- 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.
Exploring mitochondrial metabolism in health and disease using targeted biological chemistry 31 Mar 2020
The molecular mechanisms by which mitochondrial reactive species, metabolites and redox signals contribute to physiology and pathology are unclear. This is in large part because these processes are difficult to assess and modulate in vivo. Our goals are to establish general chemical biology approaches to determine the mechanisms of mitochondrial physiology and dysfunction in vivo and from this develop new therapeutic strategies. The aims are based on the success of our previous Joint Investigator Award, but the specific chemical biology approaches to be used, the insights to be attained and the models have been refined and developed, based on our work over the past four years. These goals will be achieved by addressing three research challenges in cells and in vivo: A: Can we determine how mitochondria operate during normal physiology, and are disrupted during pathology, by targeting probes to measure reactive species and alterations to signaling pathways? B: Can targeting bioactive molecules to mitochondria prevent pathological disruption of mitochondrial function and generate potential therapies? C: Can the above methods to monitor and modulate mitochondrial function be assessed in animal models of human diseases and thus drive the development of rational, translatable therapies?
Proteins entering the secretory pathway at the endoplasmic reticulum (ER) undergo a vast array of post-translational modifications some of which are essential for correct folding, assembly and secretion. Failure to fulfil these functions results in several diseases due to the lack of secretion of proteins such as insulin and antibodies, or due to cell death triggered by an unfolded protein stress response. The ER provides a unique environment for protein modifications such as disulfide formation and glycosylation. To ensure efficient protein folding and secretion the cell maintains the environment within the ER that ensures these processes occur efficiently and reacts to situations of cell stress. This proposal builds on exciting new observations from my group to dissect molecular mechanisms involved in secretory protein biogenesis. Our particular focus will be on how the cell maintains ER redox balance, how the repertoire of ER folding factors orchestrate correct protein folding and N-linked glycosylation and how the UPR sensor ATF6 is activated following proteotoxic stress. Our aims will be achieved using a combination of innovative new technological approaches and previously established robust assays to follow protein folding and assembly in both reconstituted and cellular systems.
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.
Identification of genomic components that predict transmission of the malaria parasite in different vector species 04 Mar 2020
The malaria parasite (Plasmodium falciparum) has a complex life cycle in which it must transit through multiple environments in a vertebrate host and mosquito vector. Transmission begins with ingestion of an infectious blood meal by one of 40 potential Anopheles mosquito species capable of transmitting the disease. This initiates the most extreme population bottleneck in the life cycle in which the parasite must rapidly undergo fertilisation, develop into an invasive form and transit through the midgut epithelium. The overarching goal of this proposal is to understand how this transmission through the mosquito vector drives selection on the parasite. I hypothesise that parasites have adapted to their local vector community composition, and this shapes their ability to infect sympatric and allopatric vector species. Using large-scale transmissibility assays and single-cell RNA-sequencing, I will identify genomic and transcriptomic vector-dependent signatures of transmission. I will then generate allelic-replacement parasites to unambiguously attribute phenotypic variation in species-specific transmission to specific loci in the parasite. Comprehensively understanding how vector communities shape parasite populations will guide future interventions and vector control programs by providing information that will allow for strategies to be locally tailored based on parasite genomic-surveillance and entomological surveys.
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.
The proposed research aims to (i) build fundamental understanding of mechanisms of immune evasion by helminth parasites, (ii) explore helminth modulation of the intestinal tissue niche; and (iii) to develop a new strategy towards vaccination to prevent infection. Helminths exploit a key immunological pathway within the immune system to induce suppressive regulatory T cells, and dampen innate effector cells. We have discovered a key player to be a novel parasite mimic of TGF-beta (TGM), which we will analyze structurally and funtionally on (i) immune cells and (ii) intestinal epithelium. The intestinal environment will be modelled through organoids (enteroids) in which parasites can modify stem cell differentation and therefore epithelial composition; we will investigate whether this is caused by TGM or an unrelated mediator. To promote immunity to infection, we focus on extracellular vesicles (EVs) released by parasites, which we have shown inhibit innate cell activation but can be neutralised by specific antibodies. In this model, antibodies to EVs direct them to uptake by phagocytes and lysosomal degradation, abolishing the inhibitory effect on immune cells. Taken together, the research will define how helminths may modify host signals and pathways, and how we may best interrupt this process to achieve protective immunity.
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.
Spinal circuits underlying pathological pain 03 Dec 2019
Allodynia and hyperalgesia occur in neuropathic and inflammatory pain states, and depend on circuits involving dorsal horn excitatory interneurons. Recent studies have identified several neurochemical/transcriptomic populations among these cells. We will use a multi-disciplinary approach, involving molecular-genetic targeting of these populations, to investigate their involvement in pain mechanisms at circuit and behavioural levels. We have found that neurons expressing gastrin releasing peptide receptor (GRPR) correspond to vertical cells, which transmit information to lamina I projection neurons, and are implicated in both neuropathic and inflammatory pain. We will use anatomical, electrophysiological and behavioural approaches to determine whether the GRPR cells fulfil this role. If not, we will investigate another population defined by expression of neuropeptide FF. Cells with PKCgamma are critical for neuropathic allodynia, but these can be assigned to two populations that express neurotensin or cholecystokinin. We will determine whether these are functionally different, and whether both contribute to allodynia. Finally, we will establish whether any other excitatory interneurons are interposed between PKCgamma cells and vertical cells in the pathway for tactile allodynia. The study will provide important information about synaptic circuits for pain, and the roles of different interneuron populations. Keywords: pain, spinal cord, neuronal silencing, chemogenetics, optogenetics
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.