NIHRDataInsights/HRCSData huggingface dataset:
Title: Molecular regulation of NMDA receptors in midbrain dopaminergic neurones
Funder: Wellcome Trust

Abstract: The proposed research will investigate the molecular regulation of NMDARs in DA neurones of the substantia nigra. Focussing on the substantia nigra pars compacta, where we have previously shown that the receptors are NR2B and NR2D subtypes, our key goals are to determine: (i) The relative importance of dynamin-dependent and dynamin-independent endocytosis and the role of MAGUK protein - NMDAR subunit interactions in NMDAR regulation at synaptic and extrasynaptic locations. (ii) The importanc e of NR2B and NR2D subunits in the intracellular regulation of synaptic and extra-synaptic NMDARs by kinases and phosphatases. (iii) The effects of NR2D subunit deletion on synaptic receptor density synaptic and on the biophysical properties of synaptic and extrasynaptic NMDAR. (iv) The importance of receptor trafficking and NR2D subunit-containing NMDARs in regulating phasic burst firing of DA neurones. Our approach to distinguish subunit-dependent and subunit-independent mechanisms invo lved in regulating synaptic and extrasynaptic receptors will incorporate high resolution patch-clamp recordings of NMDAR biophysical properties and application of appropriate inhibitors, activators and small interfering peptides to manipulate intracellular signalling molecules.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: From single neuron perturbation in vivo to behaviour.
Funder: Wellcome Trust

Abstract: New state-of-the-art techniques allow us to control the activity of a single brain cell and simultaneously record the activity of neighboring brain cells. Combining experiments based on these methods with theoretical predictions based on current knowledge and computer modeling, we can quantify how one brain cell affects its surrounding cells. Such networks of brain cells often have a well-defined function, such as detecting and interpreting sensory stimulation. Thus the reaction of the network t o a small perturbation can teach us about the activity of the network under normal conditions and how it performs its function. It will also allow us to test our understanding by perturbing the activity of the network while the brain is responding to a specific stimulus in order to make a decision. Combining the results from our experiments, we will gain key new insights and establish casual relationships between the activity of neurons and their role in perception, decision-making and behaviour .


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Receptors, function and plasticity in human embryonic stem cell-derived neurons.
Funder: Wellcome Trust

Abstract: Stem cells are characterized by both their abilities to self-renew and to differentiate into any cell type making them ideal candidates for therapies aimed at replacing or repairing specific cell populations damaged by disease/injury. Human embryonic stem cells (hESCs) have been differentiated into a variety of cell types including central neurons (brain cells). Such neurons appear physically similar to normally derived neurons and also express specific proteins associated with the cell types they have been transformed into. Little however is known regarding the functional capacity of hESC-derived neurons. This is especially important for neurons, as they would normally form part of a highly organized, complex cellular network. In our proposal we intend to use electrophysiological and biochemical techniques to answer fundamental questions involving hESC neuronal function and interaction. These include changes in neurotransmitter receptor expression, the ability of hESC-neurons to a dapt to changes in the neuronal network and whether the function of hESC-neurons can be manipulated by the neuronal activity of the local tissue environment into which they are transplanted. We hope that by addressing these questions, a more complete understanding of the functional capacity of hESC-neurons will be gained, allowing for a further assessment of their therapeutic potential.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL
Title: Oxford Centre for Human Brain Activity - Helium Recycling
Funder: Wellcome Trust

Abstract: Over the long-term, the aim is to establish a cutting-edge centre for investigating the human brain with real-time resolution that will be accessible in an open manner to researchers at Oxford and their collaborators; and to integrate the Centre activities with those at FMRIB, a world-leading centre that specialises in human brain-imaging methods with high spatial resolution. In the proposal, we lay out the vision for the new Centre, and describe the strategy to realise the vision. In addition t o serving the Oxford neuroscience community broadly, we will capitalise on the situation of the Centre within the grounds of the Department of Psychiatry and on the expertise of the Centre members to develop well integrated concentrations of excellence in neuropsychiatric research and basic cognitive neuroscience, and to support these with advanced developments in methodological integration and data-analysis. We then build the scientific justification for the Centre, by providing examples of th e many and varied research projects the Centre would support, by describing briefly ongoing projects by the applicants, and listing the other ongoing or currently planned projects across the current users of the Centre. (Same as above)


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: NEUROLOGICAL
Title: 4 year PhD in Neuroscience - Exosome-based gene therapy for Huntington's Disease
Funder: Wellcome Trust

Abstract: 1. To investigate the optimal strategies for exosome targeting to the brain in HD 2. To identify the optimal exosome RNAi cargo for suppression of htt expression 3. To evaluate brain-targeted exosomes for their ability to reduce htt expression in vivo and to prevent and/or reverse disease phenotype in a HD disease model.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: 4 year PhD in Neuroscience - Comparative transcriptional analysis across LRRK2 models of Parkinson's Disease to identify early pathways in disease progression
Funder: Wellcome Trust

Abstract: The goal of this project is to identify the earliest cellular pathways involved in Parkinson's Disease pathogenesis by examining the effect of the causative G2019S and R1441C LRRK2 mutations on the transcriptome of SNpc dopaminergic neurons. Towards this goal, this project consists of three distinct and complementary aims: 1) To identify and compare the perturbations in cellular pathways caused by G2019S and R1441C mutant LRRK2 in advance of PD pathology in vitro through high-resolution transcriptome analysis of the most physiologically relevant cell culture model of human SNpc dopaminergic neurons currently available. 2) To examine the emergence and evolution of these perturbations in the cell biology of SNpc dopaminergic neurons over the time course of disease progression within a whole organism using a LRRK2 bacterial artificial chromosome transgenic rat model of PD. 3) To assess the physiological and pathophysiological relevance of human induced pluripotent stem cell models to healthy and diseased human SNpc and to examine differential effects of G2019S and R1441C mutations in states of advanced disease through comparison with human post-mortem tissue from LRRK2 mutant carriers and healthy controls.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: 4 year PhD in Neuroscience - Functional properties of ontogenetically related neurons
Funder: Wellcome Trust

Abstract: The overall aim of this project is to investigate whether the ontogenetic relatedness of neurons informs the functional circuits into which they integrate. I will examine this question in the context of two structures ? the optic tectum of the Xenopus laevis tadpole and the neocortex of the mouse. There are four specific experimental goals: I. To examine the visual response characteristics of clonally-related and unrelated neurons in the optic tectum, and to determine whether related neurons show clustered receptive field properties. II. To test whether changes in the functional properties of tectal neurons induced by manipulations of neural activity, such as dark- or strobe-rearing and receptive field conditioning, correlate within clonal lineages. III. To investigate whether clonally-related neurons in mouse cortex exhibit correlated activity during periods of spontaneously generated network activity. IV. To use the activation of cortical inputs to test whether clonally-related and unrelated cortical neurons differ in their response to evoked network activity.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: The structural and functional diversity of anti-glycolipid antibody repertoires and their nerve binding domains in human autoimmune neuropathy.
Funder: Wellcome Trust

Abstract: Imagine yourself standing arm in arm with a partner, or both in isolation across a room. Despite being fundamentally unchanged, you cast very different physical impressions when combined, and when apart. Similarly molecules may bond together to form new shapes that make them distinct from their individual parts. When two glycolipids (sugars anchored in cell membranes by fatty tails) are next to each other, they form such an interacting complex. This heterodimeric complex can then be bound by a n antibody that cannot bind either glycolipid alone, owing to unique new shapes formed by the partnership. Equally, some antibodies are obscured from binding one glycolipid by the presence of another. Some partners are better at this than others. Furthermore, other antibodies don t care, binding their glycolipid target whether in partnership or not. We call these three patterns of antibody binding complex enhanced , complex inhibited , and complex independent . This has not been studied in de pth before as researchers have overly focused on individuals, rather than couples. We believe this new discovery has a profound bearing on autoantibodies that cause the devastating human paralytic disease, Guillain-Barr syndrome and here set out to explore its importance through wide ranging human and mouse modeling studies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: VEGF signalling in the nervous system.
Funder: Wellcome Trust

Abstract: This project aims to examine if VEGF-C patterns the nervous system during axon guidance or synapse formation, and to define the molecular pathway by which VEGF-A signals in neurons independently of its role in blood vessels. Define the role of VEGF-C and its receptor VEGFR3 in axon pathfinding Determine if VEGF-A and VEGF-C function co-operatively to control axon pathfinding Identify NRP1 co-receptor(s) essential for VEGF-A signalling in neurons Examine if VEGF-A and/or VEGF-C control synapse development and function


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Formation and function of the avian circuitry for sound source localisation
Funder: Wellcome Trust

Abstract: The localisation of sound sources is critical to animal survival and relies on the anatomy and physiology of a neural circuit located in the hindbrain. Several features are likely to be critical to the function of this circuit including its cellular organisation as a lamina, site of action potential initiation, phase-locking of neuronal firing to sound frequency and the number of cells within the circuit. We have identified several genes that are likely to be crucial to the development and function of this important circuit. We shall investigate: 1. The molecular and cellular origins of the neurons of the auditory hindbrain. 2. The role(s) of FHF family members in modulating neuronal firing within the auditory hindbrain. 3. Gap-junction coupling between cells of the auditory hindbrain.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Olig2 and the regulation of neural stem cell fate.
Funder: Wellcome Trust

Abstract: During development of the central nervous system (CNS), neuroepithelial stem cells (NSCs), residing in the ventricular zones (VZ) of the embryonic brain and spinal cord, divide and differentiate to generate all the neurons and glial cells (astrocytes and oligodendrocytes) of the mature CNS. Typically, neurons form before glia. In the ventral spinal cord, for example, embryonic NSCs of the pMN progenitor domain generate several subtypes of motor neurons (MNs) before switching abruptly (at E12.5 in mouse) to production of oligodendrocyte precursors (OLPs). The OLPs then migrate away from the VZ into all parts of the spinal cord before associating with axons, differentiating into post-mitotic oligodendrocytes (OLs) and synthesizing myelin. We aim to address how NSCs switch at a predetermined time from neuron to glial production ? specifically, the mechanism of the MN-OLP fate switch in the ventral spinal cord. Broadly, the proposed project aims to characterize the role and regulation of the basic helix-loophelix transcription factor Olig2 in the MN-OLP fate-switch. Recent work from the Richardson lab showed that a specific serine residue (S147) in Olig2 is phosphorylated during MN specification and de-phosphorylated at the switch to OLP production. What triggers de-phosphorylation of Olig2 at the time of the MN-OLP switch? The sequence surrounding S147 conforms to a protein kinase-A target site, but the identity of the putative phosphatase responsible for dephosphorylation has not been established. What are the targets and co-factors of Olig2 in its different phosphorylated states that coordinate the temporally-defined switch in NSC fate? And what are the functions of the other predicted Olig2 phosphorylation states? This project will involve three distinct lines of investigation. 1: Characterizing the expression of candidate phosphatases/phosphatase inhibitors in the ventral spinal cord at the time of the MNOLP fate-switch. 2: Identifying target genes of Olig2 in its phosphorylated and de-phosphorylated states. 3: Characterizing the developmental function of another Olig2 phosphorylation site, S263, a potential target of p38 mitogen-activated protein kinase (MAPK).


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Dissection of mechanisms underlying the development of neuronal lineages.
Funder: Wellcome Trust

Abstract: The nervous system is a complex network of interconnected cells that form from a much simpler set of developmental modules, so-called progenitor cells. These divide to generate particular types of nerve cells. Nervous system function depends on the appropriate specification of the nerve cells, particularly two defining characteristics: i) the brain regions into which cells put their communication terminals, and, ii) the type of messages (e.g. excitatory or inhibitory transmitters) they release w hen communicating with other cells. A fair deal is now known about the specification of progenitor cells on the one hand, and, on the other hand about the formation of connections between neurons. Our goal is to study the less well understood mechanisms that regulate how progenitor cells develop so as to produce appropriate types of nerve cells. To achieve this we have developed methods to genetically label lineages of nerve cells produced from single progenitors. This allows us to identify th e elementary developmental principles and mechanisms that regulate in which order and what combination(s) particular types of nerve cells are made. It will bridge the current gap in our understanding between early and late events in nervous system development.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Systems neuroscience: From networks to behaviour - Understanding plastic changes induced by non-invasive association stimulation
Funder: Wellcome Trust

Abstract: Project Aims: The project aims to characterise changes in the following after a non-invasiveafferent stimulation protocol: Intracortical connectivity in motor and somatosensory cortex; Corticospinal output from the motor cortex; Responses to cutaneous and muscle afferent stimulation in the motor and somatosensory cortex, and the cuneate nucleus.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Systems neuroscience: From networks to behaviour - Role of identified interneurons in motor processing.
Funder: Wellcome Trust

Abstract: 1. By combining the use of several different pharmacological and neurophysiological measures formulated in vitro, we aim to identify cortical inhibitory interneurones (IIN) in vivo based on their extracellular spiking 2. These methods for interneuron identification will be used to: a. Assess how interneuron activity modulates during preparation and initiation of voluntary movement b. Determine how intracortical and peripheral stimuli activate different interneuron classes c. Determine how interneurons contribute to the generation of spontaneous beta-band oscillations within the primary motor cortex


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Understanding epilepsy in the active brain.
Funder: Wellcome Trust

Abstract: Epilepsy is the most common neurological condition in the UK, affecting 1 2 % of the population. Epilepsies often involve only a small area of the brain - the epileptic focus and the abnormal activity can propagate out from there. Although surgery is often curative in epilepsy, effective intervention relies on the correct identification of the location of the epileptic focus. Current pre-operative techniques are of limited use in this regard, but the new generation of imaging techniques base d on changes in blood perfusion of active areas offer great promise. However, we currently have very little understanding of how epilepsy affects the relationship between brain activity and perfusion. Our research will use state of the art techniques in an animal model of epilepsy to characterise, define and measure the relationship between activity and perfusion in the epileptic state. We will also assess whether any long term changes in this relationship persist after epileptic activity, and w hether antiepileptic medication can return the relationship to normal. The research we propose will develop the use of imaging techniques as a tool for pre-surgical localization of epileptic foci in epilepsy and ultimately improve outcomes for surgical interventions on human epilepsy patients.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Spinal cholinergic interneurones influencing sympathetic function: a wider role in integration?
Funder: Wellcome Trust

Abstract: The autonomic nervous system is an almost involuntary component of the nervous system that contributes to the control of vital organs to maintain a healthy and functioning body. Within the spinal cord, there are a number of pathways that affect overall level of activity in the autonomic nervous system and these are comprised of specialised neural cells (neurones). Astonishingly, there are huge gaps in our knowledge about these neurones in terms of what they look like, their intrinsic behaviour and what other cells they communicate with. One of these groups of neurones contains acetylcholine, a chemical released to alter autonomic activity. This chemical has far reaching effects in other central nervous system regions so it is important to determine how it affects spinal cord function. We will examine many properties of these neurones to determine how widespread their action is. Our preliminary data suggests that they have a potential vital role in co-ordinating not just autonomic activity but functions such as movement and how we respond to pain. We propose to determine how these neurones fit into pathways within the spinal cord. This will help us understand how they may dysfunction in disease states or in spinal cord injury.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Identification of factors involved in Purkinje cell dysfunction and death.
Funder: Wellcome Trust

Abstract: A group of brain diseases cause poor balance and inability to coordinate movements. This results from damage and death of nerve cells (Purkinje cells) in the cerebellum, the brain area responsible for coordinating movement. It is unknown why, in people with the disease, Purkinje cells don t function properly and why they die. We have made mice lacking the protein (beta-III spectrin) known to be faulty in patients with one form of this disease (spinocerebellar ataxia type-5). We find these mice h ave similar symptoms to patients: their hind-limbs are splayed when walking, they are very poor at tasks requiring coordinated movement, they tremble when doing such tasks and Purkinje cells die. The project s aim is to further understand what role certain cells and proteins play in the disease process. We want to discover whether reduced removal of glutamate, a chemical toxic at high levels, causes Purkinje cell death and whether other cell types are required for their survival. We will also look at the effect faulty forms of beta-III spectrin have on proteins found to be altered in the mouse. This will provide information for therapies to slow down or stop Purkinje cell death in a group of presently incurable diseases.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Fractalkine/CX3CR1 modulation of long-term potentiation at the first pain synapse.
Funder: Wellcome Trust

Abstract: Pain is a symptom of many conditions and the management of chronic pain remains unsatisfactory. Chronic pain can occur as a result of trauma to a peripheral nerve or disease, such as diabetes and arthritis, or as a side effect of treatment for cancer. At present chronic pain is poorly treated by existing therapies and controlling pain may dramatically improve the quality of life of many patients. One possible mechanism which contributes to chronic pain is long-term potentiation (LTP), an amplifi cation of neuronal responses that leads to excessive activity in the spinal cord. I propose to study how specialized immune cells (microglia) in the spinal cord modulate LTP. In models of chronic pain microglia contribute to enhanced pain by releasing inflammatory proteins that sensitize neurons, and therefore may also contribute to LTP. I also wish to study how Fractalkine, a protein that is thought to mediate the spread of pain between neurons and microglia, may contribute to LTP. This novel l ine of research will help to understand the mechanisms of chronic pain which may lead to the development of novel treatments.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL