NIHRDataInsights/HRCSData huggingface dataset:
Title: Structural and functional connectivity and association to cognitive performance in memory disorders.
Funder: Wellcome Trust

Abstract: Memory problems limit sufferers in many ways during their day-to-day life. In the UK there are already over 800,000 people with dementia and this number is set to rise rapidly in the next 20 years as the population ages. Alzheimer's disease is the commonest of many causes. The way different parts of the brain connect and work together may be altered in memory disorders like dementia and also an autoimmune form of encephalitis. This project will use advanced and new MRI brain imaging techni ques to look at the way different parts of the brain connect and the changes in these diseases. We know there are changes in a number of areas in the brain, and it is likely that the connections or nerve pathways between these areas are also altered. With MRI we can map these pathways and show how they connect to particular brain regions. If we understand which connections and brain regions are altered, and relate this to symptoms, we will be in a better position to try to detect these diseas es early and to develop targeted drug treatments.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Molecular and life course aspects of APOE and TOMM40 in cognition.
Funder: Wellcome Trust

Abstract: Alzheimer's disease (AD) is common and will become increasingly so as the population ages. There is no cure. Variation in the APOE gene is the best-known risk factor for AD and there is significant evidence to suggest that changes are evident in those with the high-risk gene decades before AD develops. The exact nature of these changes, timing and their effect on brain structure and function is not clear. A nearby gene, TOMM40, has recently also been linked to AD. I intend to rectify this def icit by taking advantage of cohort studies running in Bristol and the South West Dementia Brain Bank. I will study people already taking part in the ALSPAC cohort study, according to whether they have a high-risk genotype for AD or not and look in detail at how their brains are working using a series of computer based tasks. I will also look at brain samples from across the age spectrum to see if there are identifiable differences in proteins involved in signal transmission (via nerve cell ju nctions called synapses) in those with the high-risk genotype and, if so, at what age they begin. If we understand AD better then our chances of curing it improve.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: The coordination of microtubule-dependent motors during axonal transport.
Funder: Wellcome Trust

Abstract: Cellular nanomotors move biologically active cargoes, such as organelles and cellular protein complexes, between their sites of action. Long-range transport by these motor proteins takes place along cellular motorways called microtubules. There are both forward motors (kinesins), and reverse motors (dyneins), but both these motors can bind to cargo simultaneously. Very little is known about how these motors decide in which direction to move, or where and when to release their cargo. It is vital to understand this process, as inefficiently delivered cargo can have serious consequences. This is particularly true in neurons, which have long and complex protrusions called axons and dendrites that make them highly reliant on this type of long-range transport. Inefficient microtubule based motor transport in neurons has been linked to diseases such as Huntington's Disease, Alzheimer's Disease and Amyotrophic Lateral Sclerosis. The key goal of my project is to understand how a direct interact ion between kinesins and dyneins might influence their activity, in particular whether the interaction turns off the dynein motor to allow kinesin to move more efficiently. I will do this by looking at single motor molecules in vitro and labelled dynein molecules in cultured neurons and neurons of genetically-modified mice in vivo.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Heterogeneity in the adult neural stem progenitor cells contributing to CNS remyelination.
Funder: Wellcome Trust

Abstract: The nerve fibres of the brain and spinal cord (the CNS) are surrounded by an insulating material called myelin that protects the fibres and allows them to carry electrical impulses efficiently. Myelin is made by a cell called an oligodendrocyte. These cells are attacked in several neurological diseases, most notably multiple sclerosis (MS). Early in MS the brain's own stem cells can replace lost oligodendrocytes and restore myelin (a regenerative process called remyelination). However, as the di sease progresses remyelination becomes less efficient and the fibres are left without their myelin making them liable to degenerate. Therapies that enhance remyelination would have a major impact on the treatment of MS; however, none currently exist. To develop these it will be necessary to know how remyelination works. During the development of the CNS oligodendrocytes can be made from several different types of stem cell. However, it is not currently known whether this diversity persists into adulthood and whether the origin of a stem cell determines its ability to participate in remyelination. This project will use newly available genetically engineered mice in which the different oligodendrocyte generating stem cells are colour coded enabling their roles in adulthood and during remyelination to be established.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL
Title: Crosstalk Between Nrf2 And NF-kB Pathways In Neurons And Astrocytes
Funder: Wellcome Trust

