NIHRDataInsights/HRCSData huggingface dataset:
Title: Investigating the mechanisms of structural plasticity in mouse visual cortex in vivo using chronic two-proton imaging
Funder: Medical Research Council

Abstract: Circuits in the brain have the ability to adapt to novel experiences and environments. These changes are facilitated through a combination of functional plasticity, such as long-term potentiation (LTP) and long-term depression (LTD), and structural changes, such as the addition or subtraction of boutons and spines, the putative pre- and postsynaptic components of the synapse. While both aspects of plasticity are important, the study of long-term structural plasticity in vivo has only recently become feasible with the advent of two-photon microscopy. In this proposal, I outline a series of experiments that investigate the mechanisms of structural plasticity using chronic in vivo two-photon and intrinsic signal imaging techniques in combination with molecular tools. Previously, we developed a retinal lesion paradigm in mice that induces massive functional and structural plasticity in both excitatory and inhibitory cortical neurons. Because the plasticity occurs in the visual cortex, optical imaging and/or electrophysiology in combination with visual stimulation can be used to measure the degree of functional plasticity. I will utilize this paradigm as a tool to investigate the mechanisms that drive structural changes at the single cell level. In the first set of experiments, I will investigate the degree to which activity drives structural plasticity (as suggested by in vitro experiments, as well as my own data). Using molecular tools, such as the genetically encoded calcium indicator TN-XXL, which allows for the chronic measurement of structural and functional dynamics in a single cell, I will measure the functional and structural changes that occur after the retinal lesion plasticity paradigm. Then, using channel rhodopsin 2, a light-gated algal channel that reliably generates action potentials when stimulated with blue light, I will stimulate cells in control animals with the previously measured activity patterns to determine the degree to which activity drives structural plasticity. In a second set of experiments, I will investigate the role of molecular signaling in structural plasticity. I will first investigate the role of Otx2, a molecule known to be important in functional plasticity, using Otx2 knock-out mice. Using the same molecular tools described above, I will determine the degree to which structural plasticity is altered in these transgenic mice. In the long term, after characterizing mechanisms of structural plasticity, I plan to investigate which of these mechanisms are deficient in disease states with altered structural dynamics, such as Fragile X syndrome and Alzheimer’s disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Engaging with Older People to Develop and Deliver Interventions for the Self-management of Chronic Pain (EPIC).
Funder: Medical Research Council

Abstract: Some suggest that with increasing age comes an increase in the incidence of chronic pain (Ferrell et al), with a potential to impact upon 50% of community dwelling older adults over the age of 65 (Helme & Gibson 2001). While adults with chronic pain may view their health as poorer (Reyes-Gibby et al 2002) there has been limited research that has focussed upon the specific impact of chronic pain amongst older adults as perceived by them and a limited attempt to identify their preferred pain management strategies (Schofield et al 2005) The strategic vision of this study is to obtain a deep understanding of chronic pain and its economic impact as experienced by older adults. At the same time we will determine the perspectives of health care professionals through a series of interviews and surveys and by conducting a comprehensive review of the literature. This period of data collection will lead to the development of self-help materials along with the most acceptable and feasible ways of delivering these self-help materials. Therefore we will make recommendations for modes of delivering educational material, information & support to older adults living with chronic pain in the community. The study will comprise five phases, each informing the other and delivered between three institutions. Fundamental to the study will be the views and perspectives of the older adults who will inform each phase in a meaningful way.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: NEUROLOGICAL
Title: Development of Quantitative PET Imaging Probes for Neuroinflammation
Funder: Medical Research Council

Abstract: The main aim of this research proposal is to shape a Post-Graduate Training Program in PET Methodology focused on the mathematical modelling of novel TSPO tracers in the normal and diseased brain. The TSPO is consistently expressed in the active microglia population in response to mild, acute or chronic brain injury. Microglia are the resident immuno-competent cell of the central nervous system and, in their active state, release pro-inflammatory molecules that initiate and sustain the immune response. This state is generally referred to as ?Neuroinflammation?. Microglia activity is not only regarded as the most sensitive marker of brain disease but it has also been proposed as pathogenic agent in neurodegenerative diseases, Alzheimer?s and Parkinson?s disease in particular. In-vivo TSPO imaging using PET started more than 20 years ago using 11C-PK11195, a positron emitter labelled antagonist for the TSPO but, because of the poor sensitivity of this tracer, research for novel TSPO tracers has surged in the last 5 years with more than 50 new PET TSPO-markers under various stages of clinical validation. It is because of this exceptionally large number of novel tracers and the importance of neuroinflammation for the clinical neurosciences that we define as the main objective of the proposed training program the identification of the optimal TSPO PET probe(s) and of the associated quantitative methodology. The training program is proposed in three phases. The first one (3 months) will provide the trainee with the basic knowledge on PET methodology. The second phase, (21 months) will consist in a set of 3 months supervised research projects, that will look at various aspects(biological/pathology/chemical/kinetic) of novel TSPO ligands and supply data to a metric (the elaboration of which is one of the research questions) that will inform on the best amongst all candidates and on its quantification procedure. The last phase of the research program (24 months) will be carried out independently by the trainee in the field of TSPO data quantification and will make use of the wealth of clinical and pre-clinical data available at the participating PET centres. We believe that this proposal has unique strengths in the form and content of the training program, in the relevance of the theme for the neurosciences, in the quality and breadth of experience in PET Methodology of the proponents, and the strong academic/industrial partnership (Imperial/GSK) that characterizes the environment.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: MRC Collaborative Training Programme in Radiochemistry for NeuroPET
Funder: Medical Research Council

Abstract: This proposal is to establish a pilot advanced neuroPET radiochemistry training programme linking major centres for molecular imaging in the UK in a collaborative network. The programme will be aimed at post-doctoral chemists. Two four-year training fellowships will be created by our programme. The initial two years of each will be focused on developing foundation skills in a structured, ?hands-on? pedagogical framework. In the latter six months of this two-year foundation training period, trainees will take on a mentored evaluation of potential approaches for new neuroPET radiotracer refinement or development. In the final two years of the programme, trainees then will work in one of the collaborative sites as the lead in a programme to develop one such radiotracer concept. The new radiotracer development will be pursued in a way that will allow the rapid translation of the work to benefit multiple partners in the collaborative network (and others). The outcomes of this programme will include new collaborative partnerships between UK molecular imaging centres, newly trained radiochemists able to lead independent programmes and a contribution to the development or refinement of novel PET molecular imaging radiotracers.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Formation of the earliest circuits in the cerebral cortex
Funder: Medical Research Council

Abstract: Cortical circuit formation is a fundamental developmental process underpinning all aspects of complex mammalian behavior later in life. Development of the cortex involves transient, dynamic cortical circuits, which get substantially remodelled according to the interplay between the developmental program and the environment. Subplate constitutes a fascinating transient cortical neuron population. They are amongst the earliest generated neurons of our brain and lay the foundation of our developing cerebral cortex. Since most initial cortical input and output are directed through subplate neurons, understanding how the connectivity and functional integration of subplate develops, how the transient subplate circuits co-exist with the more permanent cortical networks and how regional variation across the cortex is programmed, are issues critical to a broader understanding of cortical function. After subserving these functions, the majority of subplate neurons die and give way to the permanent cortical circuits. The developing brain is particularly vulnerable if these transient circuits are damaged or malfunction. Subplate has been implicated in several brain developmental disorders (childhood epilepsy, schizophrenia, autism and cerebral palsy). The Molnar group made significant contributions to the field of early thalamocortical interactions and more recently to the identification of novel markers and the molecular characterisation of subplate. This has provided a unique opportunity to generate genetic models to both monitor their dynamic integration and modulate their synaptic input and output characteristics. The current proposal builds on the work previously supported by MRC CEG (2004-2009) and aims to use an integrated, coordinated interdisciplinary approach. The program will require substantial commitment, development of new methodologies, establishment and generation of transgenic mice colonies (which the group will share with collaborators), and establishing and maintaining longer-term clinical collaborations. In this proposal we aim to (1) study the integration of subplate neurons into the cortical and extracortical circuitry using reporter gene expressing mouse transgenic lines (including Golli-tau-eGFP, CTGF-GFP, Edg2-GFP); (2) use optogenetic tools to dissect the developmental and mature circuitry, (3) identify and validate further subtype specific markers of these selected groups of subplate neurons; and (4) utilize genetic approaches (Golli-cre) to selectively ablate activity (stop-floxed Kir2.1) or output (conditional Snap25 KO) of subplate during development. The validation of murine subplate markers in human shall be initiated and through clinical collaborations this knowledge will be disseminated to clinicopathological analysis.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: A parkin knockout zebrafish model of early onset Parkinson's
Funder: Parkinson's UK

Abstract: Parkin mutations are the most common identifiable cause for early onset Parkinson's (EOPD) and single mutations may also play a role in late onset Parkinson's. The precise mechanisms as to how parkin deficiency leads to neuronal cell death remain to be elucidated. Pilot data: We have cloned the parkin homologue in zebrafish. Transient parkin knockdown in zebrafish embryos was achieved using morpholino antisense oligonucleotides (MO) which resulted in reduced complex I activity and specific loss of ascending dopaminergic neurons. Aims/Objectives: Our main aim is to create a stable parkin knockout zebrafish line to study the effect of parkin deficiency on: 1) Dopaminergic and other neuronal subpopulations as well as mitochondrial morphology in both embryonic and adult zebrafish 2) Gene-gene interaction; 3) Gene expression; 4) microRNAs as regulators of protein translation. Experimental design: Targeted parkin disruption will be achieved using new zinc finger nuclease technology. 1) Morphological stains, specific neuronal markers and electron microscopy will be used 2) Gene interactions will be determined by undertaking either overexpression/rescue or MO knockdown, but also by crossing the parkin knockout line with other stable mutant lines. Genes of interest: A) Other PARK genes, B) Mitochondrial fusion/fission genes. 3+4) Agilent gene expression arrays and Exiqon MicroRNA arrays will be used to explore RNA profiles with additional focussed in situ analysis for miRNAs of particular interest. Outlook: A stable parkin knockout zebrafish line will hopefully not only provide important insight into the pathogenesis of (EO)Parkinson's, but also become useful for future drug screens.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: The postnatal development and plasticity of central pain circuits
Funder: Medical Research Council

Abstract: The early postnatal weeks are a critical time for developing pain pathways when nociceptive circuits are shaped, endogenous pain control systems are activated and pain behaviour is organised. During this period, repeated peripheral tissue damage, such as arises in neonatal intensive care or surgery, alters the physiological balance of sensory input and can change the course of pain development. In the adult CNS, endogenous control systems gate the transmission of nociceptive information to the brain and increase or decrease pain according to the needs of the individual. We have shown that these pain control systems do not mature until well after birth and before that time appear to operate differently from the adult. Here we plan to investigate the functional developmental of these control systems and determine how they influence the maturation of somatosensory and pain. We will test how neonatal tissue damage leads to life long alterations in these control systems and hence the ability of the CNS to modulate nociceptive circuits. We will use electrophysiological analysis of nociceptive synapses and circuits in neonatal and adult spinal cord and cortex, supported by molecular, cellular and behavioural analysis to investigate the postnatal development and plasticity of (i) spinal inhibitory interneuronal circuits, (ii) descending brainstem-spinal controls and (iii) spinal neuronal-glial immune interactions (iv) early cortical pain activity. These studies will form an important translational link between our laboratory and clinical research.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Molecular and structural determinants of plasticity in the cerebral cortex
Funder: Medical Research Council

Abstract: The aim of this study is to understand the connection between early synaptic plasticity events such as LTP and LTD, which can be described at the cellular level and receptive field plasticity such as experience-dependent potentiation and depression that can be described at the systems level. Our hypothesis is that structural plasticity occurring at the level of spines and presynaptic axons is controlled by the same factors that control LTP and LTD, thereby explaining why similar factors are critical for LTP and experience-dependent potentiation and LTD and experience-dependent depression. To test this idea we will capitalise on our recent findings that GluR1 knockouts show potentiation but not depression and conversely that CaMKII-t286a point mutants show depression but not potentiation to identify the corresponding components of spine plasticity in vivo using 2-photon imaging. We will also test whether signalling pathways that lead to LTP with different pre- and post-synaptic loci in the neocortex also have different pre- and post-synaptic structural sites of action. To test this we will use GluR1 knockouts that show predominantly presynaptic LTP and alphaNOS1 knockout that show predominantly post-synaptic plasticity and compare the dynamics and nature of their spine and axon plasticity. In order to link these new structural plasticity studies with the existing literature on LTP and receptive field plasticity, these experiments will be performed on layer II/III cells electroporated with GFP rather than the layer V cells that are normally studied in structural plasticity experiments. This is a vital distinction because we have recently found differences in the mechanisms of plasticity in the two sets of layers. Finally, we will characterise the receptive field plasticity of layer V cells in order to link it to the existing literature on structural plasticity. We will study the source of the experience dependent depression and LTD mechanism in layer V that is not shared with layer II/III cells. Because of the diversity of layer V pyramidal cells we will distinguish between plasticity of sublaminae Va and Vb and between septal/barrel subdivisions and between intrinsic burster versus regular spiking cells.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Biomarkers for Deep Brain Stimulation
Funder: Medical Research Council

Abstract: Parkinson?s disease (PD) and dystonia are two of the most common movement disorders. Recently there has been immense interest in the neurosurgical treatment of these debilitating disorders through deep brain stimulation (DBS). However, the cost of DBS, its partial efficacy and side-effects mean that there is still a need to improve current therapy. One major problem is that present neurostimulators only provide continuous and fixed ?open-loop? stimulation which increases side effects and habituation, while reducing battery life. Our growing understanding of how different patterns of activity in the basal ganglia (BG) are associated with different symptoms raises the possibility of improving DBS through closed loop stimulation. In closed-loop mode, stimulation is titrated using a biomarker to determine when and how much stimulation is necessary. Here we will extend our studies of BG local field potential (LFP) activities in patients undergoing neurosurgery in order to clarify the pathophysiology of PD and dystonia and thereby to identify local biomarkers suitable for closed loop stimulation regimes. To this end we will refine our ?noisy signal? model of BG disease, based on the hypothesis that it is the balance between synchronised activities indexed in the LFP, rather than one activity per se, which determines motor state. Our intention is to equate these diverse changes with psychophysical processes, and thereby formulate a model that links various levels of observation, has heuristic value and proffers more sophisticated biomarkers. The reliability and mechanistic importance of these biomarkers will then be assessed through a series of correlational and interventional experiments in patients. Establishing which biomarkers are causally linked to symptoms is critical in both understanding disease processes and in identifying legitimate targets for emerging ?smart? stimulation approaches. In addition, we will define how current DBS works. Specifically we will test the hypothesis that DBS acts as a high frequency dither injection similar to that used to quench low frequency oscillations in nonlinear feedback control loops. Our intention is to model this process in the BG, which will in turn allow the identification of the most effective stimulation regime in individual patients. Finally, we will optimise algorithms for closed-loop stimulation based on LFP features, and prove closed loop stimulation can be effective in a double-blind cross-over trial of closed-loop versus current open-loop DBS in PD. Understanding gained in this research program will lay the foundation for improved DBS therapy for motor and other disorders.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Forebrain development: From neural plate to cortical specification
Funder: Medical Research Council

Abstract: Our lab aims i) to understand the molecular and cellular events that generate forebrain regionalization, ii) to assess their modulation associated to the generation of telencephalic complexity and ii) to identify the mechanisms driving coordination of neuronal differentiation required to develop functional circuits. The seven hypotheses explored in this programme (listed below) stem from our recent findings concerning cellular behaviour and fate specification inside the neural plate. They aim to understand how signalling centres interact during forebrain regionalisation (Part I) and explore the temporal, cellular and molecular changes that may drive transformation of a zebrafish forebrain neural plate towards a more mammalian one (Part II). It will also assess the coordinating role of the wedge-shaped signalling centre formed across forebrain areas inside the newly formed neural tube (part III). The set of hypotheses are: Part I: A. The telencephalon emerges from a BMP-driven repression of an Rx3-controlled eye field identity. B. Subpallial identity is established by degradation of P-Smad1, via an inhibitory interplay between Fgf and Wnt signalling activities. C. The anterior diencephalon territory acts as a boundary compartment between ANB and MHB signalling activities. Part II: A. The relative extents of telencephalic and diencephalic territories are controlled by temporal, spatial and/or quantitative variation in ANB and MHB induction. B. The diversity in forebrain complexity may be initiated by size modulation of the forebrain areas during neurulation. C. The emergence of a cerebral cortex formed by the dorsal telencephalon (pallium) is accomplished by quantitative changes of ANB properties. Part III: A hard-wired temporal coordination of forebrain neuronal differentiation (formation of a pre-circuit) may be required for the coherent formation of neuronal circuits. To test these hypotheses, we propose a set of original cellular, molecular and genetic approaches to understand the establishment of forebrain territories in vertebrates. Our ambition is to couple this understanding to the identification of early generators of forebrain complexity. We will use zebrafish and, to a lesser extent, mouse genetics (existing mutants and new mutants produced using in-house zinc finger nuclease targeted mutagenesis), conditional mis-expression (existing CreER and heat inducible transgenic lines), trans-species transplants, high-resolution imaging, and RNA profiling. Forebrain organisation will be analysed using routine markers for neuronal differentiation and axonal connectivity.


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