NIHRDataInsights/HRCSData huggingface dataset:
Title: Human mechanosensation: From 1st-order neurone to somatosensory cortex
Funder: Medical Research Council

Abstract: Our research addresses tactile sensation and perception in healthy and neurologically compromised patients. We will build on established experimental designs and analyses to map the representation of the fingers in the human somatosensory cortex in individual subjects. We will measure the cortical mapping of the fingers at very high spatial resolution using ultra-high field functional magnetic resonance imaging (UHF-fMRI) at 7T. By using 1mm isotropic voxels in our fMRI experiments, we have already been able to reveal the fine-grained topographic map of the digit representation in somatosensory cortex much better than in any previous studies. We will extend this mapping to other aspects of the organization of somatosensory cortex that occur at the sub-millimetre length scale. In particular, we will characterize digit organization patterns across inter-areal boundaries in primary somatosensory cortex (SI), between SI and SII (secondary) somatosensory cortex, and measure cortical layer specific activity to determine the microcircuitry underlying inter-hemispheric inhibition in healthy individuals. We will combine functional measures with high resolution structural MRI measures of cortical thickness, myelin content and fibre connections, and will assess spatial and spectro-temporal mapping and synchrony between SI/II using MEG. We will also combine neuroimaging (UHF-fMRI and MEG) with single-unit intraneural microstimulation (INMS) of peripheral nerve afferents to explore the relationships between bespoke patterns of stimulation in 1st-order neurons, their perceptual consequences, and cortical/areal correlates in primary somatosensory cortex. Using these methodologies, we will reveal the mechanisms underlying maladaptive plasticity associated with abnormal sensory input and assess the effect of therapeutic interventions in two clinical conditions - carpal tunnel syndrome (CTS) and focal hand dystonia (FHD).


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Neurovascular protection of the brain following ischaemic stroke and the role of the hamartin/mTOR pathway
Funder: Medical Research Council

Abstract: Ischaemic stroke, caused by a thrombus in a major cerebral artery, leads to depletion of the supply of oxygen and glucose to the brain causing neuronal death. A major consequence of this is blood-brain barrier (BBB) breakdown producing extravasation of harmful plasma components. BBB integrity is regulated by cells of the neurovascular unit (NVU) such as brain endothelial cells, pericytes, and astrocytes, which are also cell types involved in cerebral blood flow (CBF) regulation. Drug targets that protect neurons and maintain NVU function by restricting BBB breakdown and preserving CBF are desired as a therapeutic strategy for stroke. One such target could be the hamartin/mammalian target of rapamycin (mTOR) pathway. We have shown that hamartin, a protein that forms part of the tuberous sclerosis complex and inhibits mTOR, protects both neuronal cells and brain endothelial cells following oxygen-glucose deprivation (OGD) in vitro. The rat middle cerebral artery occlusion (MCAO) model will then be used to assess how the hamartin/mTOR pathway is affected under ischaemic conditions, and to test whether hamartin upregulation (with lentiviral particles) or mTOR inhibition (with drugs) can provide protection to the brain and maintain BBB integrity. We will then assess the effects of mTOR inhibitors on basal and evoked CBF using the whisker stimulation model in naïve and MCAO rats, with a focus on capillary flow and pericyte function. The cell types and mechanisms responsible for neurovascular function preservation will be determined using individual NVU cell cultures exposed to OGD and treated with mTOR inhibitors. To provide clinical relevance of this pathway, we will explore changes in the hamartin/mTOR pathway following human stroke. Overall, these results will hopefully provide the basis for which further pre-clinical development of mTOR inhibitors for stroke can begin, with the ultimate aim of improving stroke patient outcome in the clinic.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Vasopressin and the retina
Funder: Medical Research Council

Abstract: Circadian rhythms in physiology and behavior are orchestrated by the hypothalamic suprachiasmatic nucleus (SCN), the "master" clock of the body's circadian systems. The primary determinant of the output of the SCN is the 24-h environmental light/dark cycle, reflecting a direct retinal innervation of the SCN, but exactly how the retinal input entrains the rhythm of the SCN is unclear. Several neuropeptides, including vasopressin, have been linked to the regulation of the circadian clock. The SCN contains a large population of vasopressin neurons, but we recently found that the retina also contains many vasopressin-expressing retinal ganglion cells (RGCs), and that, strikingly, these project exclusively to the SCN. Vasopressin signaling in the SCN determines the speed of re-entrainment the environmental clock after a phase advance in the light-dark cycle. Generally it has been assumed that the time-dependent ability of a light pulse to re-entrain circadian rhythms reflects the circadian state of the target neurons in the SCN. We hypothesize that the vasopressin-expressing RGCs are a major, light-activated excitatory pathway that has a key role in regulating circadian rhythms. The research will use contemporary molecular physiology approaches (including optogenetics, transgenic rats, and adenoviral transfection systems) to define the cellular targets of this projection in the rat SCN, and establish whether this input is essential for the photic induction of immediate early gene expression that is associated with circadian entrainment. These final experiments will indicate if modulation of the retina-SCN pathway might be considered as a therapeutic approach to mitigate the adverse effects of disrupted circadian regulation.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Tackling autophagy and apoptosis for the potential therapy of Huntington's Disease
Funder: Medical Research Council

Abstract: Huntingtin's Disease (HD) is a progressive neurodegenerative disorder, caused by mutant huntingtin gene (htt) with expanded CAG repeats, which are translated into expanded polyglutamine (polyQ) stretch. The expanded polyQ forms toxic aggregates that induce neuronal death. It has been well characterised that mutant Htt (mHtt) aggregates can be degraded by autophagy, a lysosome-dependent bulk degradation system, and autophagy upregulation ameliorates HD and other neurodegenerative diseases. Autophagy consists of autophagosome synthesis (cargo delivery) and autophagosome-lysosome fusion (cargo degradation). The initiation of autophagosome synthesis is tightly regulated by a set of autophagy genes, such as Atg1, Beclin 1 and class III PI-3 kinase Vps34. The Beclin 1-Vps34 localisation at ER is critical for the formation of autophagosomes. We found that pro-apoptotic protein Bim restricts Beclin 1-Vps34 complex to microtubules away from its functional site ER, thereby suppressing autophagy. Bim is therefore a dual regulator that promotes apoptosis but inhibits autophagy. Our preliminary data show that the protein and mRNA levels of Bim were significantly enhanced in human HD post-mortem striatum, confirming previous data that Bim levels are increased in HD mouse and cell models. Collectively, these suggest that Bim may a driving factor to progression of HD pathology. We observed that depletion of Bim with RNA interference significantly reduced mutant Htt aggregation and toxicity in cells. Importantly, a peptide derived from Bim (Bim-P) promotes autophagy by antagonising Bim's autophagy inhibition, and reduces mutant Htt aggregation and toxicity in HD in vitro. Based on the preliminary data, we will establish the mechanism by which Bim is upregulated in HD, examine the effect of Bim in HD progression in vivo using HD mouse models and test the efficacy of the Bim-P in treating the HD mouse models.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL
Title: A Unified Mechanism for Functional Neurological Symptoms
Funder: Medical Research Council

Abstract: Functional neurological symptoms (FNS) are one of the commonest reasons for people to come to see a neurologist - 16% of all new neurology outpatients have these symptoms. Patients with FNS (also known as medically unexplained symptoms, psychogenic symptoms, non-organic symptoms) are typically of working age (average age 40), and 67% remain with persistent disabling symptoms, leading in 50% of cases to cessation of work and in 27% to receipt of illness-related financial benefits. A major gap in understanding FNS is the absence of a theory to explain how, at a mechanistic level, physical symptoms of the sort seen in FNS could arise from the brain. A secondary effect of this "explanatory gap" is that within FNS, different symptom types are often classified and conceptualized differently, based largely on historical views on aetiology. This fragmentation of FNS is contrary to the very common co-occurrence of different functional symptoms in the same patient which would suggest a shared pathophysiological mechanism for FNS. The aim of the work proposed here is to test a novel pathophysiological theory of functional neurological symptoms. We will build on existing work in patients with functional movement disorders and functional sensory loss to test if this theory can also provide a convincing mechanistic explanation for paroxysmal motor symptoms (non-epileptic attacks) and interoceptive symptoms (fatigue). We will combine this work with experimental studies in patients with functional motor symptoms before and after treatment. This will assess the link between change in clinical symptom severity and change in markers of our proposed pathophysiological mechanism and will demonstrate its relevance to clinical symptomatology and provide potential biomarkers for use in future therapeutic studies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: The UK GENetic Frontotemporal dementia Initiative (UK GENFI)
Funder: Medical Research Council

Abstract: Frontotemporal dementia (FTD) is a common cause of young onset dementia, approximately equal in frequency to Alzheimer's disease in people below the age of 65. Its effect on people of working age with young families represents a major health and economic burden on society. The only known risk factors for FTD are genetic, and around a third of FTD is familial. There are currently no treatments that can delay the onset or prevent the progression of genetic FTD but there are now potential disease-modifying therapies in development. However, there are still no biomarkers of genetic FTD that can confidently predict when disease-modifying therapy should be initiated or how the response to it should be monitored. By studying participants who carry a mutation and are thus destined to develop the disease we can explore the entire disease pathway, using mutation negative first-degree relatives as controls. A pilot study has created a common methodological platform to study genetic FTD. This follow-on study aims to capitalize on the work of the pilot, extending both the platform and expertise generated to a UK-wide study of genetic FTD. Specifically, we will establish a UK-wide familial FTD cohort of 200 participants which will (1) lead to greater understanding of the biological underpinning of the cognitive and behavioural deficits seen in FTD; (2) permit large-scale cohesive and integrated longitudinal biomarker studies of familial FTD with the specific remit of informing clinical trial design; and (3) provide a "readiness" cohort of patients for disease-modifying drug trials. The experimental plan includes longitudinal clinical and neuropsychological assessments, neuroimaging and both blood and spinal fluid sampling, with the key outcomes including improved understanding regarding the selective vulnerability of the specific neural systems affected in FTD, robust biomarkers of disease onset and progression, and estimation of sample sizes required for trials.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Towards a new neurological model of language that explains outcome after stroke.
Funder: Medical Research Council

Abstract: We will investigate the combinations of brain areas that are critical to core language functions. In Step 1, for each function of interest, we select patients who each have difficulty performing all the tasks that are assumed to tap that function. For example, when the function of interest is speech production, we select patients who have difficulties with all speech production tasks (object naming, reading and fluency) but not on tasks that don't (picture-word-matching etc). The lesion site in each of the selected patients is defined in high-definition 3-dimensional space and becomes a region of interest (ROI) with the assumption that the ROI must include brain areas that contribute to all the neural pathways that have the potential to support the tasks and functions that the patient has difficulty with. Further analyses are then required to determine which parts of the ROI are critical or not, and whether the different parts contribute to the same neural pathway or a separate pathway (if there are different ways that the same task can be performed). In Step 2, we select other patients who either have damage that includes all or a part of an ROI. The language abilities of each of these patients determine which parts of the ROI are critical and how the lesion-deficit relationship varies (i) across patients and (ii) with time post stroke. If different parts are from the same neural pathway, we expect that damage to each part will impair task performance. If different parts contribute to different neural pathways (for the same task) then we expect task performance to be worst when damage includes all relevant pathways than when it includes just one or a subset of pathways. Each result will be validated in new cohorts of patients who are closely matched for lesion site and followed up longitudinally. All results will be integrated in a new neurological model of language that can predict both initial symptom severity and the likelihood of recovery in new patients.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: MICA: Monocyte and macrophage manipulation for the control of chemotherapy-induced pain
Funder: Medical Research Council

Abstract: Painful peripheral neuropathy constitutes a major dose limiting side effect of chemotherapeutics that remains poorly controlled by available analgesics. Elucidation of mechanisms underlying chemotherapy-induced pain will identify targets for prophylactic and therapeutic analgesia. We recently showed that monocyte/macrophage infiltration in sciatic nerve orchestrates the development of vincristine (VCR)-induced allodynia in mice. Specifically, VCR administration induced expression of endothelial adhesion molecules and CX3CR1+ monocyte infiltration into the sciatic nerve. CX3CR1 receptor activation with endothelial fractalkine (FKN) induced formation of reactive oxygen species (ROS) by macrophages. ROS activated TRPA1 channels on sensory axons which evoked a pain response. VCR-allodynia was prevented by blocking monocyte trafficking into the sciatic nerve. However, mouse (and human) monocytes include a heterogeneous population of cells. Here we plan to identify the specific monocyte subsets that mediate initiation and maintenance of VCR- and paclitaxel-induced allodynia. Our hypothesis is that chemotherapeutic administration results in alteration of sciatic nerve microvasculature so that patrolling monocytes (CX3CR1+CCR2-) are retained by the endothelium as an early response. They trigger the generation of a local inflammatory environment and promote inflammatory monocyte (CX3CR1+CCR2+) to infiltrate the nerve. By combining behavior and immunohistochemistry with intravital microscopy in transgenic mice (KCL), we will define location and function of monocyte subsets in the sciatic nerve during chemotherapy-allodynia. Furthermore, we will establish whether manipulation of monocyte trafficking in the sciatic nerve provides prophylactic and therapeutic analgesia by testing CCR2 receptor antagonists and peripherally restricted Medivir cathepsin S inhibitors (by inhibiting enzymatic release of endothelial FKN, CX3CR1-monocyte activation is blocked).


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Regulation and function of the stem cell activation factor Ascl1 in constitutive and injury-induced adult neurogenesis
Funder: Medical Research Council

Abstract: Our main objective in this proposal is to identify and compare the molecular pathways that control the expression and function of the transcription factor Ascl1 in neurogenic stem cells of the adult brain and in astrocytes stimulated by injury. We have previously shown that adult neural stem cells induce the expression of Ascl1 when they become activated and that Ascl1 function is essential for stem cells to exit quiescence and proliferate. Our collaborators have shown that ischemia induces Ascl1 expression in a population of astrocytes restricted to the striatum. However, only a subset of these Ascl1-expressing astrocytes initiates a neurogenic programme. Here we will use cultures of neural stem cell and astrocyte as well as conditional mutant mice to characterize the signaling pathways that induce Ascl1 expression in activated neural stem cells and activated striatal astrocytes. This will help us understand why Ascl1 is not expressed more broadly by astrocytes in ischemic brains. We will also characterise the gene expression programme activated by Ascl1 in neurogenic astrocytes and we will study the signaling, transcriptional and epigenetic mechanisms responsible for the resistance of non-neurogenic astrocytes to Ascl1 function. This project will shed new light on two important steps in the activation of neurogenic programmes in the adult brain, the induction of Ascl1 expression and the stimulation by Ascl1 of cell proliferation and neurogenesis. Identifying the pathways that control these two steps in striatal astrocytes will help us decipher mechanisms that limit the neurogenic potential of adult brain astrocytes. In the longer term, our findings will help design strategies that overcome these limitations and stimulate more broadly Ascl1 expression and its activity in astrocytes in response to injury.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: The role of CASPR2 in regulating sensory neuronal excitability and chronic pain
Funder: Medical Research Council

Abstract: Chronic pain is associated with enhanced excitability within both the peripheral and central sensory nervous system; our understanding of the pathophysiological mechanisms underlying this sensitisation is still incomplete but is critically important for the development of new analgesic therapies. We will focus on a novel molecular pathway involving the protein CASPR2 (contactin associated protein 2). This is a member of the neurexin superfamily and recently two groups have independently shown that autoantibodies directed against this protein are associated with a high incidence of neuropathic pain in patients. The mechanism of this effect is however completely unknown. In our initial studies of mice lacking CASPR2 animals show behavioural hypersensitivity to noxious stimuli and dorsal root ganglia neurons derived from these animals show an enhanced response to chemical algogens. We will further define the behavioural phenotype of these animals and investigate the mechanism of this hypersensitivity using anatomical outcomes, electrophysiology, calcium imaging and assessment of voltage gated potassium channel trafficking (ion channels with which CASPR2 is known to complex). We will establish a new pain model induced by passive immunisation of rodents with CASPR2 autoantibodies in order to understand pathophysiological mechanisms and to test treatment outcomes. We have recently found that levels of CASPR2 significantly fall following traumatic nerve injury and we will therefore investigate the hypothesis that reduced CASPR2 expression contributes to acquired neuropathic pain syndromes. Finally we will establish if normalising CASPR2 levels can reverse pain-related hypersensitivity.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Pathogenesis of neuromuscular synaptic dysfunction and transmission failure in organophosphate toxicity
Funder: Medical Research Council

Abstract: Organophosphorus (OP) toxicity is a global health problem affecting industrialised and developing countries. While OP nerve agents are a worldwide threat, OP pesticides kill more than 200,000 people per annum. One major cause of death is secondary, delayed neuromuscular junction (NMJ) failure (the 'intermediate syndrome', IMS), for which there is no effective treatment. Patients therefore require mechanical ventilation over days and weeks. We have set up pig and mouse models of OP poisoning, focusing on agricultural dimethoate to better understand its pathogenesis. Preliminary data indicate that toxicity arises from additive or synergistic effects of the pesticide metabolites, specifically omethoate and the solvent metabolite cyclohexanol. Electrophysiological analysis indicates that these metabolites produce a prolonged, use-dependent hyperactivation of acetylcholine receptors (AChR) that is partially mitigated by pretreatment with the nicotinic AChR antagonist rocuronium. We will test our AChR hypothesis: a) by measuring separate and combined effects of omethoate and cyclohexanol on the conductance, open-channel probability, and desensitisation of human nicotinic AChRs expressed in HEK cells, using outside-out patch recording and administration of ACh by a concentration-jump technique; b) by using a novel ex-vivo organ culture paradigm to examine the role of activity and the mitigating effects of potential treatments against toxicity of pesticide ingredients and metabolites; c) by measuring the protective benefits of rocuronium and other blockers that we identify as candidates ex-vivo, on neuromuscular transmission, combining novel methods of confocal microendoscopy and electrophysiology and applying them to our pig model of IMS in vivo. The results will inform our ongoing clinical studies in Sri Lanka. Rapid translation of our findings from the present study into clinical practice could potentially save thousands of lives annually.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL