NIHRDataInsights/HRCSData huggingface dataset:
Title: Hippocampal-Hypothalamic Network Mechanisms of Maladaptive Contextual Eating
Funder: Medical Research Council

Abstract: First, we will assess how repeated contextual eating affects HPC network dynamics by performing multichannel recordings of spiking activity and local field potentials (LFPs) in HPC regions of adult male and female mice that lose contextual control over food intake. Using spike train and LFPs analyses, we will consider single-neuron firing activity and cooperative spiking activity forming cell assemblies. These will allow assessing whether escalated feeding biases HPC activity towards the representation of food-paired context, explaining loss of control in novel food intake and reduced ability to perform other mnemonic operations. Next, we will uncover the corresponding activity motifs of the HPC-to-LH pathway using dual-site recordings of neuronal ensembles and LFPs in HPC and LH with optogenetic identification of specific LH neuronal populations in Cre-driver mouse lines injected with the neural activator channelrhodopsin-2. Anterograde trans-synaptic optogenetic targeting of LH neurons receiving direct HPC inputs will be followed by anatomical analyses. These will allow identifying the electrophysiological (e.g., spike waveforms, inter-spike interval distributions and preferred theta phase) and the molecular (e.g., Vgat, Vglut2 and Orexin) profiles of HPC-connected LH neurons and identify activity changes (e.g., theta-gamma coupling and HPC-LH assemblies strengthening) caused by heightened eating along this pathway. Finally, we will manipulate HPC neuronal representations and the HPC-to-LH pathway to restore normal contextual eating in "TetTag" mice expressing the neural silencer ArchT in an activity dependent (due to the immediate-early gene cFos), input-dependent (due to trans-synaptic viral constructs), and cell-type-selective (due to the Cre recombinase) manners. These will allow probing two strategies for reprograming HPC food-context representations into neutral representations and rebalancing HPC-to-LH activity using real-time closed-loop systems.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;3.3 NUTRITION AND CHEMOPREVENTION
Health categories: NEUROLOGICAL
Title: Vulnerability of long-range axons in tauopathy
Funder: Medical Research Council

Abstract: Early in dementia, impaired coordination of activity in different brain areas is linked to cognitive symptoms. In fact, this regional disconnection is impacted before local activity. This suggests that long-range axons that connect that neurons in distant regions are especially vulnerable. We propose that impaired axonal trafficking associated with dementia-related aberrant tau has preferentially detrimental effects on long-range axons, impacting their synapse function and driving their pathology. Here we will use a combination of imaging approaches to compare long-range and local axon branches from the same neuronal population in a mouse model of tauopathy. Using in vivo 2-photon microscopy, we will measure the dynamics of axonal transport of intracellular cargoes such as mitochondria and endosomes in different parts of axon and relate this to function and plasticity of synapses in those locations as they become affected by the disease. We will use the CLARITY tissue clearing technique to aid assessment of pathology of axonal branches in relation to their intact anatomy. The subcellular organisation of those axon branches, in relation intracellular organelles, will be revealed using Expansion Microscopy to achieve super-resolution assessment of their localisation that is so crucial to axonal function. Finally, we aim to show proof-of-concept for ameliorating long-range axonal pathology using pharmacological rescue of specific axonal trafficking defects. These experiments will reveal how distinct regions of the axon are differentially affected by abnormal tau signalling, defining a basis for the regional disconnection seen in the brains of patients in early stages of dementia. Rescue of axonal trafficking defects to delay or halt the pathological vulnerability of long-range axons has tremendous potential for therapeutic benefit for symptoms linked to coordinated brain activity and on pathology that is downstream of early synaptic disconnection.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Partitioning the effects of schizophrenia risk variants on dynamics of the local synaptic translatome in cortex
Funder: Medical Research Council

Abstract: Genetic studies have revealed numerous alleles conferring risk to schizophrenia, but poor understanding of how their effects converge on discrete cellular processes has impeded use in drug design. Growing evidence, supported by my own research, suggests that genetic risk is enriched in activity-dependent synaptic genes under the control of local translation and is therefore likely to confer risk through effects on these systems. Recent discoveries of rare penetrant variants contributing substantial risk to schizophrenia facilitate testing this experimentally. I will perform the first study quantifying effects on the local synaptic translatome caused by highly penetrant mutations conferring risk to schizophrenia, focusing on loss-of-function variants in TRIO and GRIN2A. Both these genes are important for activity-dependent synaptic development and plasticity but have different developmental expression profiles. I hypothesise that their loss of function confers risk via age-specific effects on selected locally translated transcripts. To test this, I will profile ribosome-bound mRNA in frontal cortex synaptoneurosomes of mice with heterozygous Trio or Grin2a loss-of-function alleles at multiple stages of postnatal development. Single-cell transcriptomics will be applied to isolate affected cell types and contrast local vs cell-wide effects. Finally, I will use human post-mortem developmental transcriptomes, including cell-specific data, to relate my findings to human expression dynamics and predict which co-expressed transcripts are most susceptible to schizophrenia risk and may be amenable to pharmacological intervention. This work is expected to demonstrate how risk contributed from different genetic variants converges on synapse function to bring about vulnerability in particular cell types during brain development that can lead to psychiatric illness. In doing so, the results will expose candidates for the prioritisation of therapeutic targets.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Inhibitory engrams in learning and memory consolidation
Funder: Medical Research Council

Abstract: Nervous systems face a fundamental problem: how do neural circuits undergo modification to meet the demands of an ever-changing environment, while not compromising previously learned information? In other words, the brain must set a trade-off between plasticity and stability that ensures new learning does not interfere with memories from the past. This trade-off is thought to be set by homeostatic mechanisms. However, the details of these mechanisms remain poorly understood in relation to behavioural read-outs of learning. A recent hypothesis proposes that following changes in cortical excitatory synaptic strength, homeostasis is maintained by matched increases in inhibitory synaptic strength, otherwise termed 'inhibitory engrams'. These inhibitory engrams may help preserve neural coding schemes that rely upon a tight coupling between excitatory and inhibitory transmission. Here, across Work Packages 1-3, we will investigate how inhibitory engrams form, together with their effect on behavioural readouts of learning. In our past research, we have developed techniques to index the formation of excitatory and inhibitory engrams in healthy human volunteers, using non-invasive functional Magnetic Resonance Imaging, combined with non-invasive brain stimulation and Magnetic Resonance Spectroscopy. We will use these techniques to measure the strength of inhibitory engrams after new learning. In Work Package 1, we will investigate the mechanism that drives formation of inhibitory engrams, with a focus on the role of offline memory reactivation. In Work Package 2 and 3, we will then disturb and delay the formation of inhibitory engrams, to prolong the period of neural instability after new learning. This will be achieved using two double-blind placebo-controlled drug studies designed to manipulate cortical GABA. Following drug intake, in Work Package 2 we will measure the effect on memory interference, while in Work Package 3 we will assess the effect on generalization.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: NEUROLOGICAL
Title: Targeting Kir4.1 To Control Brain Excitability And Seizures
Funder: Medical Research Council

Abstract: Neural activity elevates extracellular K+ and thus boosts cell excitability, potentially leading to runaway excitation, such as epileptiform activity. Astrocytes dynamically control K+, mainly by engaging Kir4.1 channels, and Kir4.1 downregulation has been related to seizure susceptibility. However, the causal relationships between the Kir4.1 expression patterns, the external K+ dynamics, local neuronal excitability and synaptic function remain poorly understood. This knowledge gap hampers our search for feasible routes of therapeutic intervention. We aim therefore to understand how the Kir4.1-dependent K+ buffering regulates network excitability and synaptic circuit function in the brain, and whether targeting Kir4.1 function, pharmacologically or genetically, can alter susceptibility to overexcitation and seizures. Our research strategy involves five specific objectives, taking advantage of the newly established techniques in acute slices and in vivo, including: gene-targeting protocols enabling visualisation of Kir4.1-overexpressing astrocytes while monitoring glutamate release at local synapses; a nano-technology to monitor extracellular K+ landscapes in situ using a microencapsulated ratiometric FRET dye; a computational platform ASTRO for theoretical probing of K+ dynamics in realistic astrocyte models; and a novel multi-electrode electrocorticography technique based on flexible graphene transistor arrays enabling full-band current recordings in awake animals. These and related breakthroughs, backed by a large body of pilot results and proof-of-principle tests, helped formulate a feasible strategy to achieve our goal. The outcome will provide new knowledge about the mechanisms by which astroglia regulate neuronal excitability through the Kir4.1-dependent control of K+ dynamics. Based on such knowledge, a therapeutic strategy could be developed to help reduce brain susceptibility to runaway excitation, such as in epilepsy and related disorders


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL
Title: The Dynamics And Clinical Relevance Of Grey Matter And Periventricular White Matter Pathology In Multiple Sclerosis
Funder: Medical Research Council

