NIHRDataInsights/HRCSData huggingface dataset:
Title: Psychiatric Imaging Programme Transition
Funder: Medical Research Council

Abstract: Schizophrenia (SCZ) is a top ten cause of disability in young adults. Treatments are inadequate, particularly for the cognitive impairments, which increase early in SCZ. A leading hypothesis proposes that synaptic terminal loss is central to SCZ pathoetiology, leading to impaired neural function & symptoms, including cognitive impairments, & that the complement protein C4 plays a key role in this by tagging synaptic terminals for elimination. Converging preclinical, genetic & post-mortem evidence supports it. PET imaging measures of a synaptic terminal marker, synaptic vesicle glycoprotein 2a (SV2a), mean the hypothesis can now be tested in vivo. PET studies in chronic SCZ show lower SV2a levels relative to controls. Preclinical studies show that lower SV2a levels lead to reduced neural activity & cognitive impairments, & we found that lower SV2a levels correlate with poorer cognitive performance & lower neural responses in SCZ. The critical outstanding questions are thus: 1. Are SV2a levels lower at onset of SCZ & is there further loss? 2. Do C4 & SV2a levels predict increasing cognitive impairments & other symptoms in SCZ? 3. Does lowering SV2a activity impair neural function in SCZ? Finally, synaptic loss may begin in adolescence during the prodromes to SCZ & other neurodevelopmental disorders, & also affect post-synaptic proteins. However, the field lacks the in vivo human approaches needed to test this. We plan to address these issues in three related work-packages. The first two comprise imaging & experimental medicine studies in patients, whilst the third involves testing new human imaging approaches. These have the potential to identify novel treatment targets for SCZ, & biomarkers to assess them. They will also have benefits for understanding mechanisms in multiple other CNS disorders where synaptic protein loss, including of SV2a & post-synaptic proteins, is implicated (eg: autism, Alzheimer's disease & depression).


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: AI-driven brain modelling for personalised cognitive enhancement
Funder: Medical Research Council

Abstract: Drugs that target the cholinergic system, such as donepezil and galantamine, are commonly used to alleviate cognitive decline in dementia and mild cognitive impairment (MCI). However, these drugs only provide a modest benefit in a subset of patients. Artificial intelligent algorithms are showing high promise in predicting and classifying brain disorders, including dementia. However, they are typically used as black box approaches which fail to provide insights on how biological mechanisms should be rescued to improve clinical outcomes. Recently we have developed AI-driven brain models that offer great promise at bridging the clinical and fundamental neuroscience gap. In contrast to standard approaches, our AI-driven brain modelling approach enables us to map precise neuronal mechanisms onto cognitive processes in health and disease. Our models predict that Cholinergic neuromodulators enable the development of neuronal task-specific representations in biological neural networks with improved resilience to perturbations, such as neuronal death. In this project we will study how the cognitive robustness to neuronal death predicted by our model depends on cognitive training conditions. This will enable us to identify the optimal training regimes for improved cognitive robustness. Next, we will build on these findings together with a model of cholinergic drugs (donepezil and galantamine) to propose how to best combine cognitive training with drug administration, and why under some conditions cholinergic drugs might not be efficient. These results will guide the development of personalised treatments for cognitive enhancement through a combination of existing cholinergic drugs with cognitive training. Overall, this project will showcase how AI-driven brain modelling closely informed by decades of experimental research can inform clinical neuroscience.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: All-optical interrogation of neural circuits during behaviour
Funder: Wellcome Trust

Abstract: Neural circuits display complex spatiotemporal patterns of activity on the millisecond timescale. Understanding how these activity patterns drive behaviour is a fundamental problem in neuroscience. To address this challenge, I have recently introduced a novel approach that combines simultaneous two-photon calcium imaging and two-photon targeted optogenetic photostimulation with the use of a spatial light modulator (SLM) to provide 'all-optical' readout and manipulation of the same neurons in vivo. I propose to probe the neural code in mouse barrel cortex during sensory-guided behavioural tasks by using this approach to uncover the underlying mechanisms of decoding and encoding of information by ensembles of neurons. I will train mice to make perceptual decisions based on quantitative control of cortical activity, as well as perturb neural activity in somatosensory cortex while animals are performing discrimination tasks using their whiskers. I can perform decisive tests of theoretical models describing the neural code by assessing the spatiotemporal pattern of activation required in somatosensory cortex to drive a behavioral response. These experiments will shed light on how many neurons with which functional signature are minimally sufficient to subserve a percept.