Abstract: Neuronal health is dependent on effective paracrine communication between neurons and astrocytes. Defects in this process can lead to neurodegeneration or cell proliferation, during tumour development. A key factor in this relationship is the regulation of pathways that control metabolic balance between the two cell types. It has been shown that activation or inhibition ofthe Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and/or Nuclear Factor-?B (NF-?B) signalling-pathways can regulate metabolism in some tissues.However, these pathways do not work in isolation, there is growing evidence ofcomplex patterns of crosstalk, co-stimulation and antagonism between the two processes, depending on the cell type in question and the stimuli applied. In this project we intend to use state of the art live-cell imaging techniques tocompare the mechanisms of crosstalk that operate between Nrf2 and NF-?B signalling pathways and its effects on cellular metabolism in both neurons andastrocytes.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Laminar organisation and development of complex sound representation in auditory cortex
Funder: Wellcome Trust

Abstract: The functional development of the response properties of auditory cortical neurons has been extensively studied, but this research has been limited to neurons found in the middle layers of the cortex and has only investigated their responses to simple sounds such as pure tones. It is not known how sensitivity to complex sounds develops and the laminar organisation of complexsound representation in the auditory cortex of adult animals is poorly understood. We aim to address these issues by recording electrophysiologicallyfrom neurons in the auditory cortex of mature and developing rats in order to characterise the representation of complex sounds across the layers of the cortex in adulthood and throughout development. The role of the environment inestablishing the adult organisation of these response properties will be investigated by rearing rats in different sound environments and the behavioural consequences of this manipulation on sound discrimination will be investigated. The synaptic mechanisms underlying these developmental processeswill also be examined. The results of this study will enhance our understanding of the cortical processing of behaviourally relevant sounds and of the steps by which this neural representation emerges during development.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Characterisation of genes regulated by S-nitrosylation of HDAC2 during radial neuron migration.
Funder: Wellcome Trust

Abstract: The generation of the laminar structure of the cerebral cortex relies on the radial migration of post mitotic neurons. This proceeds under the control of extremely precise regulatory networks requiring input from multiple extracellular signalling pathways and the co-ordinated expression of nuclear factors that result in specific programmes of gene expression. Recently, in the Riccio lab, we have shown that S-nitrosylation of HDAC2 is required for polarization and radial migration of cortical neurons during the formation of the cerebral cortex. A screen was carried out to identify genes regulated by S-nitrosylation of HDAC2 during cortical neuron migration. Druing this project, 2 candidate genes identified by this screen will be selected and their role in cortical development will be characterised. Key goals which have been set in order to achieve this include the following: 1) Verifying that these genes are upregulated in response to HDAC2 S-nitrosylation. 2) Characterisation of candidate genes expression in vivo 3) Analysis of candidate gene promoter and interaction with HDAC2 4) Characterisation of the function of the candidate genes in cortical neuron polarization and migration, which will include the generation of 2 knockout mouse lines.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: The angiogenic niche of neurogenesis.
Funder: Wellcome Trust

Abstract: Research in the last decade has demonstrated that the adult rodent brain is not a stable,unchanging organ, but that new neurons are born in two germinal regions throughout life. These neuron-generating regions reside close to blood vessels. Moreover, the vascular endothelial growth factor VEGF-A promotes adult neurogenesis. The constellation of neurogenesis in a vascular micorenvironment has been termed the 'angiogenic niche of neurogenesis', yet it is still not known how important this niche is to regulate adult neurogenesis. Moreover, in vivo models have not yet been applied to determine whether VEGF-A signals directly to neural progenitors to influence neuron generation (Fig. 1B, Hypothesis 1), or if it instead promotes neurogenesis by enhancing vessel growth and promoting the release of pro-neurogenic factors from vessels (Fig.1C, Hypothesis 2). I will use the mouse embryonic hindbrain as a model system to examine the importance of an angiogenic niche for developmental neurogenesis and determinewhich of the alternative hypotheses for niche function applies to hindbrain neurogenesis. Specifically, I will use genetic manipulations to assess VEGF-A is essential for self-renewing or neuron generating neuronal progenitor neurogenesis, and whether its influence stems from direct signalling to neural progenitors or if it indirectly regulates neurogenesis bypromoting the growth of pro-neurogenic vascular endothelium. This research will help define the cellular and molecular mechanisms of the angiogenic niche of neurogenesis and provide important information on whether the niche may, in the future, be exploited in therapiesaimed at repairing damaged neural tissue, for example in neurodegenerative disease. This researchwill also shed light on potential neurological side-effects of anti-VEGF-A therapies designedto inhibit pathological angiogenesis.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: A physiological and computational investigation of the role of acetylcholine receptors in hippocampal gamma oscillations in vitro.
Funder: Wellcome Trust

Abstract: A variety of optogenetic systems for inducing gamma oscillations in hippocampal slices will be developed. These include light induced activation of excitatory cells in CA3, inhibitory cells in CA3 and activation of medial septal inhibitory inputs to the hippocampus. Each system will be characterised electrophysiologically and assessed for closeness of fit to in vivo characteristics. A model describing the hippocampal CA3 network will be used to further explore gamma oscillations. The currents mediated by and synaptic effects of acetylcholine receptor activation will be included in the model and systematically disrupted to predict their contribution to the gamma oscillation. These hypotheses will then be investigated in the in vitro,optogenetic model. The effect of application of specific acetylcholine receptor antagonists on light evoked oscillations will be measured and the model will be accepted or adapted accordingly. This will provide an insight into the role acetylcholine receptors play in the mediation of hippocampal gamma oscillations.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: The role of experience dependent plasticity during the critical period of layer 4 to layer 2/3 in circuit function and connectivity
Funder: Wellcome Trust

Abstract: During development the neuronal circuit formation begins at the periphery gradually moving toward more central processing structures, requiring both spontaneous and sensory evoked electrical activity 1'2. This project will investigate (1) what changes in functional network structure underlie maturation of receptive fields in layer 2/3, using fluorescent activity indicator two-photon imaging of barrels in the somatosensory cortex before, during, and after the critical period of layer 4 to layer 2/3 plasticity. Offline computational methods will be developed to generate functional connectivity maps, in order to identify changes in network structure in relation to graph theory. (2) How sens.ory-driven and intrinsic activity influence functional network maturation, will be investigated by whisker deprivation before, during and after the critical period followed by two-photon imaging and analysis of the network activity with and without sensory stimulation. (3) Subsequent online analysis will be developed in orderto characterise the role of neurons in network synchronisation and plasticity during this critical period using in vivo patch clamp. A network model will bedeveloped to further identify how underlying synaptic plasticity mechanisms drive network maturation.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Wellcome Trust Clinical PhD Programme at the University of Oxford: 'Autoimmunity in idiopathic epilepsies and encephalopathies of childhood'.
Funder: Wellcome Trust

Abstract: Immune mechanisms are thought to be involved in the pathological disease process in a significant number of childhood (and adult) epileptic syndromes, and seizure related disorders (i.e. encephalitis). The hypothesis that the body's immune system plays an important role in these disorders is based on the following observations: 1) Occurrence of highly specific autoantibodies to important neuronal proteins (VGKC-complex proteins, NMDAR, AMPAR, GABAbRs), in the blood and spinal fluid of affected patients. 2) Beneficial and/or curative effects of immunotherapies. 3) Association of these illnesses with factors that are known to trigger autoimmune disorders, for example preceding exposure to a viral illness or immunisation. The goals of this project will be to; 1) Test patients' sera and CSF samples to identify autoantibodies to specific neuronal membrane/cell surface proteins, using a variety of established assays including immunoprecipitation of radiolabelled antigens (VGKC-complexes) and binding to cells transfected with specific proteins (eg. NMDARs). Attempt to identify new antigens using immunohistochemistry/immunofluoresence on brain tissue sections and neuronal cell cultures (eg. hippocampal), followed by immunoprecipitation, mass spectroscopsy and proteomic analysis. 2) Perform transfer of IgG from carefully selected patients to rodents with in vivo studies to demonstrate antibody mechanisms/pathogenicity. 3) Collect clinical information to classify the affected children and relate the antibody reactivies to their clinical syndromes This integration of basic science research and clinical work will serve to increase understanding of the pathogenic role of auotantibodies in childhood seizure disorders.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: C-Slide - The contributions of Sherrington and Le Gros Clark to our understanding of the brain and nervous system.
Funder: Wellcome Trust

Abstract: Virtual microscopy has great potential for safeguarding and improving access to the historical slides and related documents which underpin modern neuroscience, but which are inaccessible and/or too fragile to use, and in constant danger of being discarded or lost in medical schools and bioscience departments across the UK and internationally. There is considerable research, teaching and general interest in these slides (and their associated research, documents and images) from academics, students and the public, in the history, medicine and wider science communities. This project aims to build a web-based community collection of important historical slides ? ?C-Slide?. The first stage is digitisation of two collections of nearly 1000 slides and associated notes from Sir Charles Sherrington (1932 Nobel Prize in Physiology or Medicine) and Sir Wilfred Le Gros Clark, FRS which also contain examples from contemporaries such as Ruffini and Fritsch. Ten other UK and international medical and bioscience departments will also be invited to submit their 20 most important historical slides and associated documents as a way of engaging the wider community and building the collection. Users will be able to research, contribute to, and learn from slides and related information and the project will create a new community of interest in the history of medicine across traditional boundaries. The project team will embed the slides in their historical context using the resources available both within the Department, the Bodleian library and elsewhere. Slides and associated original documentation with be preserved using appropriate methods.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: NEUROLOGICAL
Title: Properties of GABAergic inhibition in the prefrontal cortex.
Funder: Wellcome Trust

Abstract: The molecular mechanisms underpinning GABA receptor mediated synaptic and tonic inhibition in the prefrontal cortex (PFC) will be investigated. Dysfunction of the PFC is implicated together with GABA neurotransmission in numerous neurodevelopmental disorders. The main objective of this project is to analyse the basic mechanisms involved in inhibitory transmission in the PFCand understand how these can be modulated by dopaminergic and serotoninergic pathway activation and by neurosteroids. We will target PV-positive GABAergic interneurons and their target pyramidal neurons in layer II/III of the PFC. Inhibitory transmission will be studied using acute and organotypic brain slice preparations as well as dissociated neuronal cell cultures. The underlying mechanisms will be explored using biochemical, chemical, electrophysiological, imaging (single particle tracking), pharmacological and molecular approaches involving mutated GABA receptors and photo-active receptor ligands. Our understanding of inhibition in the PFC will be used in conjunction with mouse models to try and corroborate their significance with


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Investigating the pathogenesis and novel therapeutic approaches in Spinal Bulbar Muscular Atrophy (SBMA).
Funder: Wellcome Trust

Abstract: Using the AR100 transgenic mouse model, we will examine the mechanisms that contribute to motor neuron (MN) degeneration in SBMA. AR100 mice have a progressive neuromuscular phenotype accompanied by MN degeneration, and therefore mirror the human disease. Our recent results show that ER stress is present in SBMA MNs, even during embryonic development, suggesting that this mechanism plays a key role in SBMA pathogenesis. In this study we plan to investigate the mechanism by which ER stress results in cell death in SBMA, bytesting 1) whether the MN -specific Fas/NO induced cell death pathway plays a role in SBMA; 2) whether the ER chaperone, Calreticulin (CRT) forms a link between the Fas/NO MN-specific death pathway and ER stress, by testing if changes in CRT levels influence MN vulnerability in SBMA and 3) examining the role of astroglia in SBMA MN degeneration. In addition, in view of our findings that inhibition of ER stress rescues SBMA MN in vitro, we will examine whether this approach is also effective in vivo, by testing the effectof an ER stress inhibitor on disease progression in SBMA mice.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Neuronal and glial energy use and supply
Funder: Wellcome Trust

Abstract: Processing and propagation of information by neurons is energetically expensive. We will investigate the following aspects of energy supply and demand in the grey and white matter of brain slices: (1) how sodium pumping by neurons (which consumes most brain ATP) is regulatedin response to sodium load and is related to oxygen consumption, (2) how a lowered energy supply affects information transfer across synapses, (3) which cortical synapses are mainly responsible for increasing energy supply when neurons are active, and (4) how energy is supplied to developing oligodendrocytes (glial cells) duringmyelination.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Representation of sensory information with temporal codes.
Funder: Wellcome Trust

Abstract: We will investigate how specific features of visual stimuli are represented bythe sequence of activation of neuronal populations in mouse V1 using high speed in vivo calcium imaging techniques. Temporal coding will be studied by measuring the latencies of both excitatory and inhibitory neurons, which will be distinguished with genetic labelling. In order to understand the temporal dynamics in the network we will also compare the spatial frequency preference and latency of neighbouring cortical cells. Stimulus-evoked latency differences are likely to arise in the retina, where ganglion cells respond with different latencies. However, recurrent connectivity in the cortical network could also introduce temporal delays and underlie neuronal activation sequences, especially those observed in the absence of visual input. We will compare the sequence of neuronal activation in response to visual stimuli to patterns of activity in the absence of input. In the last phase of the project, these population level properties will be linked to the single neuronand dendritic level by measuring the patterns of activation in apical


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL