NIHRDataInsights/HRCSData huggingface dataset:
Title: Cellular and molecular mechanisms of behaviour.
Funder: Medical Research Council

Abstract: Elucidating the mechanisms by which nervous systems process information and generate behaviour is among the fundamental problems of biology. Ultimately, it is desirable to understand these processes at the most basic level, that of molecules and cells. We are investigating these questions using the nematode Caenorhabditis elegans, which has an anatomically simple and well-defined nervous system and is tractable to molecular and classical genetic analysis. Using recently developed methods for in vivo optical neuroimaging, we are investigating how the activities of individual neurons correlate with behaviour, and how genes with interesting behavioural phenotypes affect the activities of individual neurons in defined neural circuits. We are particularly interested in molecules that mediate responses to mechanical, chemical or noxious stimuli. We are using a combination of genetic, molecular, and neuroimaging approaches to elucidate the mechanisms by which neurons sense aversive stimuli such as touch, salty and sour taste, and noxious chemicals. Of particular interest are the TMC proteins, which function in vertebrate hearing as well as touch and taste in nematodes. We are investigating how these detect sensory stimuli to control neural activity, and exploring the roles of uncharacterised TMC proteins from vertebrate genomes in transgenic C. elegans. Since these and other sensory transduction mechanisms are known to be evolutionarily conserved between nematodes and humans, these studies will provide important insights into general mechanisms underlying the sensation of touch, hearing, taste and pain, and identify genes potentially involved sensory neuropathies in humans. We are also exploring how the neural circuitry integrates sensory stimuli from different sensory pathways to control behaviour, and how these behaviours are modified by the animal's experience. In particular, we are interested in the roles of electrical synapses and extrasynaptic modulation in neuronal circuits. These connections are understudied compared to chemical synapses, but they play important roles in the connectome; for example, gap junction microcircuits function as coincidence detectors in sensory integration, while a network of extrasynaptic neuropeptide signaling mediates arousal. We anticipate that these studies will reveal fundamental principles of neural circuit function that are the foundation of computation in bigger nervous systems.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Understanding and preventing the deposition of misfolded proteins
Funder: Medical Research Council

Abstract: Neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD) and Amyotrophic Lateral Sclerosis (ALS) are devastating and affect an increasing number of individuals in the ageing population. Theses diseases are caused by the progressive dysfunction and death of specific nerve cells in selective regions of the brain due to the accumulation of specific proteins of aberrant shape. The disease-causing proteins are expressed throughout life but neurodegenerative diseases are mostly late-onset. This suggests that the different disease-causing proteins gradually become detrimental over time. While it is now well established that misfolded proteins cause distinct neurodegenerative diseases, why they accumulate remains largely unclear. Cells normally strive to ensure that proteins get correctly folded and indeed all cells have powerful and sophisticated protein quality control systems that very efficiently handle potentially harmful proteins for decades. However, the protein quality control mechanisms seem to gradually fail with age, leading to the accumulation of misfolded proteins with the resulting catastrophic consequences for cells and organisms. My long-term goal is to understand the mechanisms that govern the deposition of misfolding-prone proteins, why they persist in aged cells and to identify strategies that could reduce the burden of misfolded proteins for cells and organisms. My work focuses on fundamental cell biological processes with the view that some of our discoveries will benefit human health.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Neural circuit basis of olfactory perception in Drosophila
Funder: Medical Research Council

Abstract: The long-term motivation of our work is to understand how neural circuits process sensory information and transform this into behaviour. We are particularly interested in behaviours that are encoded in the genome through the specification of the development and function of neural circuits. We use the olfactory system of the fruit fly as a model system. Our strategy is to combine high-resolution neuroanatomy down to the level of single identified neurons with targeted in vivo neurophysiology and behavioural analysis. Olfactory receptor neurons project axons to form a highly stereotyped olfactory map in the first olfactory centre in the brain, the antennal lobe. Second order neurons, called projection neurons, relay this information to two higher olfactory centres, the lateral horn and the mushroom body. The mushroom body is required for olfactory learning but apparently dispensable for innate olfactory behaviour. We are therefore focussing our efforts on the lateral horn. We hypothesise that this poorly characterised brain centre is where odour information starts to be transformed into a representation appropriate to instruct behaviour. Using genetic cell labelling and image registration to combine data from multiple brains, we have produced a comprehensive map of sex differences in the wiring of the fly brain. We identified sexually dimorphic higher order olfactory neurons that are likely to underlie sex-specific olfactory behaviour. Detailed analysis defined a novel circuit element, a bidirectional circuit switch in the brain, for the first time in any animal. This switch re-routes pheromone information between two target neuron populations and may underlie sex-specific behavioural response to pheromones. Ongoing work includes complementary investigations of general odour processing in the lateral horn, where we find neurons with a huge range of tuning properties. The lab also continues to develop new technologies in support of our scientific questions, that should be of widespread utility. These include methods for ultra-rapid tissue labelling along with computational tools to map and compare neuronal structures. Future work will dissect the developmental basis and behavioural significance of the sexually dimorphic switch we have identified. We will also follow the processing of non-pheromone odours that appear to have substantial innate odour significance. We will study behavioural and neuronal integration of coincident positive stimuli (such as food and pheromone) and stimuli of opposite valence. We will also investigate the relationship between learned and innate odour responses. Finally we will continue our work in genetic and computational methods development.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Nitric oxide mediated toxicity in neurodegeneration and disease
Funder: Medical Research Council

Abstract: This programme aims to investigate cell signalling pathways involved in Nitric Oxide (NO)-induced neurotoxicity and identify putative targets for therapeutic intervention(s). Abnormal NO signalling has been implicated in several neurodegenerative diseases related to misfolded proteins or induced by exogenous factors such as pesticides (i.e. organophosphates, OPs) but its exact contribution to neuronal death remains elusive due to the great complexity of downstream nitrergic targets. Elevated NO levels, as seen in many diseased states, can lead to the formation of cytotoxic peroxynitrite (ONOO-) which in turn can directly modulate a wide range of protein functions via nitration of tyrosine residues (3-Nitrotyrosination). Furthermore, at higher concentrations, toxic NO signalling can alter the functioning of proteins in a process known as S-nitrosylation. Both signalling pathways have been widely reported, rendering it of similar functional importance to phosphorylation and ubiquitination processes. The key aim of this proposal is the identification of substrates subjected to this regulation by nitrergic signalling pathways. To date, little is known as to what extent NO-mediated post-translational modifications contribute to or exacerbate neuronal dysfunction. The identification of novel nitrergic signalling pathways and correlation with early functional changes prior to any disease onset will allow a better understanding of cytotoxic NO signalling.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Human brain development in cerebral organoids
Funder: Medical Research Council

Abstract: The overall aim of this programme will be to identify and characterize unique characteristics of human brain development that pertain to its evolution and the pathogenesis of human neurological disease. To this aim, we will make use of a newly established in vitro method, termed cerebral organoids, which recapitulate many aspects of human brain development that cannot be studied in model organisms. We will take a comparative genetics approach to identify candidates in human brain evolution and test their functional roles in human brain development using this powerful method. We will additionally target candidates in human neurological diseases, such as autism and intellectual disability, and test their potential roles in brain pathology associated with these disorders. The initial phase of this programme involves genetic analyses. We will take a comparative genetic approach to identify candidate genes in human compared with closely related primates that may play a role in brain size determination. Additionally, we will make use of genetic analyses of human patients with developmental neurological disease to identify candidates in pathogenesis of brain malformations affecting size or morphology. Initially, we will focus on microcephaly, macrocephaly with autism, and lissencephaly. The second phase will make use of modern gene-editing technologies, such as CRISPR, to target candidates in human pluripotent stem cells. We will focus on 10-20 candidates initially, with the potential for scaling up using a CRISPR based screening approach. Mutant pluripotent stem cells will then be used to generate cerebral organoids following our established protocol. We will analyze brain tissue development in this human model system to identify novel evolutionary and pathogenic mechanisms. We will focus specifically on regulation of neural stem cell fate determination and the generation of specific neural cell fates. In this manner, we hope to establish key factors in human specific brain size determination and pathogenesis of disorders that affect brain size and morphology. This approach will seek to identify mechanisms unique to human brain development. In so doing, we hope to identify new potential avenues for clinical research into many neurological diseases that have so far eluded attempts at modelling their pathology and generating novel routes to therapeutic intervention.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Neuronal model systems and neurotoxicity
Funder: Medical Research Council

Abstract: Neurodegenerative diseases are characterized by the differential vulnerability of specific neuronal cell populations to endogenous or environmental toxic insults. For example, in Parkinsons disease specifically the dopaminergic neurons of the substantia nigra degenerate, while the ventral tegmental area neurons remain relatively spared. The reasons for the selective degeneration of neuronal cell types are still largely unknown. The research in our group aims to identify the mechanism underlying the selective vulnerability of specific neuronal cell types to neurotoxic insult. We are developing an embryonic stem cell model system that can be used to study these processes in vitro. Recently, we have shown that forced expression of neuronal lineage specific transcription factors can direct the differentiation of embryonic stem cells into several clinically relevant neuronal cell types including dopaminergic-, serotonergic- and noradrenergic neurons. Using a similar approach, we are planning to generate homogeneous populations of neuronal cell types that are affected in Parkinsons, Alzheimers and prion disease. We will compare the gene expression profile of affected neuronal cell types to neurons that are more resistant to stress. In addition, we will analyse the differential responsiveness of these cells to neurotoxicity by using chemicals or by introducing disease causing gene variants. Our second line of research is focussed on understanding the molecular mechanism underlying dopaminergic neuronal subtype specification. Dopaminergic neurons located in the midbrain are a very heterogeneous cell population and are implicated in several important neurological disorders including Parkinsons disease, Schizophrenia and anxiety. We will use embryonic stem cell derived dopaminergic neurons and mouse genetics to gain insight into processes controlling the diversification of dopaminergic neurons and the characterization of the distinct dopaminergic neuronal subtypes. Ultimately, our research may contribute to the understanding of the etiology of neurodegenerative diseases and may lead to the development of novel treatments.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: NEUROLOGICAL
Title: ACA5. Decision making in dementia
Funder: Medical Research Council

Abstract: Advances in new treatments for dementia require a new mechanistic understanding of disease, linking changes in cognitive function to underlying neural systems and their pharmacology. They also require new tools to identify the signatures of nascent pathology in (as yet) asymptomatic patients that can be used to safely and reliably track the emergence of disease in the context of preventive and therapeutic clinical trials. In the first part of this program, we develop new models of cognitive function, based neurophysiological models of decision making circuits. We examine decisions about behavioural control (including response inhibition), volition and the perception of environmental cues that guide actions. Using accumulation-to-threshold models of perception and behaviour, we will determine the processes by which sensory inputs are transformed to motor outputs, and the vulnerability of these processes to two different disorders: Parkinson’s disease and Alzheimer’s disease. In the second part of the program, we will examine the problem that some people have increasingly poor cognitive function with age. This may be the presence of subclinical dementias, and we will compare neural signatures in healthy older adults to those with early dementia. However, unsuccessful cognitive ageing is not necessarily just a matter of early dementia. Even those without emerging dementia will vary in their cognitive ageing profile, for reasons that we will elucidate. This builds on the CamCAN study of healthy ageing, bringing in for the first time those adults who performed poorly on screening tests. We will apply a tailored battery of imaging and psychological assessments, using MRI, fMRI and MEG, and use supervised machine earning methods to identify the neural factors that are associated with poor function. These will be compared with neural factors associated with early AD. This program links directly to the Cambridge Centre for Ageing and Neuroscience (CamCAN) and the Dementias Platform UK, both in terms of the Synaptic Health Theme for Experimental Medicines, and the Deep and Frequent Phenotyping study of prodromal dementia. The MRC “ACA5. Decision making in dementia” provides vital links between normative studies, ageing and neurodegeneration. Through my Wellcome Trust Senior Research Fellowship and the NIHR Biomedical Research Centre’s Neurodegeneration and dementia theme we are developing pharmacological interventions to restore cognition, with direct translation from ACA5 innovations to clinical populations.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Disease susceptibility Pathways in Multiple Sclerosis
Funder: Medical Research Council

Abstract: Goals To provide a functional understanding of how MHC class I and class II genes confer risk to multiple sclerosis (MS). Our research has focussed predominantly on exploring the pathogenesis of a HLA-associated disease of the central nervous system – multiple sclerosis (MS). We have translated MS-associated genotypes to phenotypes and in doing so have shed light on disease mechanisms and provided therapeutic opportunities. We have shown that the DRB1*1501 allele is the primary risk gene in MS and that its disease-mediating effect can be modified by the linked DRB5*0101 (1). We have demonstrated functional interactions between MS associated genes and shown how protective genes can regulate risk genes, leading to less severe disease (1-4). Further, we have determined the functional and structural bases for interactions between MS-risk genes and environmental factors. Our studies in autoimmune encephalomyelitis (EAE) an animal model of MS, have shown that the acid sensitive ion channel ASIC1 is important in pathogenesis. Tissue acidosis in the spinal cord of EAE mice causes the ASIC1 channels to open, and as these are permeable to Na+ and Ca2+ ions (2) the clinical deficit and axonal degeneration caused by excessive accumulation of these two ions is reduced. Thus we have identified this acid sensing ion channel as a potential therapeutic target in MS. Future research plans Future work will focus on the study of several immune genes showing MS associated variations by using humanized and transgenic mouse models: (a) the KIR receptors that are expressed on NK cells, and their interaction with difference HLA-C alleles; (b) tumour necrosis factor-receptor 1; (c) the interleukin-7 receptor alpha chain; and the (e) the T-box transcription factor eomesodermin (EOMES) gene region. We will also carry out multiple MS family whole genome sequencing. References: (1) Gregersen et al 2006 Nature 443:574 (2) Friese et al 2007 Nature Med 12:1483 (3) Friese et al 2008 Nature Med 14: 1227 (4) Harkiolaki et al 2009 Immuity 30: 348 (5) Fugger et al 2009 Nature Rev Immunol 9: 408.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Analysis of mitochondrial homeostasis in ageing and neurodegeneration
Funder: Medical Research Council

Abstract: The survival of our most active tissues, such as the brain and heart, throughout decades of a human lifespan presents an extraordinary biological challenge. Mitochondria are central to the life and death of these tissues. They provide the cellular energy required by these cells and protect them by buffering potentially lethal levels of cytoplasmic calcium, while at the same time mitochondria produce many of the molecules that cause cellular damage and contain a lethal arsenal of apoptotic cell death machinery. Thus, these organelles require exquisite maintenance processes to keep them intact and prevent potentially catastrophic disruption. Failure in mitochondrial homeostasis is strongly linked to age-related conditions such as neurodegeneration. To perform the myriad essential cellular roles in such morphologically elaborate cells as neurons mitochondria must be extremely dynamic organelles. Individual mitochondria must be transported over large distances to respond to changing spatiotemporal demands for energy and calcium buffering. Locally, interaction with multiple other organelles and the mitochondrial network undergoes frequent fission and homotypic fusion events. These dynamic events are known to be important in the regulation of cellular and mitochondrial homeostasis, and been linked to several neurodegenerative disorders. The long-lived, post-mitotic nature of adult neurons permits the accumulation of oxidatively damaged macromolecules. When cellular defence mechanisms become compromised, especially with age, mitochondria are particularly susceptible to accumulated damage. One key mechanism that mediates the destruction of terminally damaged organelles is through the selective degradation by autophagy, known as mitophagy. The identification that two genes linked to Parkinson's disease, PINK1 and parkin, regulate mitophagy has emphasized the importance of this process to neuronal survival. However, much of our current understanding comes from in vitro studies, so we still have a poor understanding of this process in a physiological context. Our group’s aim is to understand the influence of mitochondrial dynamics on maintaining normal neuronal function and survival, and its impact on neurodegenerative diseases such as Parkinson’s disease and motor neuron disease. We use a combination of the powerful genetic techniques of Drosophila and molecular, cell biology and biochemical approaches in mammalian cells. Insights into these mechanisms will deliver a greater understanding of the role of mitochondrial dynamics in the health and dysfunction of the nervous system in a physiological context and will help guide therapeutic development to combat neurodegenerative diseases.


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