NIHRDataInsights/HRCSData huggingface dataset:
Title: Developing cell lines that propagate human prions
Funder: Medical Research Council

Abstract: Prion diseases share a mechanism related to seeded polymerisation and aggregation of a misfolded form of the normal prion protein. Other more common neurodegenerative conditions, including Alzheimer's disease, are also associated with misfolded protein aggregates; a wealth of evidence has led the field to pursue so-called "prion-like" mechanisms as fundamental to the entire group. Animal models have traditionally formed the basis for research into prion diseases, but are cost, time and resource-intensive. Cell lines are invaluable for in vitro studies of many complex diseases processes. Mammalian cell lines that propagate mouse prions have significantly advanced prion biology, and the development of an automated mouse prion infectivity assay at the Medical Research Council Prion Unit has revolutionised their study. However, there are no cell lines able to reproducibly propagate human prions - this remains one of the crucial goals of research into prion diseases. The primary objectives of this proposal are: 1. Develop cell lines that can reproducibly propagate human prions 2. Establish an automated system for rapid and accurate titration of human prions We propose using a "reconstitution" approach, analogous to successfully established prion animal models. Short hairpin RNAs and negative live cell sorting will be used to silence native prion protein expression in cells susceptible to prion infection, followed by reconstitution with human prion protein, infection with human prions and sequential single cell cloning. Established lines will be used to develop an automated human prion infectivity assay, permitting direct titration of prions in body tissues (analogous to HIV viral load), as a diagnostic and therapeutic biomarker, and allow the crucial direct study of human prions in vitro. Understanding the fundamental mechanism of how prions propagate and cause neuronal damage is likely to have wider significance for common neurodegenerative diseases.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Understanding and Enhancing the Therapeutic Function of Sleep
Funder: Medical Research Council

Abstract: Although evidence from healthy adults and clinical patients suggests that sleep deprivation impairs our ability to manage memories of intense emotional experiences, little is known about the role of sleep in emotional memory processing. The proposed research consists of four sections (A to D), which are designed to provide converging evidence on the mechanisms by which emotional memories are supported by sleep. The aim of Section A is to determine the necessity of sleep for emotional memory. To this end, the planned experiments will employ behavioural testing, electrodermal activity (EDA), electrocardiography (ECG) and functional magnetic resonance imaging (fMRI) to compare the brain's ability to manage emotionally salient memories after sleep and sleep deprivation. Section B will proceed to examining the roles of distinct components of sleep. In particular, an auditory stimulation technique will be used to boost the expression of sleeping brain oscillations previously linked to emotional memory. Behavioural testing, EDA, ECG and fMRI will then be employed to determine the emotional memory effects of such oscillatory enhancement. Section C will seek to foster our understanding of the mechanisms by which the sleeping brain supports emotional memory. Intracranial electroencephalography (iEEG) will be used to study interactions between hippocampal oscillations during auditory stimulation, whereas simultaneous EEG-fMRI will be used to study emotional memory reactivation and reinstatement in sleep. Finally, Section D is aimed at evaluating the clinical impacts of enhancing sleeping brain oscillations via auditory stimulation. As such, the experiments of Section B will be repeated in MD patients, opening a potential door to a novel therapeutic intervention. In sum, this research will provide unique insights into the emotional memory function of sleep and, in turn, the fundamental biology of mental health and disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Two Types of Grasp: Dissecting Cortical and Sub-cortical Contributions to Primate Hand Function
Funder: Medical Research Council

Abstract: Unlike in lower mammals, the primate corticospinal tract connects monosynaptically to motoneurons. Such connections allow primates flexibly to choose from a range of grasp types. By contrast, non-primates only use a whole-hand 'power grip'. In primates the neural systems for power grip may also exist, providing parallel control circuits allowing different modes of hand function. This probably involves descending outputs from motor and pre-motor cortex which target sub-cortical relays including the brainstem reticular formation (origin of the reticulospinal tract), propriospinal interneurons located in spinal segments C3-C4, and segmental interneurons located in the cervical enlargement. We do not know how these centres contribute differently to power and precision grasps. This is important, as damage such as spinal cord injury or stroke frequently impairs corticospinal function. Recovery of hand function may then rely on the systems normally subserving power grip. In this project, we will train monkeys to perform different grips, and then record cell spiking from primary motor cortex, ventral pre-motor cortex, supplementary motor area, the reticular formation, C3-C4 and C6-T1 spinal cord interneurons. Task-related firing will reveal how these areas contribute to different grasps. We will also focally inactivate each region by injecting inhibitory agonists, and assess the grip deficits produced. In anaesthetised monkeys, we will assess the cortical inputs to sub-cortical regions by testing the responses to cortical microstimulation via implanted electrodes, and transcranial magnetic brain stimulation with the stimulating coil held in different orientations. This information will allow us to design and interpret non-invasive methods to probe specific neural circuits in humans. After testing such approaches in healthy subjects, we will use them to quantify how different centres contribute to hand function in individuals after recovery from spinal cord injury.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Oxytocin pathways affecting metabolism
Funder: Medical Research Council

Abstract: As obesity develops, the brain becomes resistant to signals which normally balance body weight, such as adipose-derived leptin. Reversing obesity will require bypassing this resistance, by identifying accessible targets downstream of leptin signalling. One such target being investigated is the oxytocinergic system. Chronic administration of oxytocin (Oxt) decreases food intake and increases energy expenditure (EE) in leptin-resistant models. Intranasal Oxt, which can access the brain, has acute effects on food intake, reward and craving in humans, and eight weeks treatment is reported to reduce body weight in obese patients. We will provide evidence that Oxt neurones can reduce appetite without causing adverse effects, while at the same time increasing both EE and peripheral lipolysis. We will use the latest techniques of chemo- and optogenetics to demonstrate that these major actions of Oxt are mediated by distinct central pathways. We predict that Oxt-receptive, OxtrBNST cells, form local inhibitory connections with GABA BNST to LH neurones, which have been shown previously to cause a strong feeding response, and with GABA BNST to VTA neurones which increase reward. Activation of either pathway can induce place preference and/or self-stimulation, indicating an increase in motivational valence. Thus, the OxtPVH to OxtrBNST to GABABNST pathway would inhibit BNST outputs to both the lateral hypothalamus and ventral tegmental area and decrease the motivation to eat (i.e. reduce hunger). Concurrently, OxtPVH neurones projecting to the brainstem would inhibit gastric emptying via the parasympathetic system and this would indirectly reduce food intake. Thus, the OxtPVH to OxtrNTS to AChDMX pathway induces satiation and increases satiety. Finally, a direct innervation of sympathetic neurones in the intermediolateral spinal cord (OxtPVH to AChIML) would induce thermogenesis in brown adipose tissue (leading to increased EE) and enhance lipolysis in white adipose tissue.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: Is the microglial response in Alzheimer's disease determined by a dysfunctional balance of proliferation and survival?
Funder: Medical Research Council

Abstract: We hypothesise that an accelerated microglial turnover in response to Abeta accumulation in AD is triggered at disease onset, driving replicative senescence in microglia and unleashing the detrimental inflammatory profile characteristic of AD. We will define the basic parameters regulating the number of microglia in a mouse model of AD-like pathology (APP/PS1), including the definition of the time-course of the rates of proliferation and apoptosis, and the cell cycle length, using pulse-chase studies coupled to flow cytometry (FC). We will then profile the transcriptome of microglia isolated at different stages of the pathology, in order to understand the correlation of any observed changes in microglial turnover with the alteration of the inflammatory profile. With these two sets of data, we will be able to predict the time when a microglial cell can develop replicative senescence, arising from the accumulation of an excessive number of cycling events. Then, we will use TetO-APPSweInd mice, which will allow to control the onset of Abeta pathology, in order to accurately define the sequence of linking the early onset of amyloidosis to delayed changes in the microglial inflammatory phenotype. We will then prevent the transition of microglia to a detrimental phenotype by interfering with microglial proliferation or apoptosis, as a mechanistic intervention to discover the functional contribution of these mechanisms to the observed pathological changes. Using TetO-APPSweInd mice will also allow switching off Abeta pathology, and downstream analysis of the reversibility of the observed changes in microglial turnover and phenotype. We will collaborate with relevant experts in key technical aspects of the proposal, allowing a comprehensive analysis of our hypothesis. These experiments will define the time course of the contribution of microglia to AD, allowing the understanding of the events developing in the brain years before the onset of AD's clinical manifestations.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: IMPC: Characterisation a novel Alzheimer's disease susceptibility locus
Funder: Medical Research Council

Abstract: It would be of great assistance in the design of new drugs for Alzheimer's disease (AD) and other dementias if the biological mechanisms that make some people and not others susceptible to these diseases were understood better. This would assist drug companies to choose the best targets when they design new drugs and enable them to trial drugs that already exist but whose use is not obviously indicated in the treatment of AD. Many new genes that are associated with increased susceptibility to AD and other dementias have been implicated recently through big genetic studies, but in most cases it is not clear how these genes influence disease. One of the problems is that the genetic variants detected mostly do not have an obvious biological function. In our recent studies we have detected a number of variants predicted to have direct biological effects on proteins, which we can test experimentally. One such variant is in a little studied gene called ABI3. We are interested in the protein produced by ABI3 because it is also part of a network of proteins that we have previously identified as being critical in AD pathogenesis and it is expressed at high levels in microglia, an immune cell of the brain. In this proposal we will test the hypothesis that ABI3 regulates microglia functions that contribute to the development of AD; we expect that understanding the pathways controlled by ABI3 will provide novel insight into the mechanisms underlying the development of AD. We will use recently generated Abi3-deficient mice to determine the key functions of the Abi3 protein in the first steps to understanding its contribution to disease susceptibility in AD.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Distributed anatomical circuits for decision-making, inference, and learning
Funder: Medical Research Council

Abstract: We will investigate the neural basis of decision making, learning, behavioural change, and inference in PFC and ACC. Neural activity will be recorded in macaques with fMRI and probed with a range of interventions including lesions, focal ultrasound neurostimulation, and possibly microstimulation. Effects on behaviour and neural activity will be measured. The aim of each project is not simply to assess involvement of brain areas in cognitive processes of interest but instead it is to derive a mechanistic understanding of the way in which the areas operate and the way in which they interact with other brain areas. With careful task design it is possible to identify neural activity covarying with quantitative estimates of choice value and value comparison. It is then possible to determine the nature of PFC and ACC representations when a decision is made between choices, when an inference is made about a choice's value on the basis of past experience, and when estimates of choice values or behaviour values are being updated during learning. Computational models will be used to guide analyses. The models will be used to make quantitative predictions of behaviour and neural activity that can be contrasted with actual observations. We will investigate: 1) simultaneous representation of multiple learning rates in dACC; 2) different reward representations in lOFC and amygdala in relation to credit assignment; 3) independent versus interactive nature of vmPFC and dACC during decision making; 4) hippocampus-dependent map-like representation to guide decision making in vmPFC and pgACC; 5) model-based versus model-free reward learning mediated by lPFC and vmPFC interaction; 6) activation and suppression of stimulus-reward representations in OFC; 7) a mechanism for determining speed, accuracy, and task engagement dependent on average reward and temporal structure of the environment; 8) distinct representations of surprise and prediction error in PFC and striatum.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Role of the GABA transporter, GAT-3, in regulating network excitability in the hippocampus
Funder: Medical Research Council

Abstract: GAT1 and GAT3, are the two main GABA transporters in the hippocampus. These play a critical role in regulating the concentration of the major inhibitory transmitter GABA in the extracellular space. This is crucial as extracellular GABA can act on extrasynaptic GABA(A) receptors on neurons to mediate a powerful form of tonic inhibition of neurons, regulating signal processing and memory. These two transporters, however, serve different roles and have a distinct distribution, so that GAT1 is mainly expressed on neurons, whilst GAT3 is mainly expressed on glia. GAT1 is the main regulator of extracellular GABA in the hippocampus, whilst GAT3 only comes into play during excessive neuronal activity. We have recently shown that GAT3 serves a secondary role in that it enables glia to detect extracellular GABA concentrations and consequently network activity and to respond to this by releasing gliatransmitters that have a marked influence on network excitability. This may serve as a powerful homeostatic mechanism regulating network excitability over long time periods. However, many questions on the role of GAT3 remain unanswered. Can it work in reverse to increase the concentration of GABA in the extracellular space and under what conditions? What is the range of inhibitory and excitatory gliatransmitters that are released with GAT3 activation and does this depend upon circumstances (eg the degree of GAT3 activation and the activation of other glia receptors)? What is the role of GAT-3 during excessive neuronal activity such as occurs with seizures? What is the impact of changes in GAT3 expression that occurs during the development of epilepsy and other neurological disease? Addressing these questions is critical as GAT3 is a druggable target that could be used to treat a range of neurological and neurodegenerative conditions from epilepsy to Alzheimer's disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: The differential role of specific POMC neuronal circuits in mediating the beneficial and detrimental effects of opioids.
Funder: Medical Research Council

Abstract: Opioids have potent analgesic properties and remain first rank therapies despite significant adverse central side-effects such as addiction risk, sedation and respiratory depression. The opioid drugs bluntly and globally mimic the action of endogenous opioids, of which beta-endorphin is particularly important in the modulation of pain. The endogenous release of beta-endorphin is not associated with the same profile of side effects but it is not known why. Therefore, a better understanding of the opioidergic circuitry within the brain is needed to help to separate the beneficial from the harmful effects of opioidergic activation. Beta-endorphin is a cleavage product of pro-opiomelanocortin (POMC) and the primary source in the CNS are the POMC neurons of the arcuate nucleus (ARC) and the nucleus of the solitary tract (NTS). We have recently shown that these NTS neurons produce opioid receptor mediated analgesia and alter cardiorespiratory regulation. Our pilot data indicates that activation of these neurons is anxiolytic but not rewarding or sedating. We propose that activation of the POMC NTS neurons may produce useful analgesia that has fewer confounding side effects. We will investigate the consequences POMC neuron activation or inhibition using DREADD expression. Excitatory and inhibitory DREADDs will be expressed in ARC or NTS POMC neurons by microinjection of a Cre-inducible viral vector into POMC-Cre mice. These neurons can then be specifically activated or inhibited by administration of CNO. The role of these neurons will be assessed in several behavioural paradigms i.e. measures of acute pain, anxiety, sedation, reward, and stress-induced analgesia. Furthermore, the analgesic effect of POMC-neuronal activation in the context of chronic neuropathic and inflammatory pain will also be investigated. These studies will increase our knowledge of the endogenous opioid circuits with the goal of identifying novel therapeutic strategies for analgesia.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Critical function of Kir4.1 for the life-long generation of oligodendrocytes and myelin
Funder: Medical Research Council

Abstract: The proposal is to test the hypothesis that Kir4.1 potassium channels expressed by oligodendrocyte progenitor cells (OPCs) are vitally important for the life-long generation of oligodendrocytes and myelin. Oligodendrocytes are specialised to form myelin in the CNS. Myelin is essential for rapid neuronal connectivity throughout the CNS and underlies the massive computing power of the human brain. Moreover, the myelin sheath is essential for the long-term integrity of myelinated axons. Fate-mapping studies in mice provide direct evidence that myelin is replaced throughout life by oligodendrocytes newly generated from endogenous OPCs. The failure of repair has devastating effects on brain function and neuronal integrity in multiple neuropathologies, including multiple sclerosis, leukodystrophies, stroke and traumatic injury. Hence, knowledge of the mechanisms regulating oligodendrogliogenesis in the adult brain are relevant to understanding the life-long maintenance of healthy myelin and potential mechanisms of neuropathology. The applicants provide new evidence of a fundamental role for the inwardly rectifying potassium channel Kir4.1 in oligodendrogliogenesis and myelination in the mouse brain. To take this work forward, we have developed an inducible Cre/LoxP mouse line that targets Kir4.1 specifically in OPCs. These mice provide a major new advance that provides us with the temporal control of Kir4.1 function specifically in OPCs and enables us to determine the importance of Kir4.1 in the control of the regenerative capacity of OPCs in the developing and adult brain and following damage. This is fundamental research that is relevant to multiple neuropathologies and is in line with the MRC Neurosciences and Mental Health Board themes of 'resilience, repair and replacement' and 'living a long and healthy life'.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Decoding the effects of neural transplantation in patients with Parkinson's disease: a multimodal imaging study
Funder: Medical Research Council

Abstract: Early trials of human fetal mesencephalic tissue (hfVM) in Parkinson's disease (PD) provided evidence that such grafted cells can survive, restore dopamine release and cortical motor function, enabling dramatic clinical improvements in motor symptoms and quality of life with the cessation of their PD drugs in some cases. While later double-blind trials failed to confirm such efficacy and even generated dyskinesias, patients still exhibited significant increases in dopaminergic function and partial relief of symptoms, indicating that outcome heterogeneity thus far had resulted from inconsistent and sub-optimal protocols. In 2006 we set up an international working group that sought to collate and analyse the data from all the existing hfVM trials with the aim of identifying how best to take this therapy forward, especially as we enter an era of stem cell treatments. This led to the funding of TRANSEURO (EU FP7 programme). Unlike previous trials patients in this programme are younger with less advanced disease and no significant LIDs, they were transplanted with more standardised tissue preparations, and have undergone a novel extensive multimodal imaging protocol thus providing a uniquely well-characterized cohort. In this new project we propose to study 15 grafted patients and 15 matched PD patients from TRANSEURO using a comprehensive clinical and multimodal imaging battery in order to understand the complex underlying neural networks related to this cell repair strategy and to develop optimal imaging assessments for future stem cell transplants. In this regard, while hfVM based therapies will never become mainline therapies for PD for logistical and ethical reason, they nevertheless will pave the way for the next generation of stem cell treatments. These therapies are now approaching first in human clinical trials and as such the study proposed in this application, will be vital in the testing of this new exciting restorative therapy.


Research activity codes: 6.4 SURGERY
Health categories: NEUROLOGICAL