- Total grants
- Total funders
- Total recipients
- Earliest award date
- 17 Oct 2005
- Latest award date
- 30 Sep 2020
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
This proposal examines the neural mechanisms supporting decision-making and prospective planning. We will examine how prefrontal cortex (PFC), hippocampus, and entorhinal cortex (EC) interact to support these processes. We will examine how non-human primates (NHPs) make choices in large decision spaces, particularly when novel choice-values have to be inferred ‘online’. We will test different models of value-coding, particularly whether PFC uses a ‘place-like’ and ‘grid-like’ code to construct cognitive maps of values spaces. We will examine how NHPs make ‘online’ choices when sequentially navigating between stimuli/states as rewards move or paths blocked. We will test whether ‘replay’ provides a neural mechanism supporting model-based planning. We will use Transcranial Ultrasound Stimulation to selectively disrupt regions of PFC/hippocampus/EC to examine its effect on neural selectivity and behaviour. These tasks are high-dimensional, yet amenable to mathematical description, and will be combined with high-density recordings to map these computations. Exp.3 will integrate our home-cage training system with wireless data-logging to record neural data continuously, across tasks and sleep, to examine how neural signatures change across days with learning, and acquisition of ‘learning set’. This provides the technology to continuously map the NHP brain during performance of diverse and naturalistic tasks, radically transforming primate neuroscience.
Many severely and profoundly deaf children struggle to learn to read because written text is a visual representation of spoken language, to which they have limited access. I have shown that speechreading (lipreading) relates to deaf children’s reading development. Fully understanding the mechanisms underlying the speechreading-reading relationship is fundamental to harnessing speechreading as a tool to improve deaf children’s reading. My goal is to investigate this mechanism in 1) a longitudinal study, to determine the relationships between speechreading, phonological skills, language skills and reading over time and 2) in neuroimaging studies with deaf children and adults to investigate neural representations of visual speech and written text and the relationships between them. All deaf participants involved in the studies above will use speechreading. A subset will also have learned British Sign Language from an early age. Good quality early sign language exposure is beneficial to reading development in profoundly deaf children. However, the mechanism underlying this relationship is unclear. I will employ parallel methods to those used in the speechreading studies to examine 1) the longitudinal relationships between sign language, fingerspelling and reading and 2) the neural representation of these visual language inputs in deaf children and adults.
Animals accomplish goal-directed behaviours by performing sequences of motor actions. A central goal of neuroscience is to understand how neural circuits regulate behaviour in accordance with external events and internal drives and precisely choreograph diverse actions for a successful outcome. To meet this challenge, I will exploit the unique accessibility of the larval zebrafish and focus on a conserved behaviour – hunting – in which a sequence of discrete, specialised actions mediates pursuit and capture of prey. I will use a powerful experimental strategy that combines cellular-resolution calcium imaging, behavioural analyses, optogenetic circuit manipulations, neuroanatomical tracing and computational modelling to discover how brain-wide circuits operate at the cellular level to flexibly control the expression and coordination of behaviour. This paradigm will enable me to discover (1) how sensory and internal state information are integrated to control the sensorimotor decision to hunt, (2) how specific hunting actions are generated and (3) how command signals operate alongside dynamic sensory inputs to assemble a goal-directed sequential behaviour. Overall, the project will produce a mechanistic, cellular-resolution circuit model that explains how the brain controls and patterns multi-component behaviour. I expect this will reveal fundamental principles about the operational logic of the nervous system.
During development the embryo needs to generate functional organs composed of many different cell types, often originated in different embryonic location. Thus, it is clear that cell differentiation and migration need to be tightly coordinated, although they are often studied as independent processes. Here I will test the hypothesis that cell migration and differentiations are coordinated by tissue mechanics in vivo. Specifically, I will challenge the current view that cell migration is the result of differentiation, by testing instead whether the reverse occurs, i.e. migration controls differentiation. I will use neural crest cell, a multipotent embryonic cell population in which cell differentiation is always linked to cell migration. One of the problems to study biomechanics in vivo is the limited number of tools to measure and modify mechanical properties in vivo. Here I will develop new tools to analyse and change tissue stiffness in vivo. We will analyse how these mechanical changes influence cell migration and differentiation, and we will identify the molecular response elicited in the neural crest cells. We expect that this multidisciplinary project will provide answers to a central yet unresolved question in developmental biology: how cell fate and migration are integrated during embryo development.
The Impact of Pneumococcal and Malaria Vaccines on Bacterial Resistance, Febrile Illness and Antibiotic Usage in Young Children In Malawi 30 Nov 2019
Across much of sub-Saharan Africa, pneumococcal disease (otitis media and pneumonia) and malaria are leading causes febrile illness, and therefore drivers of both appropriate and inappropriate antibiotic use. Prevention through vaccination has the potential to influence antimicrobial resistance (AMR) both directly and indirectly. We are in a unique position to leverage two large funded cluster-randomised vaccine evaluations in Malawi: 13-valent pneumococcal conjugate vaccine (PCV13) schedule change (3+0 to 2+1; extending immunity and potentially herd protection); and RTS,S malaria vaccine introduction. We will ask what are the direct and indirect selective effects of pneumococcal and malaria vaccines on antibiotic resistance, febrile illness and antibiotic usage in young children in Malawi? We will determine whether in children S. pneumoniae carriage isolates; the upper respiratory tract resistome; and stool carriage of extended spectrum beta-lactamase (ESBL) E. coli or Klebsiella. We will assess whether the pneumococcal or malaria vaccines alter the frequency of febrile illness and antibiotic use in children
The Biosocial Lives of Birth Cohorts 28 Jan 2020
This four year project examines birth cohorts as sites of knowledge, practice and participation in the UK, Europe and Latin America. It aims to understand how they provide an infrastructure for and are a technology of biosocial science. It is the first study to take birth cohorts as an object of ethnographic inquiry in comparative national contexts. In an era of post-genomics, studies that follow research participants over their lifetimes have become vital to understanding how material and social environments ‘get under the skin’ and are dynamically shaped across the lifecourse. This is increasingly described as ‘biosocial science’, reflecting the importance to this field of the interaction between social and biological factors. Whilst a notion of the biosocial is not new, singular nor uncontested it is now being re-shaped in global research terrains with longitudinal cohort studies as important tools and technologies. By examining the ‘biosocial lives’ of birth cohorts in the global north and south, I will provide insight on the socio-cultural specificity of these developments. Comparison will inform theorisation of what the biosocial is, whilst an ethnographic perspective will facilitate methodological innovation in examining and intervening on birth cohort research and how biosocial science is coming into being.
Seizures are a common manifestation of brain injury in newborn infants. Controversies still exist over whether seizures may themselves cause further damage to the developing brain, when to treat them, what drugs to use and how to improve detection. There is an urgent need for a better understanding of the pathophysiological changes to improve our management strategies. My key goal is to assess the impact of seizures on the newborn brain. I propose to use a new optical platform (combined broadband near-infrared spectroscopy and diffusion correlation spectroscopy) for a comprehensive real-time assessment of cerebral metabolism (using oxCCO and CMRO2), haemodynamics (using CBF and CBV) and oxygenation (using TOI) together with video-electroencephalography(EEG) at the cot-side to investigate seizure-induced changes inside brain. I aim to deliver a translational and clinical strategy to investigate these changes in healthy brains of an animal model and in a cohort of babies in neonatal intensive care who developed seizures after brain injury. I will further investigate the impact of phenobarbitone on brain metabolism and haemodynamics. Short and long-term impacts will be assessed with neuroimaging and neurodevelopmental outcome data. These findings will improve our understanding and will support an evidence-based approach for the management of neonatal seizures.
Inhibitory control of visually-guided behaviour 03 Dec 2019
The brain utilises cortical and subcortical pathways to transform sensory information into action, giving rise to learned and instinctive sensory-guided behaviours. How these pathways interact to generate flexible behaviour, allowing animals to react differently to the same environmental stimuli depending on circumstance, remains poorly understood. We propose that inhibitory circuits in the thalamus are essential for flexible control of sensory-guided actions. Our pilot data show that the ventral lateral geniculate nucleus (vLGN) - a prethalamic structure composed of different classes of inhibitory projection neurons - provides inhibitory control of an instinctive visually-evoked behaviour. We will identify the neural circuit mechanisms of this control and determine when it is engaged. Moreover, since the vLGN is extensively connected with visual circuits in the neocortex and the midbrain, we will test if and how this nucleus can coordinate these visual pathways to guide both instinctive and learned visually-guided behaviours. We will achieve these aims by combining genetic tools with calcium imaging, electrophysiological recordings, cell-type specific optogenetic manipulations and quantitative behaviour in animals performing visually-guided tasks. This work will generate detailed understanding of mechanisms by which the brain can orchestrate behavioural responses to environmental stimuli.
Hearing is critical to human communication and intelligence. The cascade of neuronal processes that enable hearing remain poorly understood, particularly in computational terms. These gaps in knowledge limit our ability to design treatments for hearing impairment. The proposed research has three goals. First, to develop new computational models that can account for human perceptual abilities and neuronal responses. Second, to reveal representational transformations within auditory cortex that contribute to auditory recognition. Third, to use these models to develop auditory prostheses that augment human hearing. The overarching hypothesis is that the functional organization and tuning properties of the auditory system are constrained by ecologically important tasks (speech recognition, sound localization etc.), such that task-optimized models may converge to the structure of the auditory system. We will leverage deep learning to develop new neural network models of auditory computation. These models will be evaluated for their matches to behavior and brain data using sound synthesis methods introduced by the PI. Candidate hearing aids will then be derived by backpropagating recognition errors through the model to optimize a front-end audio transformation. Such audio transformation should restore model performance given an impaired model cochlea. We will then test their benefits for hearing-impaired listeners.
The cerebral vasculature and glial cells play crucial but poorly understood roles in initiating Alzheimer’s disease (AD) and related dementias, contributing to cognitive decline via a loss of synapses and neurons. We have shown that: (i) a major reduction of cerebral blood flow occurs early in human AD because oligomeric amyloid beta (Aß) evokes constriction of brain capillaries by contractile pericytes; (ii) the blood flow reduction in AD may reflect microglia controlling pericytes; (iii) microglia-mediated phagocytosis, which removes both Aß and synapses, is regulated by ion channels and receptors; (iv) decreased blood flow and AD alter node of Ranvier length in myelinated axons, which will change axonal conduction speed and thus neural circuit function. Now, focusing on Aß and decreased blood flow, we will investigate how vascular and glial function contribute to dementia, by: (A) defining the mechanisms underlying Aß-evoked capillary constriction, and developing therapeutic approaches to restoring blood flow; (B) characterising how microglia and astrocytes remove Aß and synapses, and investigating how to control this; (C) studying how Aß and decreased blood flow damage myelin and nodes of Ranvier, and how to prevent this. Together, this work will identify novel non-neuronal therapeutic targets for treating dementia.
Several long non-coding RNAs (lncRNAs) are capable of scaffolding ribonucleoproteins (RNPs) that condense and phase-separate nuclear membraneless compartments. Both, lncRNAs and RNPs play many key regulatory roles in development and their function in cell fate choice is further enhanced by their cross-regulation. To demonstrate the importance of such cross-regulation for fine-tuning developmental decisions I will build a framework of experimental and computational methods to study how lncRNAs scaffold nuclear RNP compartments and hence understand how interactions between lncRNAs and RNPs within these compartments create networks that coordinate molecular processes in early development. To interrogate the developmental role of these network motifs between lncRNAs and bound RNPs, I will also establish new tools that allow rapid manipulation of lncRNA condensation in advanced in-vitro embryogenesis system. Collectively, this proposal will reveal the cross-regulatory mechanism of nuclear rewiring by lncRNA condensation that plays a role not only in development, but when perturbed, could also be implicated in diseases such as ALS and cancer.
Neuro-computational mechanisms of information acquisition and integration in social contexts 06 Nov 2019
Understanding the social cognitive mechanisms that enable people to learn from and interact with others has been of considerable interest to psychologists and neuroscientists for decades. Yet, the mechanisms underlying our ability to gather information from other people and to learn from them by integrating this information into our beliefs remain to be elucidated. Here, I proposed to use a neuro-computational approach, combining behavioural experiments, neuroimaging, brain stimulation, and computational modelling to provide an integrated framework of how information acquisition and integration are influenced by social contexts. Three key questions form the core of this proposal: How are choices of information sources influenced by social confirmation bias? How do people learn from misinformation in social contexts? How do these social influences interact with anxiety? Across four studies in three international sites, this research will (i) further our understanding of the behavioural and neural mechanistic computations underlying these processes, (ii) determine the causality of the neural mechanisms, and (iii) elucidate how these computations vary with psychiatric symptoms. Addressing these questions will not only contribute to advancing multiple disciplines, from social neuroscience to behavioural economics, but also has potential implications for wider societal questions, from mental health to policy−making.
Understanding and predicting individual differences in cannabis-induced psychosis-like experiences 06 Nov 2019
Acute pharmacological challenge and observational studies in humans have shown that cannabis can induce psychosis-like experiences. However, not all individuals exhibit adverse experiences, implicating individual differences in cannabis-sensitivity. While a number of studies implicate a genetic contribution to cannabis-sensitivity, such evidence relies on genetic variables of limited interpretability, such as pre-selected candidate genes for schizophrenia or family history of schizophrenia. So far, there is no genome-wide evidence exploiting advanced methods from genetic epidemiology to elucidate the role of (genetic) vulnerabilities in cannabis-sensitivity. Furthermore, there is no evidence as to whether prediction models can effectively identify those at high risk for cannabis-sensitivity. The lack of evidence highlights the need for more research on this subject. To advance the study on cannabis-sensitivity, my project has four main objectives: to systematically summarise the available evidence on factors associated with cannabis-sensitivity, to employ advanced genomic association and functional analyses to study biological pathways underlying cannabis-sensitivity, to apply cutting-edge genetically informed inference methods (e.g. Mendelian randomization) to study the role of individual vulnerabilities (schizophrenia liability) and traits (e.g. neuroticism liability) in cannabis-sensitivity and to use machine learning approaches to develop and evaluate prediction models for cannabis-sensitivity. Keywords Cannabis Psychosis Genetic Epidemiology Prediction Causal Inference
The way we perceive the world is strongly influenced by our expectations about what we are likely to see at any given moment. However, the neural mechanisms by which the brain integrates sensory inputs and expectations, and thereby generates the contents of perception, have yet to be established. I propose that, upon presentation of a predictive cue (e.g., a siren), memory systems pre-activate templates of expected stimuli (an ambulance) in the deep layers of visual cortex, leading to biased processing of sensory inputs from the very moment they arrive. Such biased processing then leads naturally to biases in perception, in extreme cases even hallucinations. I will test this proposal by addressing three complimentary questions: 1) How do the neural computations underlying perception unfold over time? 2) What is the fundamental computational architecture of visual cortex? 3) What is the neural source of expectations? I will combine psychophysical tasks probing participants’ perception with neuroimaging tools with exquisite temporal (MEG) and spatial (high-field fMRI) resolution to address these questions. The overarching aim of my research is to provide a mechanistic account of subjective perception. Ultimately, these insights may improve our understanding of clinical disorders characterised by aberrations in perception, such as psychosis.
Sex education can positively impact upon sexual behaviour and reduce the likelihood of adverse sexual health outcomes, but the quality of provision and coverage of topics is variable. There is a need for evidence-based ways to improve knowledge of sex and relationships that speak to people across the lifecourse and from all walks-of-life. Uniting internationally-recognised scientists in sexology, epidemiology, and education, with the UK’s leading charities (Brook and the Sex Education Forum) promoting young people’s sexual health and the delivery of quality life-long relationship and sex education (RSE), we will use creative arts and online technologies to produce innovative resources that meet this need. Evidence from Britain’s nationally-representative sexual health survey (the National Survey of Sexual Attitudes and Lifestyles, ‘Natsal’) and our previous public engagement will be used: (i) to create a free-to-use interactive online resource for the general public, allowing exploration as to what is ‘normal’, the factors that shape sexual lifestyles, and the underpinning scientific research; (ii) as a catalyst to facilitate dialogue with and between young people on issues around sex that matter to them. This young people-centred learning will be translated into resources to better equip teachers to deliver RSE, crucially coinciding with the introduction of mandatory RSE in schools in England (2020) and Wales (2022). These evidence-based tools will empower people of all ages to improve their knowledge of sex and relationships, their sexual health and wellbeing. They will also demonstrate proof-of-concept around novel mechanisms for engaging the public with Natsal and science more broadly.
Learning as Bayesian Influence 11 Mar 2020
The Imbizo is a 3-week long summer school designed to connect young African computational neuroscientists with the international community. Computational Neuroscience (CN) is underdeveloped as a research field in Africa. The Imbizo is changing this, providing educational and career development opportunities in a place where they are very scarce. We are applying for continued funding to run the Imbizo for the years of 2021-2023, in Cape Town, South Africa. The Imbizo brings together world leaders in CN and machine learning with approximately 18 African and 12 non-African students. Students come from diverse quantitative backgrounds including computer science, mathematics, physics and engineering. These disciplines are strong in several African countries. The intensive course comprises of lectures, tutorials, coding and brainstorming sessions. Extra-curricular team building and networking opportunities also take place. We organise workshops and surgeries on grantsmanship, manuscript writing, and CV clinics to prepare candidates for future job applications. After 18 days of intense course work, we will have exposed some of Africa’s most talented analytic students to a new field and helped them build networks with experts. We will create opportunities for students from relatively disadvantaged institutions to move into CN and potentially grow collaborations and develop their skills and scientific ideas. Every year we see more students take up internships and graduate school positions that would have not been available to them without the Imbizo. This is a direct injection of diversity into the international CN community, and an investment in Africa’s CN future.
This project will investigate a mechanism for regulating cAMP-dependent protein kinase (PKA) that is not founded on cAMP fluctuations. Neuronal PKA activity is largely dictated by rates of binding and release of PKA catalytic subunits from inhibitory type II regulatory (RII) subunits. The balance of these rates determines the fraction of free catalytic subunits. According to the canonical model, reductions in PKA activity follow from decreases in cAMP concentration since cAMP-free RII subunits bind catalytic subunits with higher affinity. Dephosphorylation of a serine in the RII autoinhibitory sequence also generates a form of RII with higher affinity for catalytic subunits, but no plausible mechanism has been uncovered that involves regulation of this site. We will investigate whether anchoring of phosphatases in complex with RII subunits enables suppression of PKA activity by shifting the Michaelis constant for RII dephosphorylation into the physiological range. We will build and test models of neuronal PKA signalling to understand the kinetic basis of this mode of PKA regulation. We will examine whether RII dephosphorylation within a synaptic signalling complex is necessary for the induction of long-term depression of synaptic strength. Finally, we will investigate interplay between Ca2+ signalling and this novel form of PKA regulation.