Abstract: To date magnetic resonance imaging (MRI) studies in multiple sclerosis (MS) have mostly focused on white matter (WM), although over the past 20 years progress has been made developing methods to detect grey matter (GM) pathology. GM atrophy, and the neurodegeneration underlying it, is now thought to ultimately be the cause of most irreversible disability in MS. However, we still have very limited insights into the tempo of GM disease, how this relates to WM disease, its associations with disability progression, and the prognostic relevance of earlier GM pathology to subsequent clinical outcomes. A decade ago we undertook a study assess GM disease in MS, and associations with clinical outcomes. We recruited 148 people with MS, 9 following a clinically isolated syndrome and 52 healthy controls. We improved the detection of GM lesions (using phase sensitive inversion recovery), and were able to identify gradients (using high resolution magnetisation transfer ratio imaging) in cortical GM pathology consistent with previous histopathological studies that had shown that GM lesions and neuronal loss was much more prominent close to the surface of the brain. We also showed that there are similar, but previously unrecognised, gradients in abnormalities in WM. We found associations between these MRI features and clinical outcomes (MS phenotype, level of neurological or cognitive impairments). We now plan to follow-up this cohort to characterise in detail the evolution of these MRI features, to assess how GM and WM MRI-visible pathology evolves, unpick pathways linking WM and GM pathology (using conventional statistical and structural equation modelling approaches), and determine how this translates into GM atrophy and disability. We will also asses the role factors such as iron deposition and hypo-perfusion, that have developed as significant MS research themes since our original study, could play in promoting cortical neurodegeneration.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Network function in tauopathic neurodegeneration
Funder: Medical Research Council

Abstract: The aim of this proposal is to understand how tauopathy affects the communication and coordination of signals in the brain, and causes deficits in brain function. Our central hypothesis is that tauopathy has a greater impact on long-distance interactions (connectivity) between brain regions. We will test this hypothesis by making measurements from the cortical visual system of two preclinical mouse models of tauopathy: an important new model in which the entire mouse tau gene has been humanised before introducing relevant mutations, and a well-characterised model (rTg4510). We will test four predictions of the central hypothesis in four experiments. The first prediction is that tauopathy has an earlier and stronger impact on global brain oscillations. We will analyse the amplitude and coordination of oscillations in the local field potential (LFP) from multiple brain regions, during longitudinal measurements over the early course of disease. The second prediction is that tauopathy has more impact on long-distance functional connectivity than local connectivity. We will simultaneously record LFP and spiking activity across multiple brain regions using large-scale devices ('Neuropixels'). We will measure the coordination of spiking and LFP activity within and between areas. The third prediction is that tauopathy disrupts long-distance structural connectivity. We will use retrograde tracing to quantify projections within and between areas, and immunohistological methods to establish which projections are more likely to develop tau-inclusions. The fourth prediction is that tauopathy will have a cascading impact, such that there will be more disruption to functional signals in the higher visual cortical areas that feed into cognitive function. We will measure the visual responses of neurons along the visual hierarchy and characterise how tauopathy affects the response amplitude, reliability, latency and tuning of neurons in each area.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Mechanisms of DNA Single-Strand Break-Induced Genetic Disease and Opportunities for Therapeutic Intervention
Funder: Medical Research Council

Abstract: My laboratory is focused on understanding how DNA single-strand breaks (SSBs) lead to human disease, and how this understanding can be exploited for therapeutic benefit. To date, at least six hereditary neurodegenerative diseases exist that are associated with genetic defects in SSB repair (SSBR), the most recently identified of which was discovered under the auspices of my current research programme (spinocerebellar ataxia autosomal recessive 26, in which the central SSBR scaffold protein XRCC1 is mutated). Notably, all six SSBR-defective diseases identified to date are caused by mutations in either XRCC1 itself or in protein partners of XRCC1. During the current research programme, excitingly, we have established that pathological activation of the SSB sensor protein PARP1 is responsible for much of the neuropathology in XRCC1-defective disease, and we have uncovered a molecular mechanism by which this activation disrupts transcriptional regulation and normal synaptic function in affected neurons (see case for support). As a result of these and other novel discoveries in my current MRC research programme, the hypotheses that we wish to address and explore in the new programme are (i), that XRCC1-mutated disease results from pathogenic activity of PARP1 at SSBs arising specifically during DNA base excision repair and that a major source of which is the regulation of neuronal gene expression by epigenetic (re)programming and (ii), that PARP1-induced pathogenicity extends beyond XRCC1-mutated disease and contributes to or causes other SSBR-defective diseases in which DNA base excision repair is affected. Finally, and importantly, we will exploit our discoveries to identify new avenues for therapeutic intervention in SSBR-defective disease, with a particular focus on PARP1 as a pharmacological and therapeutic target.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: INfLUENCE-HD: Influencing juvenile-onset Huntington's disease monitoring with remote Neurofilament light quantification
Funder: Medical Research Council

Abstract: Huntington's disease (HD) is a neurodegenerative disease caused by CAG expansions in the huntingtin gene. Typically, HD manifests in adulthood between 30-50 years. However, longer CAG repeat expansions can lead to an ultrarare (~5% of HD cases) manifestation of HD before the age of 21 years, known as Juvenile-onset Huntington's disease (JoHD). JoHD has not been studied extensively. There are currently no disease modifying therapies (DMTs) for HD, and JoHD is underrepresented in clinical trials due to inclusion criteria being >18 therefore excluding paediatric cases. Remote assessment of JoHD patients could facilitate JoHD research by alleviating physical burden and geographical limitations on the patients and caregiver, allowing higher sample numbers to elucidate its complex natural history. Response biomarkers of neuronal damage are needed for clinical trials. I reported neurofilament light protein (NfL) as the most promising such biofluid biomarker: its level predicts onset and progression in adult-onset HD and is elevated in JoHD patients compared to healthy control children. INfLUENCE-HD will harness remote sample and data collection in conjunction with international collaborations to apply plasma NfL to JoHD. I have developed a finger-prick blood collection method for NfL quantification that, from pilot data, is consistent with the standard venous blood measurement. I will continue to build the largest, international JoHD registry, JOIN-HD, and utilise it to recruit up to 100 JoHD patients for remote longitudinal plasma NfL quantification. My collaborators with share plasma samples for NfL quantification as well as clinical, phenotypic and neuroimaging data from their JoHD studies to amplify our efforts. I will develop a fine-grained model of NfL dynamics throughout the lifespan of HD mutation carrier in the context of macro- and micro-structural brain changes. INfLUENCE-HD will provide the tools and understanding for clinical trials in JoHD.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Defining the microstructural basis of tremor in vivo to identify novel therapeutic targets
Funder: Medical Research Council

Abstract: Background and objective Tremor is common, significantly impacts quality of life, and is often difficult to treat with up to 50% classed as "medically intractable". Even in the most common tremor disorders, Parkinson's Disease(PD) and Essential Tremor Syndrome(ET), how damage to different brain circuits cause, and modify, tremor remains poorly understood. In this study we aim to map the microstructural and network changes in brain using quantitative MRI(qMRI) in people with tremor due to ET or PD. Methods We will include three groups of patients PD, ET, and controls. Data from early-stage PD (Mixed rest-postural tremor n= 40; Postural only n= 36; Rest only n= 8; No tremor n= 16) and control (n= 74), from an existing study led by Dr Lambert (Quantitative MRI for Anatomical Phenotyping in Parkinson's disease (qMAP-PD). We will acquire additional data for 40 additional participants with ET who will undergo the same assessments as qMAP-PD study. Clinical assessment of tremor will use standardised tremor rating scales, augmented using video capture paired with high frequency accelerometers (GENEactiv)) to generate "tremograms". All patients will have a qMRI including diffusion study and resting state fMRI. Voxel based morphometry and quantification will be used to compare tremor subtypes. We will map the structures that give rise to the different tremor properties and identify linked clinical-anatomical networks. From these maps UK biobank data will be used to identify genetic-structural correlates for genetic annotation. We will further screen and annotate these results with drugs that can potentially target strategic locations within the network that may be suited for future trials. Outcomes a. Quantitative methodology to map tremor subtypes based on anatomical patterns b. Anatomical tremor-subtype networks - Providing potential targets for neuromodulation in targeted individuals c. Precision therapies targeting aetiologically segregated tremor syndomes


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: UK Dementia Research Institute Animal Models Programme
Funder: Medical Research Council

Abstract: The goal of this project is the development of high-quality capacity (novel resources, data-sets and collaborations) in mouse models of dementia to facilitate hypothesis-driven robust and generalizable translational research. Dementia is caused by brain pathology leading to changes in cognition and behaviour. The brain is a complex mix of highly interdependent cell-types which have key interactions with the vascular and sensory systems. Genetic and epidemiological data indicate that the immune system, metabolic state and cardiovascular health significantly impact on dementia development1,2. Thus physiology “below the neck” has a key role in disease. The DRI Animal Models programme will develop preclinical models to study this complexity for hypothesis-driven basic research. To complement future advances in organoid and cellular preclinical modelling the programme will focus on; (i) cell type diversity (regional and cell-type vulnerability), (ii) complex multi-cellular interactions within the brain, (iii) interaction of the brain with vascular, sensory systems and whole organism physiology, (iv) how neurodegeneration and interventions affect cognition and behaviour.


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