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Recipients:
University College London

Results

Sexy glia: developmental plasticity during glia-derived neurogenesis 11 Jul 2017

The overall goal of this proposal is to elucidate the cellular and molecular mechanisms that regulate natural glia-to-neuron cell-fate switches. Stably differentiated cells can sometimes display a remarkable degree of plasticity and switch fates to another differentiated cell type, in a process termed transdifferentiation. In the vertebrate nervous system, radial glia act as neural progenitors during embryogenesis. Suprisingly, stably differentiated glia can also act as neural progenitors during adult neurogenesis. We have recently discovered two cases in which stably differentiated glial cells undergo a glia-to-neuron cell-fate switch during sexual maturation in the nervous system of C. elegans, allowing us to study these events at the single-cell level in a genetically tractable system. We will combine classic genetic approaches with state-of-the-art molecular and next-generation sequencing approaches to characterise the molecular and epigenetic changes that occur during natural glia-to-neuron transdifferentiation. We will elucidate the role of cell division in this process, identify novel molecular regulators and determine the reprogramming abilities of the factors we identify. Unleashing the neurogenic potential of glia offers tremendous therapeutic possibilities.

Amount: £1,453,931
Funder: The Wellcome Trust
Recipient: University College London

Improving self-awareness: Manipulating the neural substrates of self-belief 31 May 2017

Beliefs about our skills and abilities (known as "self-beliefs") may become divorced from reality, particularly in psychiatric and neurological disorders. For instance, someone with depression may think they are unable to succeed in new pursuits, making them unlikely to try in the first place. My goal is to identify core brain processes supporting self-beliefs, and in turn leverage this knowledge to develop interventions for restoring aberrant self-belief. I will focus on a network of brain regions in medial and lateral prefrontal cortex that is theorized to support estimates of self-ability. I will address three interlocking questions: 1) How are self-beliefs constructed? 2) Which factors permit the modification of self-belief? 3) How are self-beliefs used in the control of future behaviour? I will conduct fMRI and MEG experiments using novel decision paradigms to dissect elements of self-belief computation such as prior experience and task difficulty, and reveal how mental health is linked to these computations through large-scale online data collection. This work will inform behavioural and neurofeedback interventions to modify self-belief. The overarching goal of my research agenda is to produce a comprehensive, mechanistic account of self-belief construction, thereby informing efforts to restore appropriate self-awareness in disorders of mental health.

Amount: £844,232
Funder: The Wellcome Trust
Recipient: University College London

Imaging and activation of glymphatic clearance: a novel strategy for Alzheimer’s Disease 26 Oct 2016

There is a critical need for early and accurate biomarkers of the pre-symptomatic phase of Alzheimer's disease (AD), to maximise the efficacy of emerging therapies. Recent evidence implicates cerebral glymphatic exchange as a key mechanism in early AD pathogenesis [Figure 1] [1-4]. I will develop the first non-invasive method for the quantitative assessment of glymphatic clearance, using MRI. These novel methods will be carefully validated by comparison with the invasive measures [5], that I have previously established, in normal, aged and AQP4 null mice. I will apply these novel techniques longitudinally to mouse models of ageing and AD (amyloid and tau) to investigate impairment of glymphatic clearance relative to more established markers of AD pathogenesis such as structural imaging, perfusion and histological assessment of plaque/tangle burden. As such, these data will be the first to elucidate the chronology of abnormal glymphatic clearance in AD pathogenesis. Finally, I will combine these methods with targeted optogenetics to assess the interaction of vessel tone and vasomotion to rates of glymphatic clearance in order to characterise the underlying mechanisms that drive CSF-ISF exchange.

Amount: £780,158
Funder: The Wellcome Trust
Recipient: University College London

Explicit representations of uncertainty drive attentional adjustments 19 Apr 2017

The aim of the proposed project is to understand how confidence serves cognitive control, more specifically how explicit representations of uncertainty guide attention. My own research findings and those of others suggest that humans possess an impressive ability to track and report uncertainty in the form of confidence judgements. Confidence has been found to co-vary with people’s objective performance and could thus serve as an internal teaching signal for situations when there is no external feedback that could guide behaviour. In the first part of the fellowship, I plan to study how different sources of uncertainty (internal and external) affect confidence. I predict that low confidence due to internal uncertainty should lead to an increased attentional focus (exploitation), whereas low confidence due to external uncertainty should lead to a widened attentional focus (exploration). In the second part of the fellowship, I would apply my questions to a special clinical population with impaired uncertainty processing: Patients diagnosed with obsessive-compulsive disorder (OCD) have often been found to be underconfident. I expect to find that this is due to an oversensitivity to internal uncertainty and predict to find more exploitation in OCD patients, given their inflated sense of uncertainty.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University College London

Pathological aversive learning as a mechanism in clinical anxiety 19 Apr 2017

Generalised anxiety disorder (GAD) is a common and debilitating condition. Its core symptoms are strongly related to subjective feelings evoked by uncertainty. This fellowship will build on advances in computational modelling to characterise the role of estimations of uncertainty about aversive events in GAD. The project has three key goals: 1) To develop behavioural tasks, and computational models of these tasks, that allow estimations of uncertainty during aversive reinforcement learning. I aim to achieve this by building on existing reinforcement learning tasks that manipulate uncertainty through changing stimulus-outcome contingencies, combined with models that allow explicit estimation of participants’ perceived uncertainty. 2) To determine whether individuals with GAD overestimate uncertainty, or overestimate the likelihood of negative outcomes in uncertain situations. To do this I will exploit tasks and models developed in phase 1 of the proposal to compare subjects with GAD and healthy individuals on their estimation of uncertainty in aversive environments. 3) In this phase I aim to identify the neural basis of these abnormalities using functional neuroimaging (fMRI), by combining these tasks and models with fMRI to identify neural systems underlying uncertainty estimation in aversive contexts, and examining the differential function of these systems in patients with GAD.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University College London

Neural mechanisms linking perception to action in zebrafish prey hunting behaviour 09 Nov 2016

The ultimate goal of modern neuroscience is to understand how brain activity generates behaviour. Thus far, mainly because of technical limitations, neuroscientists have been primarily focusing their research on how the activity of single neurons or small populations of neurons encodes the representation of either sensory stimuli or motor programs. However, given the current technological advancements allowing neural recording and manipulations across brain areas, it is now impelling to start tackling this crucial biological question: how do sensory representations trigger the selection and execution of appropriate motor programs? In my proposed project I aim to provide a mechanistic, cellular-level description of how larval zebrafish execute prey hunting routines in response to defined visual stimuli. Using a wide range of cutting-edge techniques, including simultaneous behavioural monitoring while performing calcium imaging/optogenetics, I will dissect the activity dynamics and circuit mechanisms of a key neural network hub in the anterior-ventral optic tectum capable of triggering the characteristic motor output of hunting behaviour. Crucially, I will reveal how this network hub is recruited by sensory neurons and how, in turn, this hub coordinates the activity of premotor neurons in multiple brain areas, therefore shedding new light on how the brain generates actions from perceptions.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University College London

An adaptive role of collective decisions: shared responsibility in the human brain 09 Nov 2016

Decades of research in collective decision-making show that the reliability of joint decisions is far from guaranteed raising the obvious question: why is collective decision making so popular in human interactions? I suggest an alternative to the quest for collective accuracy. I hypothesise that collective decisions are adaptive because (1) joint (vs. individual) decisions decrease the sense of responsibility for mistakes both at behavioural and neuronal level ; (2) individuals seek to diminish the chances of punishments through engaging in collective decisions; and (3) individuals are assigned more responsibility and punished more severely than groups. I predict that shared responsibility and punishment avoidance in group decisions modulate the same cognitive/neuronal mechanisms that underlie the sense of agency and norm-enforcement in individual behaviour. By empirically testing these predictions behaviourally and neurally (using Magnetoencephalography and Transcranial Magnetic Stimulation), I will characterize the function of collective decisions, and help clarify the utility of cooperation.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University College London

Studying murine behaviour and extending the hippocampal place cell model to 3 dimensions 27 Apr 2017

In previous decades, studies focussing on hippocampal place cell activity have resorted to using 2-dimensional simulation models. I argue that such a paradigm proves to be insufficient when extending it to real-world, heavily 3D-biased, applications. As such, in this project, I propose an alternative approach to the study of place cells in which a rat’s neuronal activity is wirelessly monitored while it is allowed to freely explore a lattice maze in all directions of Cartesian space. Most importantly, I aim to show that receptive fields are of similar sizes in the horizontal and vertical directions; I also hypothesise that concatenating receptive fields (RFs) from several place cells will yield a layered organisation with inter-RF distances being larger in the x-z/y-z planes than the x-y plane. Incidentally, this study will also provide data which I hypothesise will confirm the horizontal bias model in murine behaviour proposed by Jovalekic et al. (2011).

Amount: £0
Funder: The Wellcome Trust
Recipient: University College London

Developing a behavioural task for measuring the ability of listeners to perform auditory scene analysis. 27 Apr 2017

The auditory brain separates simultaneous sounds arriving at the ear into identifiable and localisable sources by a process known as Auditory Scene Analysis (ASA). The two steps that are involved in ASA are i) segregation of the simultaneous auditory information and ii) the integration of the sounds from the same source into one stream. To understand how these two steps are connected and how different auditory cues interact to shape the scene, this project will develop a behavioural task and analyse the performance of human listeners. A target vowel will be presented alongside with a distractor vowel, and human listeners will identify what the target is. Listeners will only be able to identify the target if they can separate the two sounds: changing the location and pitch of target and distractor will help this. In order find out whether the separation of competing sounds is facilitated by the formation of perceptual streams, the vowels will also be presented as part of a sound sequence. Our hypothesis is that the ability to identify a target vowel will be improved by the formation of two perceptual streams. The long-term goal is to develop a behavioural paradigm suitable for humans and animals.

Amount: £0
Funder: The Wellcome Trust
Recipient: University College London

Investigating the sleep modulating effect of oxytocin in zebrafish models of autism. 27 Apr 2017

In this project I will test the hypothesis that oxytocin expression and development of oxytocin-expressing neurons are altered in zebrafish with mutations in the ASD risk genes cntnap2 and chd8. I hope to find evidence for the sleep modulating effects of oxytocin, and posit whether deficiencies in oxytocin signalling pathways may contribute to sleep disorders in autism mutants. I will examine oxytocin mRNA levels across the day/night cycle for both wild-type and mutant fish established in the Rihel lab. I will then analyse the pattern of oxytocin expression in the brains of mutant embryos and their wild-type siblings. From the findings in related studies with cntnap2 mutant mice and the Rihel lab zebrafish models of autism (see references [3] and [6]), I expect to see an alteration in the amount of oxytocin mRNA for day/night between the wild-type and mutant embryos, and a change in the number of neurons expressing oxytocin. If such changes are found, they could explain the sleep phenotype observed in cntnap2 autism mutants, and elucidate a link between neuronal circuit dysfunction and behavioural perturbation in this animal model.

Amount: £0
Funder: The Wellcome Trust
Recipient: University College London

Africa Health Research Institute (GBP record) 6 month partial award 30 Jun 2016

Our aim is to reduce the huge burden of HIV and TB in KwaZulu-Natal as a precursor to the eradication of these diseases. This will be facilitated by merging the population based research excellence of the Wellcome Trust (WT)-funded Africa Centre (AC), with the cutting edge laboratory science and experimental medicine approaches of the Howard Hughes Medical Institute (HHMI)- funded KwaZulu-Natal Institute for Research in TB and HIV (K-RITH) to create an exciting, interdisciplinary South African based research initiative. Our 5-year vision is to use basic science, systems biology, health systems and social science research to undertake fundamental discoveries into the susceptibility, transmission and cure of HIV and TB. Our specific questions are: 1. How can new HIV infections best be eliminated? 2. How can TB transmission be interrupted and how can drug-resistance be contained? 3. How can the health of pregnant women with HIV and their offspring be improved? 4. How can we improve the health-system delivery and population-level impact of HIV treatment and other chronic disease care? 5. How is health and wellbeing affected by migration, economic and other inequalities

Amount: £472,230
Funder: The Wellcome Trust
Recipient: University College London

Africa Health Research Institute (GBP record) 30 Jun 2016

Our aim is to reduce the huge burden of HIV and TB in KwaZulu-Natal as a precursor to the eradication of these diseases. This will be facilitated by merging the population based research excellence of the Wellcome Trust (WT)-funded Africa Centre (AC), with the cutting edge laboratory science and experimental medicine approaches of the Howard Hughes Medical Institute (HHMI)- funded KwaZulu-Natal Institute for Research in TB and HIV (K-RITH) to create an exciting, interdisciplinary South African based research initiative. Our 5-year vision is to use basic science, systems biology, health systems and social science research to undertake fundamental discoveries into the susceptibility, transmission and cure of HIV and TB. Our specific questions are: 1. How can new HIV infections best be eliminated? 2. How can TB transmission be interrupted and how can drug-resistance be contained? 3. How can the health of pregnant women with HIV and their offspring be improved? 4. How can we improve the health-system delivery and population-level impact of HIV treatment and other chronic disease care? 5. How is health and wellbeing affected by migration, economic and other inequalities

Amount: £1,912,066
Funder: The Wellcome Trust
Recipient: University College London

Africa Health Research Institute (USD record) 30 Jun 2016

Our aim is to reduce the huge burden of HIV and TB in KwaZulu-Natal as a precursor to the eradication of these diseases. This will be facilitated by merging the population based research excellence of the Wellcome Trust (WT)-funded Africa Centre (AC), with the cutting edge laboratory science and experimental medicine approaches of the Howard Hughes Medical Institute (HHMI)- funded KwaZulu-Natal Institute for Research in TB and HIV (K-RITH) to create an exciting, interdisciplinary South African based research initiative. Our 5-year vision is to use basic science, systems biology, health systems and social science research to undertake fundamental discoveries into the susceptibility, transmission and cure of HIV and TB. Our specific questions are: 1. How can new HIV infections best be eliminated? 2. How can TB transmission be interrupted and how can drug-resistance be contained? 3. How can the health of pregnant women with HIV and their offspring be improved? 4. How can we improve the health-system delivery and population-level impact of HIV treatment and other chronic disease care? 5. How is health and wellbeing affected by migration, economic and other inequalities

Amount: £25,602,371
Funder: The Wellcome Trust
Recipient: University College London

BRAINEACv2: a resource for the interpretation of genetic variation in multiple regions of the adult human brain 16 Jun 2016

We aim to create BRAINEACv2, a resource for the investigation of the impact of genetic variation on gene expression in adult human brain. This resource will include three types of data: expression quantitative trait loci (eQTL), allele-specific expression and gene co-expression networks. Given the regional, cellular and molecular complexity of human brain, we believe there is a strong case for the creation of a tissue-specific resource. At present no comprehensive resource of this kind exists. However, our own public resource, BRAINEACv1, provides strong evidence for the popularity of such a resource with ~900 users from >80 countries accessing the website monthly. If funded BRAINEACv2 will represent a step-change improvement. It will include all 3 types of data described above (eQTL, ASE and co-expression networks), incorporate RNA-seq based gene expression quantification results and will include data from other major consortia (e.g. the North American Brain Expression Consortium). Given the success we have already demonstrated in creating a brain-specific resource for variant interpretation in human brain, we are well placed to deliver a new, comprehensive resource capable of meeting the growing interest in the understanding of the genetic regulation of gene expression in adult human brain.

Amount: £205,514
Funder: The Wellcome Trust
Recipient: University College London

Why do Norovirus pandemics occur and how can we control them? 05 Jul 2016

Noroviruses cause annual epidemics of gastrointestinal infection resulting in significant ill-health and disruption to health services. Frequent genetic mutation causing drift of epidemic strains and recombination leads to worldwide spread of pandemic strains. Approximately 3 million cases/annum occur in the UK with health-care costs exceeding £100M1. The advent of new vaccines against two genotypes is encouraging. However, ignorance about the drivers of norovirus strain evolution and spread is a barrier to effective vaccine design and deployment. This multidisciplinary consortium will investigate, through integrated studies, host and pathogen factors that lead to epidemic and pandemic norovirus spread and affect disease severity. Our international team has expertise in norovirus genome sequencing, phylogenetic analysis, norovirus antigen mapping, public health epidemiology and mathematical modelling. We will make use of existing clinical and public health datasets and samples, and an ongoing community study of norovirus burden to answer questions about transmission and carriage. Norovirus genome sequencing and phylogeography, in the context of international sequence-databases and antigenic mapping of sera will elucidate the origins and evolution of pandemic strains and outbreaks. Mathematical models, developed and fitted to the available data will provide novel insights into norovirus pathogenesis and transmission, informing vaccine design and immunisation strategies.

Amount: £2,825,452
Funder: The Wellcome Trust
Recipient: University College London

TREAT-HD: targeting neurodegeneration in Huntington's disease 08 Dec 2015

Despite their immense public health burden, and after considerable investment in therapeutics research, the pathobiology of neurodegenerative diseases remains poorly understood and we lack treatments to prevent or slow their progression. Our vision is to provide a step-change in the understanding of mechanisms underlying neurodegeneration – and recovery – using Huntington’s Disease (HD) as a model. Our three key goals are to: further understanding of HD neuropathology and its response to gene-silencing treatment. We will exploit a unique opportunity to link with the first human trial of an antisense oligonucleotide (ASO) to reduce levels of huntingtin protein. develop a new generation of ASO treatments by targeting levels of the highly pathogenic exon 1 mutant huntingtin protein. determine the earliest potential time window for therapeutic intervention. We will study a novel cohort of young adult HD gene-carriers decades before expected symptom onset to characterise the earliest signs of disease-related brain changes and identify early functional impairment. By examining this model disease in patients, we will gain understanding of general pathological processes shared across protein-misfolding neurodegenerative disorders such as Alzheimer's and Parkinson's disease. Consequently, this work has fundamental implications for the development of treatment strategies beyond HD to more prevalent neurodegenerative diseases.

Amount: £1,693,006
Funder: The Wellcome Trust
Recipient: University College London

TREAT-HD: targeting neurodegeneration in Huntington's disease 08 Dec 2015

Despite their immense public health burden, and after considerable investment in therapeutics research, the pathobiology of neurodegenerative diseases remains poorly understood and we lack treatments to prevent or slow their progression. Our vision is to provide a step-change in the understanding of mechanisms underlying neurodegeneration – and recovery – using Huntington’s Disease (HD) as a model. Our three key goals are to: further understanding of HD neuropathology and its response to gene-silencing treatment. We will exploit a unique opportunity to link with the first human trial of an antisense oligonucleotide (ASO) to reduce levels of huntingtin protein. develop a new generation of ASO treatments by targeting levels of the highly pathogenic exon 1 mutant huntingtin protein. determine the earliest potential time window for therapeutic intervention. We will study a novel cohort of young adult HD gene-carriers decades before expected symptom onset to characterise the earliest signs of disease-related brain changes and identify early functional impairment. By examining this model disease in patients, we will gain understanding of general pathological processes shared across protein-misfolding neurodegenerative disorders such as Alzheimer's and Parkinson's disease. Consequently, this work has fundamental implications for the development of treatment strategies beyond HD to more prevalent neurodegenerative diseases.

Amount: £796,863
Funder: The Wellcome Trust
Recipient: University College London

The Countdown to 2030: Global Health and Climate Action 30 Sep 2016

Climate change threatens to undermine the foundations of human wellbeing, and to reverse the last five decades of gains in global health. The 2015 Lancet Commission on Health and Climate Change concludes that the barriers to tackling climate change and improving public health are no longer economic or technological, but largely political. The report also concludes that "tackling climate change could be the greatest global health opportunity of the 21st century", with reduced greenhouse gas emissions yielding substantial health (and economic) gains. The Commission is an institutional collaboration between European and Chinese academic centres, led by University College London, Tsinghua University (Beijing), the University of Exeter, and Sweden’s Stockholm Resilience Centre and Umea University. It published its work on the 23rd of June, 2015 in The Lancet, with 11 launch events around the world. The authors of the Commission report recognise the need to carry their work forward- and to help deliver the required change. They propose a "Countdown to 2030: Global Health and Climate Action" as a mechanism for tracking progress on the implementation of policies designed to respond to climate change and protect public health. This idea draws upon the success of the Countdown to Child Survival, which galvanised evidence, interest and action to improve progress on child mortality over the past decade. The Countdown will exist as an independent, international, and multi-disciplinary coalition of organizations. The combined networks of The Lancet and the partner institutions will be utilized to ensure global reach to academics, policymakers, and the health community. It will produce an annual synthesis report on (i) the health impacts of climate change; (ii) progress in mitigation policies and the extent to which they protect and promote public health; (iii) progress with broader adaptation action to reduce population vulnerability, to build climate resilience, and to implement low carbon, sustainable health systems. The Countdown will continue its collaboration with The Lancet, who commit to publishing these Countdown Reports, as well as a number of related country- or issue-specific articles throughout each year.

Amount: £499,186
Funder: The Wellcome Trust
Recipient: University College London

Behavioural role and neural representation of temporal dynamics in sensory stimuli. 02 Dec 2015

The external world is not static but in a constant state of flux. To understand how the brain functions, we, therefore, must investigate how it extracts relevant information from dynamic, highly fluctuating sensory signals. Olfaction is an ideal modality with which to study this question. A key sense for nocturnal and crepuscular animals, such as laboratory rodents, the comparatively simple anatomy of the early olfactory system makes it highly accessible and tractable. Turbulent airflow creates a rich temporal structure in the intensity fluctuations of natural odour stimuli. Yet, how these dynamics are processed by the olfactory system and the extent to which it uses or ignores this information remains unknown. I have recently established quantitative behavioural tools, genetic and optogenetic manipulation of the early olfactory system, electrophysiological and imaging approaches in the awake behaving mouse, and the tools to measure and generate temporally fluctuating olfactory stimuli with high bandwidth. We will now combine these approaches to tackle key questions relating to the significance of natural dynamics for the coding of sensory stimuli. 1: What information is contained in the dynamics of natural olfactory stimuli?2: To what extent do neurons represent such dynamics? 3: How are stimulus dynamics used for behavioural tasks such as navigation? 4: What are the circuits and mechanisms that support, extract information from, or compensate for stimulus dynamics? My guiding hypothesis is that temporal dynamics and coherence of natural smells are decoded by the circuitry of the early olfactory system to extract information about distance, location and the nature of olfactory objects and scenes.

Amount: £1,627,188
Funder: The Wellcome Trust
Recipient: University College London

Personalising the pharmacological treatment of bipolar disorder 23 May 2018

Background Prescribing for bipolar disorder is a major clinical dilemma as long-term pharmacological treatment is often necessary. Lithium is the most effective mood stabiliser. However, only 30% of individuals have a good therapeutic response. Presently, there is no reliable way to predict response or adverse event risk, or if an alternative treatment would be better for that patient. Aim To personalise prescribing for people with bipolar disorder via prediction models that quantify potential benefits and risks of existing treatments based on clinical phenotypic characteristics of the individual. Objectives Identify individualised clinical predictors of lithium and second-generation antipsychotic response. Determine clinical predictors of chronic kidney disease in individuals taking lithium. Determine clinical predictors of pathological weight gain in individuals taking second-generation antipsychotics. Methodology Data sources Swedish population registers, Hong-Kong health registers, Taiwanese health insurance database, UK primary care data linked to secondary care admission records, and UK mental health care data. Analyses Traditional epidemiological and machine learning methods; drawing on the strengths of each approach. Prediction model generation I will combine predictors from different datasets; resulting in models predicting drug response, chronic kidney disease and weight gain. Application Prediction models will be presented as online and smartphone application clinician decision aids.

Amount: £460,704
Funder: The Wellcome Trust
Recipient: University College London