non-familial neurodegenerative disorders. (d) This will allow a greater understanding of the use of genomics in diagnostic practice and help re-define the classification of neurodegenerative diseases based on advanced understanding of the molecular mechanisms, as opposed to the traditional 'major-phenotype' based approach.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Prevention of dementia by targeting risk factors
Funder: Medical Research Council

Abstract: The objectives of our multi-cohort research programme are to: (1) examine associations of the Lancet 2017 Commission risk factors with cognitive decline, clinically-verified Alzheimer's disease and dementia using the largest individual-participant dataset in this field and a novel analytic strategy to account for bias due to reverse causation; (2) expand analyses to examine how trajectories of chronic diseases over the adult lifecourse shape risk of dementia; and (3) evaluate 233 metabolite biomarkers, singly and in combination, as early predictors of cognitive function, Alzheimer's disease and dementia, with a focus on biomarkers assessed at least 10 years before dementia diagnosis. This programme is based on existing data related to very large numbers of people with long follow-up (N up to 1.5 million), allowing to examine the temporality underpinning the established associations between risk factors, biomarkers and dementia. The sources of data include the IPD-Work consortium, DPUK, UK Biobank, the US-European metabolomics-dementia consortium, and the UCLEB consortium. Our analytic approach emphasises the importance of "time windows" when considering the role of risk factors and biomarkers for dementia. Thus, we stratify analyses by length of time between risk factor assessment and onset of dementia, assuming that the closer the risk factor/biomarker assessment is to the onset of clinical dementia, the greater the possibility the risk factors are a consequence of preclinical dementia rather than a cause. Resources are requested for research data curation and harmonisation across cohort studies, data analysis, administration and travel.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: NEUROLOGICAL