Lay abstract: Neurons in the brain process information via electrical impulses or spikes. How does the pattern of spikes drive perception, or enable performance of an action? Such crucial questions have yet to be answered despite substantial recent progress in neuroscience. I propose to use an approach I developed to answer these fundamental questions to reveal how brains work to perform computational feats surpassing what human engineers can create. Previous research on how spikes drive behaviour has taken two complementary approaches: correlating neuronal activity with what is happening in the environment, and stimulating neuronal activity while recording behavioural responses. The goal of my proposal is to bring these two approaches together. I have developed an optical approach that allows me to use light to both record and manipulate the activity of many neurons simultaneously on the level of individual spikes. I will employ this approach in the sensory cortex of a mouse performing sensory-guided tasks to manipulate neurons in a precisely targeted manner and examine the influence on behaviour to understand the ‘code’ the brain uses. Such understanding may give us new insights into the workings of the neocortex, and in turn spur development of new treatments for debilitating brain disorders.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Cortico-striatal interactions in sensorimotor decision-making
Funder: Wellcome Trust

Abstract: Associations between sensory stimuli and motor actions underlie many behaviours. The basal ganglia, a group of brain nuclei highly conserved in vertebrates, are a key structure in sensorimotor associations. The largest of these nuclei, and the first to receive sensory information from the cerebral cortex, is called the striatum. In this project, we will investigate how information about visual stimuli flows from the cortex to the striatum. There will be three specific aims, which we will address by recording and manipulating activity in visual cortex and striatum while mice perform a visually-guided decision task. The manipulations will be performed using the technique of optogenetics, whereby one can drive brain activity using light. First, we will determine which parts of the striatum are required for the task, and ask whether optogenetically activating their inputs from visual cortex can affect behavior. Second, we will compare activity in visual cortex and striatum before and after mice learn the task, and ask whether the strength of the connection between them has changed. Third, we will measure how optogenetically activating cortical activity changes activity in the striatum and beyond. These experiments should provide fundamental insights into how sensory inputs are transformed into actions.


Research activity codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: The role of rat Posterior Parietal Cortex in statistical learning
Funder: Wellcome Trust

Abstract: The world around us is complex, but at the same time full of meaningful regularities. We can detect, learn and exploit these regularities automatically in an unsupervised manner, i.e. without any direct instruction or explicit reward. For example, we effortlessly estimate the average tallness of people in a room, or the boundaries between words in a language. These regularities, once learned, can affect the way we acquire and interpret new information to build and update our internal model of the world for future decision-making processes. Despite the ubiquity of passively learning from the structured information in the environment, the mechanisms that support learning from real-world experience are largely unknown. By combining sophisticated cognitive tasks in human and rats, neuronal measurements and perturbations in rat and network modelling, we aim to build a multi-level description of how sensory history is utilised in inferring regularities in temporally extended tasks. The ability to use sensory statistics to update the internal models may be impaired in individuals with dyslexia or with neurodevelopmental disorders, such as autism, or psychosis, such as schizophrenia. Our findings can have immediate application in better understanding and designing more accurate treatments for these disorders.


Research activity codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Towards therapies for epilepsy: Dynamics of allosteric modulation in NMDA receptors
Funder: Wellcome Trust

Abstract: Epilepsy is one of the most debilitating brain disorders and to date, no drug has been able to combat it effectively. This is partly due to the fact that epileptic seizures arise as a result of a number of ion channels in the brain, one of the most important which is the NMDA receptor. The targeting of this receptor and those like it is difficult as their expression in different brain regions is varied and the specificity of the modulators for them has not yet been perfected. In this project, we aim to use a combination of computational modelling methods and electrophysiological techniques in live brain slices to understand better the effect of some of these modulators on the receptor and overall brain circuitry. This will allow a deeper appreciation of the molecular mechanisms by which these modulators can affect the receptor and by extension brain function which can lead to improved prospects in the treatment of epilepsy.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Examining the contribution of progenitor subtypes to higher order cortical circuitry
Funder: Wellcome Trust

Abstract: Neurons in sensory cortices receive excitatory synaptic inputs from the thalamus. These inputs can be divided into two broad types: “first order” inputs that carry sensory information from the periphery via first order thalamic nuclei, and “higher order” inputs that bring information from other cortical regions as a result of corticothalamocortical routes via higher order thalamic nuclei (1,2). Research has shown that the thalamic input to an adult cortical neuron reflects the embryonic progenitor pool from which the neuron was derived (3). Neurons derived from apical intermediate progenitors receive preferential input from higher order thalamic nuclei, whereas neurons derived from other progenitors receive preferential input from lower order thalamic nuclei. Using mouse barrel cortex as a model system, I am able to label these different populations of adult neurons and look at how properties of higher order cortical circuits relate to a neuron’s progenitor of origin. This work will help understand the strategies the brain uses to form functional neuronal circuits in sensory cortices during embryonic development.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Structure learning and relational reasoning in the parietal cortex and artificial neural networks
Funder: Wellcome Trust

Abstract: The environment is structured in space and time, such that objects exhibit canonical relationships with one another: for example, one animal may be “larger than” another or a ball might be “inside” a cup. In order to understand scenes and act appropriately, biological systems need to infer how the world is structured. Several recent theories aiming to explain this 'structure learning' have emerged in recent years, with many focussing on the factorisation of the structure of the environment from the objects in that environment. This has also become an important area of research in artificial intelligence. However, the computational mechanisms that support structure learning, and their implementation in biological systems, remain poorly understood. In this project, these principles will be studied using tools from cognitive neuroscience (human experiments including functional neuroimaging) and computational modelling. This computational modelling work will involve both examining the capacities of existing artificial neural networks on structure learning tasks, and using the results from the human experiments to better inform design of novel computational models. Thus, this study aims to better understand the mechanisms of structure learning (mainly in the human parietal cortex) and use this to design and implement novel computational models for this task.


Research activity codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Systems Modelling of the Adaptive Dynamics in Spiking Neural Networks
Funder: Wellcome Trust

Abstract: The brain constantly changes its activity with internal and external stimuli. This can occur with changes in strength of the connections between the connections between individual neurons, the synapses. This plasticity is an essential property of the neural systems, from insects to humans, and it is thought to underlie some important aspects of brain function, such as learning and memory, neural development and homeostasis, as well as recovery post brain injury. The logic of the local processes orchestrating these changes, called the learning rules, is an active area of study. The learning rules governing the dynamics of inhibitory synapses are particularly less known, which impedes our understanding of how the bewildering adaptive ability arises in biological neural systems. This project will build upon the previous computational models of neural systems using insights from recently emerging neuronal experimental data on inhibitory plasticity, which has the potential to solidify our understanding of neural dynamics and identify any gaps in our knowledge and hence power future experiments.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: The cognitive and non-cognitive effects tau and β-amyloid have on Alzheimer’s mouse models
Funder: Wellcome Trust

Abstract: The prevalence of Alzheimer’s disease (AD) is on the rise with most research focusing on memory deficits but gaining little in the way of treatments. The high comorbidity with affective disorders (e.g. depression and anxiety), could highlight new avenues of research looking at whether tau and amyloid pathology play a common role in both conditions. Knock-in animal models are able to look at potential mechanisms in great detail without complications from neurotoxic overexpression models. Using the KI model AppNL-G-F (Saito et al., 2014), Mehla et al. (2019) showed a disruption in affective processing areas of the brain such as the Locus Coeruleus. This area will be lesioned in WT mice and phenotype compared to deficits seen in AppNL-G-F to see what role emotional processing areas of the brain play in the pathology of AD. Building on that, the AppNL-G-F will then be crossed with another KI model, the MAPT which expresses tau pathology, to see if the addition of tau exasperates these deficits. Together, these experiments will be able to look at the underlying mechanisms of emotional deficits seen in AD with the potential for creating better treatment options or changes to quality of life for people suffering with AD.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Structure learning with grid-like and axis-aligned codes
Funder: Wellcome Trust

Abstract: Recent theories of how people comprehend and learn about the world around them have emphasised a distinction between content (i.e. what things are there?) and structure (i.e. how are those things related?). One theory puts forward that “grid-like” activity – a pattern originally discovered in rodent navigation experiments – is used to organise structural information in the brain. Other work has focused on “axis-aligned” codes that organise information along a single axis of ‘magnitude’ – such as number (low to high), time (soon to later), and probability (unlikely to likely). We will investigate the relative contributions of these two types of neural activity in structure learning tasks. We will use a combination of human behavioural experiments, functional neuroimaging, and computational modelling. We will record brain activity in humans performing tasks that test specific predictions made by the use of the two neural coding strategies, and design versions of these tasks that can be performed by neural network algorithms, allowing us to make functional predictions about the human neural data. Delineating the circumstances under which the brain uses these two types of activity will constrain or unify theories of structure learning and help understand the neural underpinnings of flexible human thought.


Research activity codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Causal pathways from cognitive function to Alzheimer's disease
Funder: Wellcome Trust

Abstract: Findings from observational and genetic studies of modifiable risk factors for Alzheimer’s disease (AD) are inconsistent with studies reporting null, positive or negative findings for the same risk factor. Educational attainment and intelligence are the only risk factors to have been consistently related with AD, with studies using different methodologies reporting greater educational attainment and intelligence to be protective for Alzheimer's disease. Recently, in a genetic study more robust to bias than traditional observational studies, we showed little evidence of an effect of educational attainment of AD once intelligence was accounted for. The aim of the project I am proposing is to investigate how structural brain and physiological (proteins, metabolites) changes, play a role in the relationship between cognitive function and AD. With the use of birth cohorts, with data on childhood measures such as brain structure, and the use of genetics methods for estimating causal effects, we aim to limit biases associated with adult and observational epidemiological studies. This will allow investigation of the relative importance of anatomical and physiological factors for cognitive function on Alzheimer's disease. This project will contribute to an improved understanding of the causes of AD and highlight potential drug targets and intervention strategies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Whole-brain structural and functional connectivity in children treated with therapeutic hypothermia for neonatal encephalopathy
Funder: Wellcome Trust

Abstract: Each year 2 per 1000 newborn babies suffer brain injury due to deprivation of oxygen to the brain around birth leading to severe physical disabilities called cerebral palsy and, in severe cases, death. Cooling therapy reduces the risk of severe brain injury, however when the cooled children reach school-age they still perform less well on cognitive and motor tasks than ‘healthy’ controls, even in the absence of cerebral palsy. Using advanced brain scans (MRI) from a cohort of cooled children, as well as data from controls with no birth complications, I aim to determine the underlying differences in brain structure and function and assess how these differences contribute to cognitive and motor performance. I will apply techniques to investigate tissue microstructure, as well as techniques from graph theory to characterise whole brain wiring. I will develop the statistical methods used in network neuroscience to facilitate more robust and informative analysis of the structural and functional brain networks. Determining particular brain regions or connections which are affected in cooled children will provide understanding of how the injury affects development and may motivate developing therapeutic interventions. Developing the statistical techniques will allow investigation of the relationship between brain structure and children’s skills.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: A system level approach to identify and validate imprinted genes involved in parental care
Funder: Wellcome Trust

Abstract: The neural pathways responsible for parenting behaviours have been well characterised, and the Preoptic Area (POA) is considered a parenting 'hub' in many mammals including mice and rats. Imprinted genes (IG) are a set of ~200 genes that have been clearly associated with the quality of parenting behaviour. Our current work plans to unite these two by investigating the role of IG expression in the neural circuitry for parenting. Using pre-existing data, we will look for enrichment of IGs in the POA and in specific POA neurons associated with parenting behaviour. We will be guided by this analysis to select an IG to characterise the parenting deficit created from a gene knock-out model. Furthermore, we will utilise RNA-Scope to examine specific gene-expression within the POA of the mouse model looking for the effect that the knock-out model will have on the parenting neurons. The quality of parenting behaviour is key to the optimal development of offspring in animals, hence the impact of this work will be to further elucidate one of the genetic underpinnings of parenting behaviour, especially valuable since previous work has associated imprinted gene expression with human pregnancy outcomes including prenatal depression and negative infant mood (Creeth, 2018)


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