NIHRDataInsights/HRCSData huggingface dataset:
Title: Impact of early life SSRI exposure on neural circuit formation and function
Funder: Medical Research Council

Abstract: SSRIs are the first-line treatment for depression and one of the most widely used drug therapies in primary care. However, the impact of elevated 5-HT on brain development is poorly understood and it remains unclear whether pregnant women should continue SSRI treatment, given the possible implications for the cognitive abilities of the offspring. To address this we will use a model system in which we can separate genetic (maternal background) from environmental factors (elevated 5-HT due to SSRIs) and directly assess the impact of the latter on circuit formation and emergent perception. Our hypothesis is that elevated 5-HT will result in early circuit abnormalities but that the neonatal brain is sufficient plastic to overcome this early insult. As such, our objective is to test the impact of SSRIs from the cellular to the system levels. We will employ genetic technologies to identify the contribution of neurons altered by 5-HT dysfunction to the developing circuit in vitro, mapping their synaptic connections through early postnatal life. In parallel, we will use optical techniques to assess the consequences for local excitatory-inhibitory balance. Combined these experiments will provide the platform for subsequent investigations that will assess the impact of altered 5-HT signalling on both sensory-evoked and spontaneous activity in vivo, giving us significant insight on global alterations in neonatal cognition. Finally, we will employ 3-photon imaging to pioneer chronic imaging across the depth of the developing cortical column, record population activity, and thereby establish the impact of altered 5-HT signalling on the dynamics of emergent perception. Together this will provide a detailed picture of the impact of SSRI exposure on brain development with significant translational value for humans. We believe that this proposal is highly relevant to current MRC strategy which prioritises the application of fundamental science to address key mental health issues.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;6.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: MICA: Dementias Platform UK 2 - Integrated Dementia Experimental Medicine
Funder: Medical Research Council

Abstract: The objectives of the Dementias Platform UK renewal (DPUK2) are to: 1. Increase the precision of experimental medicine (EM) through precision phenotyping according to genetic risk 2. Increase the capacity of EM through streamlined systems and integrated informatics 3. Increase the opportunity for EM through agile and adaptive global partnerships These will be achieved through three inter-dependent workstreams comprising: 1. Workstream A The Data Portal: The Data Portal will be enhanced to provide secure and auditable data management with an on-premise cloud, and hybrid solutions for : - Observational and EM multi-modal data discovery - In silico experiments including multi-modal and machine learning analysis - Enriched phenotyping for the Clinical Studies Register - Knowledge development and preservation 2. Workstream B The Trials Delivery Framework (TDF): The TDF will provide a recruitment and study delivery mechanisms for dementia experimental medicine: - Pre-clinical recruitment via the Clinical Studies Register - Early disease recruitment via existing NIHR and NHS investments (Join Dementia Research, BRCs, memory clinics) - Trial delivery centre network drawn from existing structures including the DPUK imaging network, EPAD and NIHR TRC-D and BRCs. 3. Workstream C The EM Incubator: The EM incubator nurtures academic-industry partnerships for precision mechanistic EM studies, demonstrating the value of this approach through a series of pump-prime funded experiments on: WP 5- Vascular Health WP 6- Synaptic Health WP 7- Neuroimmunology DPUK2 aims to develop its EM portfolio according to scientific interest and further funding.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: NEUROLOGICAL
Title: The impact of the Environment and Pollution On Cognitive Health (EPOCH): Building the knowledge base through international collaboration
Funder: Medical Research Council

Abstract: Vibrant, high-density, destination-rich neighbourhood environments provide opportunities for older residents to engage in physical, social and mental activities that benefit cognitive health. However, such environments are also associated with harmful levels of air pollution and noise, which can have a negative impact on cognitive decline and dementia. The aim of this project is to investigate the joint impact of multiple neighbourhood environmental attributes on cognitive health in later life using interdisciplinary data resources in the UK and Australia. This project will integrate data on the neighbourhood built environment (dwelling density, street intersection density, land use, public transport and different types of services), natural environment (greenness, distance to parks and natural aquatic features), pollution (air pollutants and noise) and population-based cohort studies (UK: Cognitive Function and Ageing Study (CFAS) II, CFAS Wales, English Longitudinal Study of Ageing (ELSA); Australia: Personality And Total Health through life project (PATH), Sydney Memory and Ageing Study (MAS), Older Australian Twin Study (OATS)) and develop novel analytical frameworks using the integrated datasets and a study with existing environmental measures (UK Biobank). Advanced statistical methods such as generalised structural equation modelling, nonlinear structural equation mixture modelling and multistate modelling will be used to examine hypotheses on the relationships between different neighbourhood environmental attributes and cognitive health measures and investigate the meditating effects of lifestyle behaviours (engagement in physical, social and mental activities) and the modifying effects of sociodemographic (sex, socioeconomic status) and genetic risk factors (APOE genotype). Bayesian evidence synthesis approaches will be employed to integrate results from individual cohorts within UK and Australia and provide pooled estimates for cross-country comparison.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: NEUROLOGICAL
Title: MICA: Towards clinical trial readiness of gene therapy for Niemann-Pick disease type c
Funder: Medical Research Council

Abstract: We aim to move AAV-mediated gene therapy for treating Niemann-Pick Disease Type C (NP-C) towards clinical translation. NP-C is a fatal lysosomal storage disorder caused in 95% of cases by mutations in the NPC1 gene. NPC1 deficiency causes intracellular lipid accumulation leading to systemic pathology. NP-C is usually diagnosed in childhood and premature death is associated with neurodegeneration, where patients experience progressive ataxia, dystonia and cognitive decline. No major disease modifying treatments currently exist and there is an overwhelming need to develop an effective treatment. AAV-mediated gene therapy holds great potential for treating NP-C by preventing or decelerating neurodegeneration and subsequent fatal neurological disease. Direct brain delivery of an AAV9 vector expressing the human NPC1 gene in neurons of a murine NP-C model demonstrated long-term prevention of neurological symptoms accompanied with extension in lifespan. We will optimise our approach to enhance therapeutic efficacy, by expanding NPC1 expression to also include brain glial cells. The therapeutic efficacy of a neuronal and ubiquitous promoter within our vector will be compared in the early symptomatic NP-C mouse to model the clinical scenario of providing therapy at diagnosis. We will assess biodistribution of the optimal vector in larger models, evaluating both route and rate of administration and conduct a GLP toxicology study in rodents. We will progress to clinical trial readiness by establishing vector potency assays and applying for clinical trial authorisation. We are facilitated by a unique partnership with the Fundacion Columbus that will fund and manufacture GMP AAV vector for both this proposal and a future clinical trial. This proposal is supported by (i) preliminary proof-of-concept data, (ii) our experience in pre-clinical and translational gene therapy studies, (iii) guidance from the MHRA and (iv) collaboration with the Fundacion Columbus.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL
Title: NeuroNex: From odor to Action: Discovering Principles of Olfactory-Guided Natural Behavior - NSF Proposal Number: 2014217
Funder: Medical Research Council

Abstract: The overall goal of this proposal is to understand a fundamental problem in neuroscience--- how natural stimuli are used by animal brains to generate adaptive natural behaviors. We approach this problem in the context of olfactory-guided behavior as an instance of a more general problem of many complex brain systems---how are high-dimensional, discrete, and combinatorial variables that are not simply ordered along easily discernible axes represented in brain circuits and mapped to actions? The compact olfactory circuit architecture offers unique opportunities to achieve an end-to-end understanding of the core computational logic by which brains organize and read out such high-dimensional, discrete variables to generate adaptive behaviors. We will study olfactory systems of mammals and insects, which have independently evolved common structural elements at successive levels of olfactory processing in their central nervous systems. These common elements may reflect convergent evolution towards a set of similar solutions to shared olfactory problems. The network is comprised of three interdisciplinary research groups that are designed around specific elements of an end-to-end investigation of olfaction. They encompass studies of encoding natural stimuli (IRG1), the natural behaviors that they give rise to (IRG2), and active search strategies animals use as they encounter stimulus dynamics in natural environments (IRG3). Each IRG integrates theory and experimental approaches in two or more species in ways that produce complementary, synergistic interactions across levels of biological analysis.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: NEUROLOGICAL
Title: PREADAPT: Identification of personalized inflammatory profiles of aging and senescence which are modified specifically by risk factors of dementia
Funder: Medical Research Council

Abstract: Age is the largest risk for dementia, including Alzheimer's disease (AD). However, not every person develops dementia, indicating that age-related processes may not inescapably lead to dementia. The elucidation of the processes occurring in aging will likely offer new options to prevent or postpone development of dementia. One key mechanism is cellular senescence, which causes chronic inflammation through the release of a senescence-associated secretory phenotype (SASP) profile of mediators. PREADAPT builds on the hypothesis that chronic systemic inflammation and neuroinflammation, quantified through a set of SASP mediators, affects the trajectory of senescence occurring in the aging brain, thus allowing prediction of future cognitive decline and dementia. The levels and changes of SASP mediators during aging are modulated by different genetic and environmental factors, thus defining a personalized risk for dementia. By leveraging the individual variability of large existing aged samples, we aim to integrate SASP, genetics, known AD biomarkers, and comorbidities to generate combined risk profiles which will provide personalized information on risk of dementia. To achieve these goals, PREADAPT includes a team of experts in the field of neuroinflammation, epidemiology, genetics, epigenetics, neuropsychology, and clinical research. PREADAPT has access to state-of-the-art methodology and knowhow on inflammatory markers to define a set of SASP mediators derived from preliminary research done by PREADAPT members. PREADAPT also has access to large epidemiological and clinical follow-up studies that are characterized using neuroimaging, genomics, and proteomics. This unique configuration will enable PREADAPT to identify age-related profiles to inform the personalized future risk of cognitive decline and dementia. From a translational perspective, PREADAPT will also provide first evidence showing that a SASP personalized risk profile responds to specific intervention.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: JPND: Early Detection of Alzheimer's Disease Subtypes
Funder: Medical Research Council

Abstract: We develop a novel multi-view learning strategies that relates end-stage disease manifestations observable in clinical cohorts to features of early-stage or at-risk individuals in preclinical cohorts and the general pre-affected population from population or aging studies. This approach is only possible now due to the availability of large population data, richly phenotyped AD cohorts and advances in machine learning. E-DADS uniquely assembles the necessary data and expertise. The ability to identify AD subtypes and predict them years before onset will significantly advance AD research and clinical management via precision medicine. First, it identifies distinct homogeneous groups, shedding new light on that nature and variability of disease mechanisms ultimately pinpointing effective drug targets. Second, it enables enrichment of future clinical trials for specific groups of patients likely to benefit from a particular intervention. Third, it highlights potential lifestyle interventions that may affect or delay disease onset at very early stages. E-DADS delivers the underpinning technology to achieve this through machine learning and big-data analytics together with a prototype software tool enabling future translation and uptake.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Modeling General Principles Of Motion : Generating A Species-agnostic Model Of Motor Control (IRG1 - Project Reference 1938759)
Funder: Medical Research Council

Abstract: This grant application is for the development of a general motion control model, taking account the different physical regimes under which animals move. We have developed a quantitative control analysis that brings animal motion control down to two fundamental variables: 1) the time of the behaviour and 2) the size of the animal. This mathematical formulation allows us to propose a control strategy that characterizes the mechanical resonance of the system (its characteristic frequency), and compares that to the time-course of the neural inputs - with 'fast' systems having neural inputs that are much 'faster' than the resonant frequency, 'intermediate' systems having neural inputs that are equivalent in time as the resonant frequency, and 'slow' systems in which neural inputs are much slower than the resonant frequency of the system. Because a system's resonant frequency is the square root of stiffness divided by mass, this frequency is very much determined by the size of the organism; with both mass and stiffness being size dependent. Consequently, we will be using data from the other individual research groups to look a the control of 'fast', 'intermediate', and 'slow' systems across the size range of mg (flies), g (Aplysia), to 100's of g (mice) to further refine this analysis. Lastly, we will include viscous damping to the control parameters, which will, in theory, allow our analysis to extend down to the microgram level, thus including locomotory and control strategies down to extremely small organisms. With each iteration of the control theory illustrated in case for support, we will extend the size range and physical accuracy of the model to generate a more accurate, species agnostic, model for control of organisms; with the aim to cover a size range from the extremely small (mg and smaller) to the extremely large (whales).


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: NEUROLOGICAL
Title: JPND - Multicellular organoids: modeling, mechanisms and therapy development for C9ORF72-associated neurodegeneration.
Funder: Medical Research Council

Abstract: The delivery of therapeutic agents to the central nervous system remains a major challenge. This is especially the case for the devastating disorders at the focus of the current proposal [amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)]. The most common genetic form of ALS/FTD is caused by expansion of a hexanucleotide repeat (G4C2) in the non-coding region of chromosome 9 open reading frame 72 (C9ORF72). The lack of any cure for ALS-linked C9ORF72 is attributable primarily to: i) Poor understanding of the molecular pathogenesis of neurodegeneration, the contribution of each cell type to the disease and the underlying causes of the variability that characterises the patient population; ii) Lack of reliable animal models mimicking the multicellular and multi-mechanism complexity of the human disease; iii) Delivery of therapeutically attractive molecules has been hampered by inefficient delivery methods including factors like the blood-brain barrier; iv) Ineffective targeting of therapeutic agents specifically to the diseased CNS site and/or cell type. Research efforts aimed at understanding how mutations in ALS causative genes affect various cell types and pathways, thus leading to motor neuron degeneration are of the utmost importance to enable therapeutic development for these disorders. The limitations associated with existing C9orf72 animal models can be overcome by using specific patient induced pluripotent stem cells (iPSC)- derived 3D models. Here, we assembled a multidisciplinary team with complimentary expertise to overcome some of these challenges. The overall aims of our research programme are: 1) Generate 3D in vitro multicellular organoids models from iPSCs derived from healthy and patients with C9ORF72 ALS/FTD; 2) Fully characterise the newly generated models using established assays in the consortium; 3) Explore mechanistic pathways (e.g. pro-inflammatory, anti-oxidant); 4) Therapeutic screening in collaboration with AstraZeneca.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: NEUROLOGICAL
Title: Cellular-resolution in situ transcriptomics of the mouse brain and Alzheimer's disease models
Funder: Medical Research Council

Abstract: This project will employ in situ transcriptomics to understand the spatial organization of cell types throughout the mouse brain, and how this is modified in models of Alzhimer's disease. Several methods for in situ transcriptomics are currently under development. We have recently developed a method based on padlock-probe amplification that allows hundreds of genes to be localized simultaneously at high throughput. We have developed algorithms using this data to probabilistically assign each cell to types defined by previous scRNA-seq. We have validated this approach in mouse hippocampus, confirming that it localizes fine subtypes of interneuron to their classically established spatial locations. Improvements to the method now allow up to 1000 genes to be simultaneously localized at higher efficiency, and we have automated the method to run at high enough throughput to process an entire mouse brain. We will use this new technology to localize the expression of 1000 carefully chosen genes across the whole mouse brain, at submicron resolution. The resulting data will consist of the spatial expression profiles of these genes, across 21 sagittal sections of the mouse brain, spanning its full medio-lateral extent (the same resolution as in the Allen reference atlas). We will use this to spatially localize all cell types identified by previous whole-brain scRNA-seq. We will apply the same methodology to two mouse models of Alzheimer's disease: the APPNL-G-F model and the THY-Tau22 model. This will reveal how all cell types (neuronal and other), in all brain regions, are affected by the amyloid and tau pathologies.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL
Title: Causal roles of neural synchrony in signal transmission and cognition in the human brain
Funder: Medical Research Council

Abstract: Flexible cognition depends on finely tuned communication between brain regions in large-scale brain networks. Local field potentials in non-human primates have revealed specific frequency channels that exert feedforward and feedback control of sensory processing through synchronization of oscillatory neuronal activity. However, little is known about these processes in the human brain. Our objective is to unravel the causal/mechanistic role of large-scale network synchronization, i.e. oscillatory phase-coupling, in orchestrating feedback and feedforward signal transmission and cognitive operations in humans. We will use (1) magneto- and electroencephalography (MEG-EEG) combined with cutting-edge analysis techniques to establish (a) the nature of large-scale network interactions associated with top-down control in the attention system, (b) their effect on local neural activity in visual cortex and (c) on visual task performance. Using the same analysis framework, we will integrate these data with combined transcranial magnetic stimulation/electroencephalography (TMS-EEG) in the same sample to (2) test the hypothesis that directionality of communication depends on frequency of the channel by investigating the spreading of activity induced by single-pulse TMS. Finally, we will (3) study by TMS-EEG the extent to which emulation of top-down effects by frequency-tuned rhythmic TMS relates to interindividual variability in MEG-derived hubness of frontal and parietal areas. The analysis in a common framework will allow the offline integration of all techniques (multimodal MEG-EEG-TMS) in the same sample. This will establish if the large-scale networks of top-down control play a causal (vs. correlative) role in network communication influencing perception. It will also advance our understanding of the physiological factors underlying variability in TMS outcome, with implications for experimental and therapeutic control of brain oscillations and functions by TMS.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL