NIHRDataInsights/HRCSData huggingface dataset:
Title: Investigating the role of MeCP2 within the context of chromatin
Funder: Wellcome Trust

Abstract: MeCP2 is a protein found in the brain which prefers binding to methylated DNA. It can then help to block gene expression through the recruitment of other factors. MeCP2 is essential for proper neurodevelopment and mutations in the protein often cause the autism-spectrum disorder Rett syndrome, which is characterised by a lack of speech and loss of motor skills. In Rett syndrome-like mutated mice these developmental problems can be reversed, suggesting that a future treatment for Rett syndrome may be possible.While a lot is known about how MeCP2 binds linear methylated DNA, this is not the natural state of DNA in cells. Instead DNA is often found wrapped around proteins called histones which package and compact it into chromatin. Initial evidence has suggested that MeCP2 can not only bind methylated DNA, but also to the histone proteins that the DNA wraps around. This project aims to investigate how exactly MeCP2 interacts with chromatin, understand the relevance of MeCP2’s proposed interaction with histone proteins, and discover if mutations that cause Rett syndrome also disrupt this interaction.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MENTAL HEALTH;GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: The role of post-synaptic GPCR intracellular trafficking and signalling on synaptic plasticity
Funder: Wellcome Trust

Abstract: G protein-coupled receptors (GPCRs) are the largest family of signalling receptors, regulating a variety of cellular functions including neurogenesis and synaptogenesis. Therefore, GPCRs are the main pharmaceutical targets, however, the lack of knowledge regarding the association between neuroplasticity and GPCR function makes them an underexploited target for neurodegeneration. GPCR signalling activity is regulated via their trafficking to intracellular compartments, namely endosomes. Membrane trafficking of neuronal receptors is an established mechanism in the regulation of synaptic plasticity, especially in those areas of the brain involved in learning and memory (e.g. hippocampus), although the molecular mechanisms and its link with signalling remain poorly understood. Using beta-adrenergic receptors (BARs) as prototype GPCRs, we aim to target this knowledge gap by 1) identifying BAR trafficking pathways in hippocampal neurons; 2) generating a map of BAR signalling along their endosomal trafficking; 3) determining the role of BAR spatially encoded signalling on synaptic plasticity. Through the development of novel approaches to study the local organization of synapses, this project will help to understand how GPCR activity can be modulated via targeting receptors to defined cellular locations in the hippocampal neuron and specifically within individual synapses, offering the potential for novel GPCR-based therapeutic targets for neurodegeneration.

Lay abstract: Neurodegenerative disorders are among the top ten illnesses with no treatments to cure or slow disease progress. Cognitive decline observed in these conditions is linked to impaired synaptic transmission in areas of the brain involved in memory consolidation, namely the hippocampus. Synaptic plasticity in hippocampal neurons is regulated by location of receptors in cells via their trafficking. Some of these receptors, called G protein-coupled receptors (GPCRs) are able to signal from both the cell surface and intracellular compartments. Our goal is to identify the molecular mechanisms of GPCR trafficking in hippocampal neurons, its impact on signalling and the effect on synaptic plasticity. Using super-resolution microscopy combined with newly-developed probes we will develop new approaches to visualize in live cells, in real time, the trafficking and signalling of neuronal GPCRs. Uncovering the mechanisms of GPCR-mediated synaptic plasticity will contribute to the development of cures for neuropathological conditions affecting cognition and memory.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MENTAL HEALTH;GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: Tools for Human Neuroscience Drug Research 2: THuNDR2
Funder: Wellcome Trust

Abstract: THuNDR2 is a collaboration between leading UK neuroscientists and the pharmaceutical industry that will resurrect a vital compound for human neuroscience research on one of the key dopamine receptors, the D1 subtype, that can’t currently be studied in humans. The D1 receptor is the main dopamine receptor in cortex and non-human primate studies have shown it to be vital in attention and other executive processes. It is also present in sub-cortical regions where it may play a role in reward, addiction and mood. Currently ADX10061 and ecopipam are the only selective D1 antagonists with human safety data, but ecopipam is under commercial investigation so is unavailable for independent research, probably for many years. Though there is no ADX10061 compound available, the owner company, Addex, is prepared to make the full regulatory datasets available to us so that we can re-synthesize it to the original specifications, thus avoiding the need for new toxicology studies that would make the project exorbitantly costly. This grant will provide for the re-synthesis, formulation and storage of ADX10061, for dispensing along with matched placebo to the whole research community for the period of the grant and for 4 years after the grant ends.

Lay abstract: Pre-clinical (animal/fundamental) neuroscience has advanced massively in recent decades but human brain research lags behind. This is because there are very few selective compounds available for human brain research. Most human brain medicines are not designed to be selective for specific brain systems so cannot be used to interrogate specific brain processes. This grant will rectify this by providing researchers with a highly-selective, safe compound, to address a series of key questions in human brain science, i.e. what the roles of the main dopamine receptor in brain, the D1 receptor, are in attention, concentration and addiction to tobacco and other drugs. We have permission from the pharmaceutical company that invented this drug to re-synthesise it for human research. Many research groups in the UK and Europe are interested in obtaining supplies for their projects, so this landmark grant will provide a vital boost to human brain research.

Research activity codes: 5.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH;GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: Single neuron and network computations in escape decisions
Funder: Wellcome Trust

Abstract: Computing decisions is a problem that animals must constantly solve, which requires analysing information and selecting appropriate actions. Previous work has demonstrated a role for cortical circuits in learned decision-making paradigms, but we do not know how elementary decision processes, such as integrating evidence, map onto circuit and cellular mechanisms. Our goal is to uncover these mechanisms by investigating instinctive escape decisions in mice. Recent work has identified the superior colliculus and periaqueductal gray as key circuits for escape initiation, providing a unique entry point for investigating decision-making. We aim to explain at the cellular and circuit level the processes of threat stimulus integration and selection of escape behaviour. Our experimental strategy is to record and stimulate neural activity in the midbrain, while manipulating escape decisions by varying the threat level of sensory stimuli, past experience and the spatial environment. At the circuit level we will make recordings with high-density silicon probes and calcium imaging, while at the single neuron level we will use whole-cell recordings to investigate connectivity and the biophysics of synaptic integration during decision-making. The results from this project will produce mechanistic models of how neurons integrate sensory information and past experience to generate behavioural choices.

Lay abstract: Making decisions is an every-day problem that requires evaluating evidence and choosing one of possible options. Several areas of the brain seem to be involved in this complex process, and understanding the neural circuit mechanisms for computing decisions is a big challenge. Our goal is to discover these mechanisms by studying a simple instinctive decision - escape from imminent threats. This decision is processed by a small and ancient part of the brain, which we will study in mice to understand how neurons process threatening stimuli and compute the choice to escape. We will do this by using recording neural activity from neural networks using silicon probes and calcium imaging, as well as intracellular activity in single neurons while mice decide whether or not to escape when presented with different level threats and options. These studies will help to explain how neurons process information and past experience to generate choices.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MENTAL HEALTH;GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: Characterising the neural mechanisms of human memory at high resolution
Funder: Wellcome Trust

Abstract: Our past experiences are captured in autobiographical memories that serve to sustain our sense of self, enable independent living and prolong survival. Despite their clear importance and the devastation wreaked when this capacity is compromised, the neural implementation of autobiographical memories has eluded detailed scrutiny. My goal is to understand precisely how autobiographical memories are built, how they are re-constructed during recollection and how these memory representations change over time. My aim is to identify the mechanisms involved in these processes and thereby establish a theoretically enriched account of their breakdown in pathology. This endeavour will be enabled by cutting-edge, multi-modal technology that includes a new wearable MEG system and ultra-high-resolution MRI. The ventromedial prefrontal cortex and hippocampus are heavily implicated in autobiographical memory. I will test a novel hierarchical model that specifies their distinct roles and how they interact to produce the seamless encoding and recollection of our lived experiences. Overall, this new extension of my work will expose autobiographical memories as never before, revealing the millisecond temporal dynamics, and the laminar-specific and hippocampal subfield processing that supports their evolution from the point of inception, through initial sleep cycles and then over longer timescales.

Lay abstract: Losing the ability to remember our past experiences dislocates us from life’s timeline and precludes independent living. Despite their obvious importance, it is unclear how these autobiographical memories are enabled by the brain. My goal is to conduct detailed neuroscientific studies of autobiographical memories to establish precisely how they are built, how they are re-constructed during recollection and how neural representations of autobiographical memories change over time. By addressing these issues, I aim to understand how autobiographical memories become compromised by brain injury or disease. My focus is on two brain regions known to be important for autobiographical memories, the ventromedial prefrontal cortex and the hippocampus. I will use innovative technologies, including immersive virtual reality and powerful brain scanners that inform about when and where memory-related signals occur in the brain, to examine how these brain areas interact to produce the seamless encoding and recollection of our lived experiences.

Research activity codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: MENTAL HEALTH;GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: Translational Neuroscience 2 (TN2)
Funder: Wellcome Trust

Abstract: Three years ago we established an innovative and successful 4-year Translational Neuroscience PhD Programme (‘TN1’) designed to address the fundamental problems in translating advances in discovery neuroscience to the clinic. We are equipping cohorts of outstanding students with the means to resolve these problems by providing rigorous, cross-disciplinary, cutting-edge training in the neuroscience of brain disorders across the lifespan. Demand has proved enormous. In TN2, we shall continue the key aim of TN1 by leveraging the opportunities offered by the highly collaborative Edinburgh Neuroscience community of world-leading clinical and fundamental scientists. This community has been substantially enhanced by recent key strategic developments that massively expand our portfolio of neuroscience research, including new opportunities in data science driven by a £250M CityDeal and new translational expertise introduced by our £23M Dementia Research Institute, our $20M Simons Initiative for the Developing Brain and our £50M Institute for Regeneration and Repair. By also incorporating lessons learnt from our TN1 cohorts and from relevant stakeholders to enhance student welfare, diversity and career options, our programme will provide exceptional training in translational neuroscience, key skills for research and other careers worldwide, and be a beacon of best practise in student development.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: MENTAL HEALTH;GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: UCL Wellcome 4-year PhD in Mental Health Science
Funder: Wellcome Trust

Abstract: Mental illness is a major public health problem, with poorly understood causes and highly variable treatment outcomes. While mental health research training has strength within disciplines, these typically operate in parallel, greatly impeding progress in improving clinical outcomes. The UCL Wellcome 4-Year PhD in Mental Health Science is an interdisciplinary, student-centred programme, which aims to train the next generation of research and policy leaders to succeed within mental health research fields, and foster greater cross-disciplinarity in future researchers. It leverages UCL’s outstanding mental health research environment across three broad Themes: Mechanism, Population Mental Health, and Intervention. In Year 1, students will obtain experience in these different Themes through short rotation projects and courses, including areas outside their academic background; through this they will be exposed to new concepts and techniques, learn to “speak the language” of the different disciplines, and spot the synergistic connections between them. For the main PhD project in Years 2-4, students will select a supervisory team and Thesis Committee across all three Themes, enabling interdisciplinary mentorship. A strong emphasis will be placed on developing a distinct and supportive cohort identity, with continual skills development and preparation for transition following the Programme, whether within or outside academia.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: MENTAL HEALTH;GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: International Brain Laboratory
Funder: Wellcome Trust

Abstract: Understanding the neural circuit basis of behaviour is one of the great challenges in biology. Yet no single laboratory can study the many brain regions, connections, and cell types working together o coordinate decision-making. There is thus a disparity between the capacity of individual laboratories and the complexity of problems being addressed. The International Brain Laboratory orchestrates the efforts of 21 experimental and theoretical laboratories to understand a single behavior. By standardizing experimental procedures and data pipelines, we enable the data acquired by different laboratories to be assembled into a large combined dataset. Our mouse decision-making task requires valuation of different choices based on sensory evidence, choice selection based on this valuation, and integration of prior experience to update a model of the world. We seek a comprehensive understanding of the neural mechanisms underlying these functions, at scales ranging from single neurons to local microcircuits to inter-area communication. To do so we will harness powerful electrophysiological, optical, and genetic tools, and exploit the rich set of theories and analytical approaches developed in recent years. This large-scale effort will provide the first end-to-end “standard model” of a complex mammalian behavior, and inspire new ways to collaborate on difficult problems in neuroscience.


Research activity codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: MENTAL HEALTH;GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: Wellcome Centre for Integrative Neuroimaging
Funder: Wellcome Trust

Abstract: Understanding how interactions between neurons generate human behaviour, why individual brains vary from one another, or whether a patient is likely to develop a particular disease, requires explanations that span vast differences in scale. Yet such explanations are essential if insights from neuroscience are to make a meaningful impact on human health. Precise mechanisms discovered in animal models must be related to clinical phenotypes discovered through population studies; both must be combined to improve diagnosis and treatment in individual patients. Neuroimaging offers a powerful route to connect these different scales, providing measurements that are sensitive to cellular phenomena and that can be acquired in living humans. The WT Centre for Integrative Neuroimaging will enable novel insights into brain function that span levels of description, and therefore bridge the gap between laboratory neuroscience and human health. This will require fundamental discoveries concerning relationships between species and between scales, and major technological developments for mapping big-data discoveries onto neurobiological mechanisms. We will bring together diverse investigators who can tackle different themes within this grand challenge. Within each theme, neuroimaging will be used alongside complementary methodologies, ensuring that it takes inspiration from, and has impact on, areas beyond its typical reach.

Lay abstract: No Data Entered

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MENTAL HEALTH;GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: Ethics in practice: An ethnographic study of decision-making and their implications in dementia care.
Funder: Wellcome Trust

Abstract: The aim of this study is to inform clinicians ethical practice while making decisions about communicating the results of assessments to adults with memory problems: decisions that have become more complex in light of new medical advancements in the early detection and diagnosis of various forms of dementia. The study will combine a philosophical interrogation of conceptions of autonomy that inform ethical principles with empirical research: this will include observations of clinical assess ments in memory clinics as well as interviews with experts, clinicians, patients and patients families. These methods will allow the study to bring together the philosophical basis of moral and ethical principles with the ways in which ethics are dealt with in changing clinical practice. The project will view clinical assessments and diagnoses in the context of older people and their families experiences of memory problems to better inform what ought to be considered in making decisions over the communication of information to patients and their families: what information should be communicated, when should this be communicated and how should it be communicated? The results of this study will be shared with academics, policy makers, practitioners and patients and carers who are affected by memory problems and dementia.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;7.3 MANAGEMENT AND DECISION MAKING
Health categories: MENTAL HEALTH;GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: The Role of the SNORD116 Non-Coding RNA Cluster in Energy Homeostasis.
Funder: Wellcome Trust

Abstract: Recent patient reports have identified that microdeletions encompassing the SNORD116 cluster on chromosome 15q11.2 manifest a phenotype substantially overlapping with Prader-Willi Syndrome (PWS), including characteristic hyperphagia and developmental delay. The SNORD116 cluster encodes non-coding RNAs, including multiple C/D box snoRNAs and long non-coding RNAs, which are deemed orphans' of unknown function and have no validated targets. We aim to explore the function of SNORD116 by elucidating the molecular mechanisms linking loss of SNORD116 to the PWS-like phenotype. Preliminary data from our group suggests SNORD116 is predominantly brain-expressed, and that fasting regulates Snord116's hypothalamic expression. We hypothesise thatSNORD116 may regulate a repertoire of genes impacting neuronal development andfood intake control. In this research, we will examine the functional and transcriptional consequences of perturbing Snord116 expression in primary mouse hypothalamic neurons. Secondly, we will clarify the types of RNA transcripts arising from the Snord116 cluster in mouse brain and identify their protein and RNA interaction partners. Thirdly, two mouse models with targeted Snord116 deletions will permit evaluation of Snord116's role in neural food intake control. We ultimately hope this functional investigation may reveal novel neural control pathways implicated in the hallmark hyperphagia and early-onsetobesity evident in PWS.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MENTAL HEALTH;GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: EPICure@19 - the extremely preterm young adult
Funder: Medical Research Council

Abstract: We aim to perform a further evaluation as young adults of the EPICure cohort, who were born at 25 weeks of gestation or less in the UK and Ireland during 1995 who were last evaluated at 11 years. There is some suggestion from other and more mature cohorts that there may be some amelioration of impairments, relative to controls over adolescence. At 19 years we will determine continuities in neurologic, psychological and psychiatric outcomes, to evaluate the effect of adolescence on somatic growth, lung function and cardiovascular trajectories compared to young adults who had been their classmates, to describe their employment and educational attainment as young adults. We will perform a centrally-based assessment for children with sufficient independence to attend (with or without parents), which includes a neuropsychological assessment, a brain MRI scan, lung function testing, assessment of the cardiovascular system and quantitative sensory testing. For children who have long distances to travel (Scotland, Ireland) we will organise centre-based assessments locally (for example in Edinburgh and Dublin) but may have to miss key aspects of the technology-based investigations. For those dependent on their carers, and because of this unable or unwilling to travel, we will provide a home-based assessment of their functional status. The results of this study will inform outcomes following extremely preterm birth that have relevance to today's births, as the spectrum and prevalence of disability has not changed over ten years (EPICure 2). At an age of peak physical performance we will identify key areas of outcome that have implications for adult life, that have receded as issues or show continuities through childhood, and to identify target areas for intervention.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: MENTAL HEALTH;GENERIC HEALTH RELEVANCE;NEUROLOGICAL;RESPIRATORY;CARDIOVASCULAR