NIHRDataInsights/HRCSData huggingface dataset:
Title: Do antipsychotics inflame the brain?
Funder: Medical Research Council

Abstract: Antipsychotic drugs have both pro- and anti-inflammatory effects. I have shown that clinically comparable, chronic, antipsychotic drug treatment increases microglial activation in the rat brain. Furthermore, this pattern of microglial activation overlaps topographically with brain regions that decrease in volume in antipsychotic-treated rats. The precise impact of antipsychotics on microglial function and how this relates to drug-induced brain volume changes is however, unknown. Furthermore, we do not have a detailed understanding of how antipsychotics affect the expression of the translocator protein (TSPO), a clinical imaging marker for microglial activation, but also a regulator of microglial activation state. To address these questions I will expose rats to an immune stimulus (poly(I:C) in gestation, which recapitulates pathological and behavioural deficits relevant to schizophrenia. I will then treat these animals as adults with clinically comparable doses of typical or atypical antipsychotics, or a vehicle control and pursue the following specific aims: 1) I will use a combination of in vivo and ex vivo magnetic resonance imaging, coupled with post-mortem cellular (immunohistochemistry and stereology) and molecular (gene expression from isolated brain microglia) analysis to determine the effects of antipsychotics on microglial activation state and how this relates to brain volume. 2) I will elucidate the effects of antipsychotics on TSPO ligand binding using use post-mortem autoradiography and dissect the cellular origin of this signal and consequences on microglial activation using immunohistochemistry and gene expression analysis in isolated brain microglia. 3) I will measure peripheral inflammation in the blood using multiplex cytokine and correlate these to central microglia activation, MRI and TSPO signals. This will characterise the relationship between peripheral inflammation, central markers of inflammation and brain volume (MRI).


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: Exosomal protein deficiencies: how abnormal RNA metabolism results in childhood-onset neurological diseases
Funder: Medical Research Council

Abstract: The degradation of mRNAs is an important regulatory step which controls gene expression. Three major degradation systems are responsible for the destruction of transcripts: the 5'-3' exoribonucleases, the nonsense-mediated mRNA decay machinery and the exosome. The exosome degrades and processes a variety of RNA species in the nucleus and in the cytoplasm of eukaryotic cells. The versatility and specificity of the exosome and its associated complexes regulate and maintain the fidelity of gene expression. A novel group of RNA-associated neurological disorders has been identified with mutations in genes encoding components of the human exosome. Mutations in EXOSC3 were reported in pontocerebellar hypoplasia and spinal motor neuron abnormalities (PCH1). Our group identified EXOSC8 mutations in hypomyelination, spinal muscular atrophy and cerebellar hypoplasia. We showed that the hypomyelination is caused by imbalanced supply of myelin proteins due to disturbed degradation of AU-rich element containing mRNA. The prominent neurological presentation in these cases raises the possibility that the exosome is particularly important in developing neurons. However, there are many open questions, which will be the focus of this project. We will investigate which RNA types are affected in their expression or degradation by mutations in the exosome and whether this depends on the cell type and on which exosomal subunit is mutated. We will study human fibroblasts and neuronal cells, converted and differentiated from fibroblasts by recently published methods. Zebrafish will be used as in vivo animal model to analyse how alterations of the exosome affect the development of the nervous system and the myelination of neurons. By combining our results we will identify and further explore novel targets involved in neurodegenerative diseases affecting spinal motor neurons, cerebellar Purkinje cells and oligodendroglia.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Enhancing speech fluency in people who stutter
Funder: Medical Research Council

Abstract: Developmental stuttering is a disorder affecting the fluency of speech, characterized by repetitions or prolongations of sounds and frequent hesitations or pauses. It affects 5% of children and persists to adulthood in about 1%. Changing the motor speech pattern in adults who stutter is a particular challenge for speech and language therapy and there is a need for novel interventions, therefore. One such intervention involves the application of transcranial direct current stimulation (TDCS) alongside speech therapy. TDCS influences brain activity by modulating neuronal plasticity through the application of weak electrical currents across the brain. Pairing TDCS with speech therapy has potential for producing larger or longer lasting effects and reducing time spent in therapy. The first aim of our study is to evaluate the potential of TDCS combined with speech fluency training to improve outcomes in people who stutter (PWS). We will use techniques that alter speech motor patterns, typically by slowing the rate of speech while maintaining naturalness. PWS will have this training while receiving anodal TDCS over the left motor cortex for 5 days (1mA for 20 mins per day) in a double-blind randomized controlled trial. Outcomes will be measured in terms of changes to stuttering rates and naturalness ratings as well as attitudes to stuttering. The second aim of our study is to understand how changes in sensorimotor interactions relate to changes in speech fluency in PWS. We will use MRI to measure brain structure and function during speech production. We will also image the vocal tract during fluent and dysfluent speech production and during speech motor learning. Magnetoencephalography (MEG) will provide detailed information on the timing of signals and sensorimotor interactions during speech in PWS. These studies will form additional outcome measures of the speech fluency training and brain stimulation in PWS.


Research activity codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL;6.7 PHYSICAL
Health categories: NEUROLOGICAL
Title: Synaptic and circuit pathology in a mouse model of AP4 deficiency syndrome
Funder: Medical Research Council

Abstract: Vesicular trafficking is key for correct brain wiring and function, and implicated in many physiologically important processes in neurons including neuronal migration, axon pathfinding, growth cone dynamics, the establishment and maintenance of axons and dendritic arborisations and the function and plasticity of synapses. The AP4 complex is highly expressed in the nervous system where it may play an important role in the vesicular trafficking of key cargo. Mutations in the subunits of the AP4 membrane trafficking complex in humans lead to loss of AP4 subunit protein and an associated spectrum of severe neurological problems including intellectual disability, epilepsy and spastic paraplegia but very little is know regarding the function of the AP4 complex in the brain. We will use a combination of molecular, cell biological, mouse transgenic, imaging and electrophysiological techniques to determine how AP4 complexes contribute to neuronal membrane trafficking and brain function. A key goal will be to better understand how AP4 contributes to the correct development and maintenance of neuronal and synaptic architecture and the strength of synapses. This will help to better understand how AP4 loss leads to disease and will also provide new insights regarding the circuit and synaptic pathology that underpins intellectual disability and epilepsy and may be more widely relevant to other neurological disorders including Alzheimer's disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Dementias Platform UK MR-PET Partnership
Funder: Medical Research Council

Abstract: This partnership grant aims at providing coherent and harmonised operations of the DPUK MR-PET network. It will tightly be managed within the DPUK imaging platform, where it relates primarily to the work package on clinical governance which is led by Prof. Karl Herholz. We will also closely cooperate with the DPUK imaging work packages on radiochemistry, data analysis, and IT. This will be ensured by the composition of the executive team, representation of all disciplines in the steering committee, and by overlap between network task force leadership with the broader work package leadership of the DPUK imaging platform. The imaging platform will comprise seven MR-PET scanners from two different vendors. Thus, one obvious priority is minimising differences in image quality and quantification, while still maximising the benefits of MR-PET over separate MR and PET scanning. This will be addressed by investigation into the technical characteristics of the scanning and image reconstruction, but also by providing appropriate cross-training of staff, and by devising harmonised SOPs. Initially we will concentrate on harmonising established MR protocols and tracers, in particular to provide the current standard set of imaging biomarkers for dementia research. We will also facilitate implementation of research studies using other tracers and MR techniques. Four major tasks have been identified to reach these goals. Task force 1 is providing the essential means for effective communication and reporting, task force 2 will organise training, and task force 3 will conduct the harmonisation scanning study. An additional task force (#4) will address governance, regulations and business development to ensure continuous growth of activities for long-term sustainability. Task forces will adhere to a detailed project plan with specific deliverables and annual reporting to the DPUK management board.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: NEUROLOGICAL
Title: Modelling peripheral axonal pathology of ALS in vitro - Assembly of optogenetic neuromuscular circuits from pluripotent stem cells
Funder: Medical Research Council

Abstract: We propose to develop an in vitro model of Amyotrophic Lateral Sclerosis (ALS) and neuromuscular circuitry, based on sorted pluripotent stem cell-derived motor neurons, astrocytes and myofibres, which are co-cultured in a compartmentalized tissue culture device. We plan to investigate the disease mechanism of ALS, with a focus on peripheral synaptic and axonal cellular pathology. To this end, we will equip human induced pluripotent stem cells carrying disease-associated mutations in the genes SOD1, TARDBP or C9ORF72 with genetically encoded optogenetic actuators and optical probes which will allow us to stimulate the cells, read their electrical activity and trace cellular features with live imaging. The optogenetic stem cell-motor neurons will be activated with light and used to control the myofibres connected to them through neuromuscular junctions (NMJs). We will map different ALS-associated mutations to specific patterns of early cellular degeneration, which may be initiated either centrally or peripherally. We will use this in vitro model to study the impact of different neural activity patterns, modifier genes, and small molecule compounds on early pathological features, in particular abnormal NMJs and defective axonal transport. This may enable us to pinpoint potential therapeutic pathways, and, in the long-term, develop ALS drugs which are specifically customized to the individual genotypes and phenotypes of ALS patients.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: A standardised, multilingual, Mini Linguistic State Examination (MLSE) for classifying and monitoring Primary Progressive Aphasia
Funder: Medical Research Council

Abstract: Primary progressive aphasia (PPA) is an uncommon clinical manifestation of Alzheimer's, tau- and TDP-43-positive neuropathologies. Three clinical syndromes are recognised: semantic dementia (SD) (progressive loss of word and concept knowledge in association with bilateral anterior temporal atrophy); progressive nonfluent aphasia (PNFA) (distorted speech output with largely preserved comprehension, and cortical atrophy focused on left inferior frontal and insular regions); and logopenic progressive aphasia (LPA) (difficulties with word-finding and sentence repetition, in the presence of atrophy in left posterior cortical regions). The syndromes result from different combinations of dysfunction in fundamental components of the language system: speech fluency, word retrieval, appreciation of word and object meaning, use of grammar, and reading/writing. Syndromes and pathologies are probabilistically related, allowing the latter to be predicted in up to 70% of cases. In light of PPA's relative rarity, increased recognition and coordination of large patient cohorts across multiple sites will be required to study disease biology and clinico-pathological correlations, and enable clinical trials of potential treatments. Progress in both endeavours will benefit from a common method of extracting relevant clinical information from large numbers of individuals. The development of a brief, language specific clinical instrument that can classify patients into one of the three main subtypes of PPA, and to characterise the features of atypical variants, is the central aim of this project. The language battery, based on patterns of impairment across components of language competence, will provide a unified clinical diagnostic standard. Simultaneous development in English and Italian will catalyse and inform the creation of equivalent versions in other major languages of the world, providing a common descriptive clinical currency for the sharing of larger data sets.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Neural circuits of glucagon-like peptide-1 (GLP-1) action in health and disease
Funder: Medical Research Council

Abstract: This proposal aims at characterising the exact physiological role of GLP-1R-expressing neurons in the control of energy balance and autonomic functions. We will experimentally silence or ablate GLP-1R-expressing neuronal populations in vivo by using viral gene transfer. Specific targeting will be achieved by combining a transgenic mouse line that expresses Cre-recombinase selectively in cells that express GLP-1R with viral expression vectors that are only active in cells expressing Cre-recombinase (FLEX-switch technique). The adeno-associated virus (AAV)-based vectors are injected stereotaxically into individual brain regions containing GLP-1R-expressing neurons. 3-5 weeks after the infections the animals will be tested for effects of GLP-1R neuron modulation on food intake, blood glucose control, cardiovascular and circadian activities. AAV vectors produced for this purpose will include those that inactivate or ablate GLP-1R cells permanently (Tetanus toxin light chain; Diphteria toxin A subunit), and those that inactivate GLP-1 cells transiently (DREADD hM4D), when the appropriate agonist is applied (clozapine-N-oxide). Food and water intake will be recorded, blood glucose control will be evaluated with intraperitoneal glucose tolerances tests, and cardiovascular parameters will be assessed using telemetry in awake animals. Our results will further define the physiological role of GLP-1R-expressing neurons in specific brain regions and provide crucial data on the usefulness of a GLP-1 based therapy for metabolic disease. These experiments will also specifically address the question whether GLP-1R expressed in autonomic neurons contributes to cardioprotection, and if GLP-1 in the olfactory system constitutes a novel target for the control of energy balance by GLP-1 analogues.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: C9orf72 dipeptide repeat proteins: Molecules and models
Funder: Medical Research Council

Abstract: The repeat expansion mutation of C9orf72 is the most common genetic cause of Frontotemporal lobar degeneration (FTLD). The expansion is translated producing 5 different di-peptide repeat proteins (DPRs). However, there is controversy over the role of the DPRs in disease. In various cell and animal models of C9orf72 disease DPRs are clearly neurotoxic. However, DPR pathology in patients does not correlate very well with neurodegeneration. It is possible this is due to DPR pathology being lost in areas susceptible to the DPR neurotoxicity leaving resistant areas with intact DPR pathology to be observed at post mortem. To address this we will make powerful inducible mouse models of DPRs and study the effects of DPR expression on the brain over time. We have produced expression constructs using alternative codons to those in the hexanucleotide repeat which produce inclusions without the repetitive RNA generating RNA foci.The inclusions we model are ubiquitin, p62 and ubiquilin-2 positive and recapitulate the pathology that is observed in patients. We will use these to generate state of the art inducible, single copy, Rosa26 integration site, transgenic mice. We will make one line producing cytoplasmic inclusions (pro-ala DPR) and one with intranuclear inclusions (pro-arg DPR). We will characterise the behaviour and pathology of these mice over a 18 month period. In addition, we will compare their brain transcriptome to that from a patient with the expansion. Also, to investigate the effect of DPRs on phenotype we will measure soluble and insoluble DPRs using novel western blotting and ELISA techniques in a large series of human brains. These data will be compared to clinical and pathological data. Collectively, we will generate data on the precise role of DPRs in the neurodegenerative process arising from the repeat expansion mutation in C9orf72.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Understanding the genes for Parkinson's disease
Funder: Medical Research Council

Abstract: Parkinson's disease is the most common neurodegenerative movement disorder, affecting in access of 120,000 individuals in the United Kingdom, and is uniformly fatal with no disease course modifying therapy available. Genome wide association (GWA) studies have been outstandingly successful in identifying regions of the human genome that are associated with increased risk for a wide range of common human disorders. This is true for Parkinson's disease, where in excess of twenty risk loci have been identified. The major challenge for both academic and industrial researchers is to translate the identification of these genomic regions into biological insights into the molecular aetiology of Parkinson's, which in to turn can inform drug development efforts in this area. To achieve this, the causative variants responsible for the WG association - in most cases likely to be alterations in specific genes - need to be identified and characterized. In this proposal we will use gene expression and splicing analysis to assess the functional role of genes implicated by PD GWA studies, combined with cellular and in vivo studies, to take the key next steps required for evaluation of the role of implicated genes in the molecular pathogenesis of PD and their status as putative drug targets.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: The post-natal development of hippocampal memory networks
Funder: Medical Research Council

Abstract: Our ability to form memories of our personal experiences (or 'episodic' memories, memories of events set in a spatial-temporal context) emerges late during post-natal development, and episodic memories formed early in childhood are destined to be forgotten by adulthood, a phenomenon termed 'infantile amnesia'. The protracted development of memory systems is common to many altricial mammalian species, offering the possibility of studying memory development in animal models. In this proposal, we aim to uncover the fundamental mechanisms of memory development and infantile amnesia at the level of neural circuits, by studying the development of hippocampal networks for memory in the rodent. The hippocampus is required to create new episodic and spatial memories in both humans and other species. At the level of neural circuits, the hippocampus represents space through the firing of pyramidal cells active only when the animal visits a restricted region of their environment, known as 'place cells'. This application will test the hypothesis that the developmental emergence of hippocampal memory is based on the place cell network's ability to encode and consolidate long-term memories of locations. Firstly, we will assess the ability of place cells in the developing hippocampus to encode long-term memories for locations during exploration, and we will identify which synaptic plasticity mechanisms are involved in this process at any given age. Then, we will investigate the patterns of place cell activity observed during immobility or sleep following exploration ('place cell re-activation'), which may reflect network mechanisms for memory consolidation (both intra-hippocampally, and in the interplay between hippocampal and pre-frontal cortex circuits). Finally, we will test whether the late development of memory is due to the slow maturation of a dopaminergic neuromodulatory signal in the hippocampus, as this has been shown to promote consolidation after learning in the adult.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Role of subplate neurosecretion in early cortical circuit formation
Funder: Medical Research Council

Abstract: Our long-term research programme is to study the mechanisms underlying the formation of transient early cortical circuits that are crucial for the development of subsequent more permanent adult neuronal networks. Our hypotheses for this grant are: 1. Subplate cells have a secretory function. This function is transient and it is necessary for the normal maturation of the brain including vascularisation and myelination and maybe neuronal cell survival. 2. Neuroserpin, a serin protease released from subplate neurons in the developing brain has a stage-specific function in cell survival of subplate and/or surrounding cells. 3. Neuroserpin has an additional endogenous function in preventing or reducing injury following neonatal hypoxia. This is based on our preliminary results demonstrating up regulation of neuroserpin following hypoxia in rats. 4. Increasing neuroserpin expression (via viral delivery) shall have a stage specific positive effect on the outcome (histopathological and behavioural) of neonatal hypoxia, whereas reduced neuroserpin levels (in neuroserpin KO mice) have a negative effect. These hypotheses shall be tested in animal experiments, and some findings extended to human post-mortem tissue. We will characterise the cellular localisation of proteins encoded by genes for extracellular molecules in mouse and human including neuroserpin and CTGF. We will test the proportions of these proteins that are made in subplate cells and the proportions that are taken up by them. We will characterise the role of neurosecretion from subplate cells by using animal models with reduced membrane vesicle fusion in subplate or without subplate cells. For this, we will use subplate cell specific Cre expression in the period combined with Snap25-flox or STOP-flox diphtheria toxin A mice. Neuroserpin protein levels will be analysed in hypoxic-ischemic animal models and the effectiveness of increasing or decreasing neuroserpin expression before hypoxia shall be tested.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL