NIHRDataInsights/HRCSData huggingface dataset:
Title: Space distortions: Towards a general framework of the hippocampal cognitive map
Funder: Wellcome Trust

Abstract: A fundamental question in system neuroscience is where spatial cognition is generated and how it is used for navigation. Strong evidence points at the hippocampus as a cognitive map. Hippocampal place cells are active in restricted fields and hippocampal lesion impairs navigation. Recent experiments showed that spatial representations are also found in the entorhinal cortex, an interface between the hippocampus and neocortex. Entorhinal grid cells are active in many fields arranged in equilateral triangles. How these cells interact to provide a cognitive space remains elusive. It has been suggested that grid cells represent a spatial metric system and provide major inputs to the place cells. A number of recent experiments indicate a greater role of place cells in constructing grid cell pattern. Here, we propose to investigate how these cells interact and what role they play in navigation. We will test whether grid cells act as a spatial metric of the brain. Alternatively, we suggested that they could act as a matrix system conveying the information about the proximity of locations. Furthermore, we will study how single-cell perturbations affect interconnected grid-place cell network as well as an animal’s ability to navigate.

Lay abstract: The hippocampal formation is crucial for episodic memories and represents the internal GPS system of the brain. Although the basic spatial properties of neurons in the hippocampus and its major hub, the medial entorhinal cortex (mEC), are well characterised, questions remain about where and how spatial representations are constructed and what their functional roles are in navigation. The major theoretical models assume that hippocampal spatial representations are generated by mEC cells. Our previous findings called into question these assumptions and instead suggested a greater role for hippocampal spatial cells in shaping neural activity in the mEC. To test this idea, I propose to manipulate neural activity at the single-cell level in a defined set of hippocampal cells projecting to the same mEC target cell and study how new representations emerge and how these representations are reflected in an animal’s behaviour. The mEC is one of the first areas affected during the Alzheimer’s disease. Understanding the functional role it plays in navigation would be an important breakthrough in the much-needed early diagnosis of the disease.

Research activity codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: NEUROLOGICAL;MENTAL HEALTH
Title: Establishing circuit, neuronal and synaptic mechanisms of associative recognition memory
Funder: Wellcome Trust

Abstract: Recognition memory, our ability to discriminate between new and familiar stimuli, is essential for us to lead normal everyday lives. Such memory requires encoding of information about new and familiar objects, the locations where we saw them, and the formation of robust object-location associations for subsequent memory retrieval. Associative recognition memory depends on distinct but highly interconnected brain regions within the medial temporal lobe, frontal cortex and thalamus. But which regions communicate, and when does communication occur, to form memory associations? Are the same regional connections that are necessary for encoding also required for memory retrieval? Which neuronal and which synaptic mechanisms control encoding and which control retrieval? These questions will be answered using temporally-precise, pathway-specific silencing, neuronal recordings and interrogation of synaptic mechanisms across the circuits. Activity-driven Cre-inducible gene expression in the rat, will be used to determine specifically the neuronal ensembles in different brain regions and their connections that are critical for encoding and retrieval of associative memory while ex vivo electrophysiology will reveal the synaptic mechanisms that control neuronal ensembles activated by learning. This work will establish how highly dynamic, synaptically connected neuronal populations enable associative recognition memory formation through local and long-range neural networks.

Lay abstract: Where did I park the car? Successful recall of stimuli and their previous locations is essential for us to lead normal lives. A type of memory known as associative recognition memory allows us to remember the association between items, places and time enabling us to recognise, for example, where we left the car. We know that different types of memory information rely on many different parts of the brain. However, there is little idea of how communication between these different brain regions allows us to acquire and recall different memories. In this proposal we will use the rat’s innate ability to remember objects and their locations to examine which connections are essential for successful memory formation and which cellular processes control the necessary communication between different brain regions. We will achieve this by silencing specific connections between brain regions during memory tasks and will use neurone recording methods from brain slices and whole animals, to examine the precise chemical and transmitter mechanisms that control communication at those connections. These advances in understanding of memory mechanisms will pave the way for future studies into how learning and memory decline with age or with dementia.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL;MENTAL HEALTH
Title: How confident are you now? Identifying psychological and neural predictors of suboptimal metacognitive decisions in the general population
Funder: The British Academy

Abstract: People who are able to accurately evaluate their behaviour and decisions are said to possess a high level of ‘metacognitive’ insight. Conversely, people who either over- or under-estimate the accuracy of their behaviours and decisions possess low ‘metacognitive’ insight. Metacognition differs widely across individuals and plays a crucial role in the optimisation of learning and decision-making. In an online experiment involving both perceptual and knowledge-based decision-making tasks, we propose to investigate the relationship between metacognitive insight and self-reported personality traits and psychiatric symptom dimensions in a large, heterogeneous general population sample. Additionally, in a second experiment we will employ electroencephalography (EEG) to uncover the neural activity patterns involved in both decision-making and metacognitive evaluation. If we understand these processes, we may also understand why decisions and self-evaluation are often biased and apparently sub-optimal. This knowledge would facilitate the development of future behavioural and/or pharmacological techniques to optimise accurate self-evaluation.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: NEUROLOGICAL;MENTAL HEALTH
Title: The Functional Role of Sleep-Wake Regulation in Social Perception: How Sleep Disruption Affects Social Behaviour
Funder: The British Academy

Abstract: Chronic sleep disruption related to long, unsociable working hours is a public health concern. Sleep disruption changes our mental state and actions, but, how it modifies our perceptions of other people's mental state and actions is unknown. Cognition is synchronized to our sleep-wake cycle, such that it deteriorates over wake and recovers during sleep. Whether all cognitive processes are regulated similarly is debated, and notably underexplored in social cognition. Our social perceptions dominate interpersonal interactions and profoundly impact social behaviour. We will characterise the sleep-wake regulation in social perception (in healthy individuals) in field and laboratory settings, using actigraphy, questionnaires and neuro-behavioural measures comprising performance in tasks of theory of mind, affective/motor empathy and cortical activity related to motor evoked potential. This work will provide one of the first neuro-behavioural descriptions of the cost of sleep disruption on social behaviour, thus serving as a gateway to strategies for social well-being.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: NEUROLOGICAL;MENTAL HEALTH
Title: Media use of pharmaceutical promotional literature: the case of antidepressant medication
Funder: The British Academy

Abstract: Much is published in the media about antidepressants, but how trustworthy is the information provided in newspapers and medical journals? Do journalists and health professionals rely too heavily on promotional literature provided by industry? In this project, we will compare the promotional literature with news and medical articles about antidepressants, identifying the relationships between them, and we will interview the authors of such texts to better understand and evaluate their credibility. We will also compare Britain with China, a system with much stronger state control: what are the advantages and drawbacks of less regulation concerning health information in media targeting lay people and health professionals? Findings will illuminate the conditions and processes affecting the objective and trustful supply of information for antidepressants in the media, and the implications for prescription drug advertising policy-making and media requirements will be explored by reference to the contrasting contexts of British and Chinese societies.


Research activity codes: 5.1 PHARMACEUTICALS;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: NEUROLOGICAL;MENTAL HEALTH
Title: Brain engineering: towards closed-loop, non-invasive bioelectronic therapies for neurological disorders
Funder: Royal Academy of Engineering

Abstract: This project is working to improve treatments for diseases of the nervous system. For invasive devices that are implanted in the body, Professor Denison’s team has collaborated with UK-based Bioinduction Ltd (Bristol) to create the “Picostim DyNeuMo” research platform based on their Picostim neurostimulator. The Picostim DyNeuMo research platform is exploring advanced therapy concepts to the research clinic; the first motion-adaptive system, which works like a programmable bioengineered reflex, was implanted in early 2022 as part of a research protocol developing treatments for autonomic disorders. For minimally invasive systems, Professor Denison is working to advance transcranial magnetic stimulation for brain disorders such as anxiety in collaboration with UK-based Magstim Ltd (Whitland, Wales). Professor Denison hopes to bring new solutions for the treatment of mental health disorders through advanced power electronics, machine learning, and feedback control. These technologies should provide a more patient-specific therapy for diseases poorly served with existing treatments.Ana Cavalcanti is a Professor at the University of York, and a Royal Academy of Engineering Chair in Emerging Technologies. She is the leader of the RoboStar centre of excellence on Software Engineering for Robotics. The RoboStar approach to model-based Software Engineering complements current practice of design and verification of mobile and autonomous robots, covering simulation, testing, and proof. The RoboStar approach is practical, supported by tools, and yet mathematically rigorous so that it can provide reliable evidence of trustworthiness.


Research activity codes: 5.3 MEDICAL DEVICES;6.3 MEDICAL DEVICES
Health categories: NEUROLOGICAL;MENTAL HEALTH
Title: Developing UBA1-targeted therapies for Motor Neuron Diseases
Funder: LifeArc

Abstract: Motor neuron disease (MND) describes a group of rare conditions which affect nerve cells that control muscle activity such as walking, breathing, speaking and swallowing. Over time, people with MND may lose their ability to walk or control other movements. Sadly, there is no cure – and new treatments are desperately needed to improve the outlook for people with these devastating illnesses. Professor Gillingwater’s team is aiming to develop new drugs for treating certain types of MND: amyotrophic lateral sclerosis (ALS) that causes rapid loss of muscle control and eventual paralysis – and spinal muscular atrophy (SMA), a genetic disease that affects children. Their approach involves targeting an enzyme called UBA1, which they have previously shown to have considerable potential for treating these conditions. In collaboration with Atomwise, the researchers have recently used artificial intelligence to identify around 70 potential drug compounds which are predicted to target UBA1. They will now carry out a series of laboratory experiments to evaluate their properties – with the future goal of taking one promising compound into clinical trials. They are partnering with the Euan MacDonald Centre for Motor Neuron Disease Research and the Anne Rowling Regenerative Neurology Clinic to secure a route to the clinic.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL;MENTAL HEALTH
Title: Over two years to study the metabolic phenotype of the infant of the mother with gestational diabetes
Funder: Action Medical Research

Abstract: Background Each year in the UK up to 40,000 babies are born to mothers who suffer from diabetes during pregnancy. These babies are at least four times more likely than other babies to develop type two diabetes later in life but it is not known which babies will go on to develop the condition. Type two diabetes is linked to genetic and environmental factors and although it often starts in adulthood it is increasingly being diagnosed in children. In this condition, insulin does not act efficiently and blood sugar can become high making children feel unwell. They may need to monitor glucose levels, follow a specific diet and take medications or insulin injections. The condition brings an increased risk of heart disease, stroke, vision loss and kidney disease in later life. This type of diabetes is a leading cause of death and is increasing with 2.8 million people affected in the UK. In children and adults adverse metabolism and body fat distribution increase T2D risk. The research project Dr Logan will compare metabolism and body fat distribution in infants of mothers with gestational diabetes (IGD) and other healthy babies. She will analyse metabolic fingerprints (the pattern of hundreds of naturally occurring substances in urine), the amount and location of body fat, and the amount of fat in the liver using highly sophisticated techniques that are that are safe and non-invasive. There are few centres in the world where such research is possible and these methods have not been used to study newborn IGD. Identifying children most at risk of diabetes in the future would allow preventive action to reduce these risks and could help to reduce the disability caused by type two diabetes.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;METABOLIC AND ENDOCRINE
Title: The role of galanin and its receptors in painful diabetic neuropathy
Funder: Diabetes UK

Abstract: The focus of this application is to validate GalR2 as a novel treatment for PDN. The work outlined in this grant application will address the following 4 aims:- 1. Galanin over-expressing transgenic mice (Gal-OEtet) will be used to switch on over-expression of the neuropeptide at different times after diabetes induction to allow the upregulation of galanin before or after pain behaviour (allodynia) has developed. These experiments will allow us to separate and compare the roles played by galanin in the induction and maintenance of PDN. 2. Sensitive and quantitative real-time PCR assays will be used to measure the levels of galanin and its receptors in the sensory neurons of the dorsal root ganglia (DRG) and test whether their expression is predominantly driven by hyperglycaemia or allodynia. 3. Gene chip arrays will be used to compare DRG gene expression in WT and Gal-OEtet mice after STZ, identifying genes whose expression underlies the reduction in allodynia that is observed in the Gal-OEtet mice after STZ. 4. A series of novel GalR2 positive allosteric modulators (PAMs) will be tested in the STZ model, allowing us to determine the efficacy of compounds that are peripherally restricted, and whether GalR2-activity alone is sufficient for maximal analgesic effect.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL;METABOLIC AND ENDOCRINE
Title: Role of Transient Receptor Potential A1 in diabetic pain and neuropathy
Funder: Diabetes UK

Abstract: Diabetic neuropathy is a common and often devastating complication of type 1 and type 2 diabetes. Although the major symptom of diabetic polyneuropathy is sensory loss, many patients also suffer from pain and diabetic neuropathy is a major cause of chronic neuropathic pain. Diabetic pain is poorly treated as the available drugs either have limited efficacy or intolerable side effects for the majority of patients. The detailed mechanisms responsible for the neuropathy and the painful symptoms in diabetes are unknown. This project proposal is based on our original observations that methylglyoxal, a molecule formed specifically during hyperglycaemia, evokes pain and loss of intra-epidermal nerve fibres by stimulating TRPA1. The proposed work will determine the importance of TRPA1 in the genesis and maintenance of painful and insensate diabetic sensory neuropathy. Identification of TRPA1 as an important mediator of sensory changes in diabetes and as an effector molecule of diabetic neuropathy will provide new rationales for the development of novel treatments for diabetic neuropathy. Our studies will also determine if long term restoration of insulin production by pancreatic islet transplantation can reverse established sensory disorders associated with diabetes.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL;METABOLIC AND ENDOCRINE
Title: Extracellular matrix glycation in diabetic neuropathy
Funder: Juvenile Diabetes Research Foundation

Abstract: The degeneration of sensory nerve terminals in the skin, and subsequent failure of axonal regeneration is a key pathological feature of diabetic neuropathy. Reinnervation of tissue may occur either by regeneration of degenerated axons or by collateral branching of undamaged axons. Both these processes are impaired in diabetes and degeneration occurs at a faster rate than reinnervation leading to loss of sensation. The objective of this proposal is to test the hypothesis that glycation of extracellular matrix (ECM) in the peripheral nerve environment causes the failure of sensory axonal regeneration in diabetes. The ECM is a complex of proteins, including laminin, collagen and fibronectin, which surround cells and tissues within the body. The ECM not only provides important physical support for cells, but also directly regulates cell behaviour through interaction with a family of cell adhesion receptors called the integrins. Integrin levels in sensory neurons in diabetes have not been studied to date; potentially a diabetes-associated deficit in integrin expression could contribute to the failure of axonal regeneration since integrin-ECM interactions have been shown to be crucial for axonal outgrowth in development and following nerve injury. We have demonstrated that rat sensory neurons in culture plated on glycated ECM extend fewer and shorter neurites than those plated on control ECM. Glycation of ECM proteins may cause structural changes to the protein that impair integrin-ECM interaction. Glycation may also render ECM proteins resistant to digestion by Matrix Metalloproteinases (MMPs) a family of enzymes important for essential ECM remodelling events during axonal degeneration and subsequent regeneration. This project aims to elucidate the molecular mechanisms underlying the impaired regeneration on glycated ECM, and characterise the expression of integrins and MMPs in the peripheral nervous system of STZ-induced diabetic rats. We will determine whether axonal regeneration can be enhanced by manipulation of the ECM, using MMPs and Advanced Glycation Endproduct (AGE) inhibitors (such as pyridoxamine) in vitro and translate the successful interventions into animal studies, comparing nerve function and morphology in control, untreated and treated STZ-diabetic rats.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;METABOLIC AND ENDOCRINE
Title: The role of the PPARgamma cofactors in Alzheimer's disease
Funder: Alzheimer's Research UK

Abstract: There is now convincing evidence for a link between metabolic diseases, such as type 2 diabetes (T2D) and Alzheimer’s disease (AD). The mechanisms that mediate these effects are not clear. One of the reasons could be that IR and TD2 are closely linked with chronic inflammation, which could lead to higher propensity to develop AD or to exacerbate AD symptoms We have previously demonstrated that the nuclear receptor PPARγ is a potential target for AD, since its activation by various ligands, including certain anti-diabetic drugs, decreases the levels of Aβ as well as microglial activation. In this project our goal is to assess whether the cofactors of PPARγ, PGC1α, Receptor Interacting Protein 140 (RIP140), and NCor, which have a potential role in the regulation of insulin resistance, could be involved in AD. For this purpose, we plan to assess if and how these transcriptional regulators affect the generation of Aβ and neuronal survival in cell culture and to study the molecular mechanisms behind these effects. The results of this project could be relevant because if successful, therapeutic modulation of these cofactors have a real potential for the treatment of diseases including T2D and AD.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;METABOLIC AND ENDOCRINE
Title: Unravelling the tangled molecular connections of BACE1 and GSK3.
Funder: Alzheimer's Research UK

Abstract: The pathological hallmarks of Alzheimer’s disease are plaques and tangles. Plaques are composed of a molecule called Abeta, tangles are primarily made of a modified form of a protein called tau. The enzyme BACE1 is required for the production of Abeta and the enzyme GSK3 promotes the modification of tau. We have found that GSK3 goes wrong in diabetes and that if BACE1 goes wrong it causes metabolic problems that could contribute to diabetes. Others have recently found that GSK3 can control the levels of BACE1 and that GSK3 is activated by Abeta. This suggests that when one of these enzymes goes wrong it disrupts the other, potentially giving us a molecular link between plaques and tangles, and between diabetes and dementia. Importantly, if we break the link we could improve health in both dementia and diabetes. We propose to generate evidence for this hypothesis by performing three key experiments. Firstly we will examine whether GSK3 activity changes every time BACE1 activity changes, secondly we will examine whether BACE1 activity changes every time GSK3 activity changes, and thirdly we will map the molecular highways between the two in order to find points where we could intervene for clinical benefit.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;METABOLIC AND ENDOCRINE