NIHRDataInsights/HRCSData huggingface dataset:
Title: Circuit mechanisms underlying spatial navigation deficits in early Alzheimer's disease
Funder: Wellcome Trust

Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that affects millions worldwide. AD can only be diagnosed late in its progression, when cognitive symptoms such as memory loss are prominent. Many years before this, the pathological AD processes are active and damaging the brain, but the symptoms at this early stage are subtle, making diagnosis challenging. Focusing on early affected areas in AD could hold the key to early diagnosis. An early affected area is the entorhinal cortex (EC), which supports spatial navigation. Damage here causes spatial navigation deficits. In early AD, these deficits are subtle and require the development of sensitive tests. Our goal is to help inform the development of these tests by understanding how the EC carries out spatial computations, and how they are altered in AD. To do this, we will reverse engineer the EC circuitry using optogenetics and electrophysiology during navigation tasks performed by healthy and AD mice. In conjunction, we will build computational models (virtual EC circuits) that simulate AD pathology and task performance. These studies will help explain how the EC carries out computations that underlie spatial navigation, and how they go wrong during AD, informing the development of sensitive tests for AD.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;MENTAL HEALTH
Title: Circuit and Molecular Mechanisms of Olfactory Associative Learning
Funder: Wellcome Trust

Abstract: To direct behaviour effectively, animals need to constantly update the value and predictions of the sensory stimuli they encounter. To solve this task, all brains have the ability to change sensory processing and behaviour according to previous experiences, a process termed learning. The aim of this project is to identify what changes in sensory processing underlie the integration of conflicting (rewarding and aversive) experiences which produce opposite behaviour. I will use C. elegans because it has small and anatomically well described circuits for associative learning that share functional features with those of more complex brains and can be manipulated with single cell resolution. I will combine behavioural analysis, genetic manipulation of neuronal communication and imaging of neuronal activity to dissect the mechanisms of neural plasticity that underlie a switch in odour preferences after sexual conditioning. This will consist in identifying the neurons within the circuit for odour processing that release a neuromodulator and establishing the changes in information flow arising from neuromodulation. These studies will provide a mechanistic understanding for integration and resolution of conflict during learning that will illuminate how this process occurs in more complex brains.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL;MENTAL HEALTH
Title: Using hierarchical models of habitual and goal-directed decision-making to understand compulsive behaviour
Funder: Wellcome Trust

Abstract: Two systems govern human behaviour: the ‘habitual’ system tends to repeat actions were previously rewarding, and the ‘goal-directed’ system relies on an understanding of how the world works in choosing the best action. Whilst there is evidence that this is true for simple actions (e.g. ‘eat cake’, ‘lock door’), we do not know if it holds when applied to goals (a collection of actions that work towards a goal, e.g. ‘start a business’). My research aims to investigate how we choose which goals to pursue. To test whether the two systems above apply to goals, I aim to develop a new cognitive task that involves choices between actions and choices between goals, and study how these choices are controlled by the brain. I will use a combination of behavioural, neuroimaging, and neurochemical approaches to this end. I also aim to investigate whether there are differences in how goals are chosen between healthy individuals and patients with compulsive disorders including addiction and obsessive-compulsive disorder. The broader goal of my research is to understand how the brain optimises both short-term and long-term behaviour, and potentially inform clinical models of compulsive disorders.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL;MENTAL HEALTH
Title: Neural and cognitive mechanisms of temporally-extended decision-making, goal pursuit and learning
Funder: Wellcome Trust

Abstract: Whether it be catching prey or making dinner, rewards in natural environments take time to pursue. This requires planning into the future, setting goals, and flexibly switching between different strategies when needed. In my PhD I will use computational models alongside fMRI and MEG imaging techniques to explore how humans plan and make decisions in temporally extended environments. In particular, I’m interested in the role of the human frontal lobes in prospective value-based decision-making and goal maintenance. I will investigate the neural mechanisms by which humans pursue goals and suppress alternative courses of action, versus deciding to abandon goals. In addition, I will examine how individuals differ in this tendency to commit to goals, which may have relevance for our understanding of various psychiatric disorders such as OCD, apathy, and depression. In future projects I will use MEG to investigate the moment-by-moment brain activity responsible for tracking changing rewards, and using this information to make predictions about the future. Finally, I am also interested in how humans weigh up different types of value across time, such as the value of information or increased agency.


Research activity codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: NEUROLOGICAL;MENTAL HEALTH
Title: Delineating the unique functional contribution of the retrosplenial cortex in the hippocampal-diencephalic-cingulate network
Funder: Wellcome Trust

Abstract: The retrosplenial (RSP) cortex is a cortical area located behind the splenium, As a part of the hippocampal-diencephalic-cingulate network, it has been repeatedly implicated in episodic memory, spatial memory, and navigation. Pathologically, when damaged the RSP cortex produces both anterograde and retrograde amnesia. It is among the first regions to show neurodegeneration in Alzheimer’s disease and Mild Cognitive Impairment. However, despite the region's clinical and behavioral significance, its unique functional contribution to hippocampal-dependent processes is poorly understood. To delineate the RSP cortex functions from that of other structures, I will use a combination of chemogenetic and optogenetic manipulations in rats, to examine behavioral effects. Disentangling the RSP cortex functions will not only elucidate the intrinsic processes underlying cognitive function, but also potentially provide a new target for the treatment of memory disorders.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL;MENTAL HEALTH
Title: Adaptive motor learning through systems-level modelling of neural populations
Funder: Wellcome Trust

Abstract: The brain can learn a variety of motor skills, from using chopsticks to playing the piano. Some skills are easier to learn than others, and this may be affected by the skills that you already have. We are interested in how motor learning occurs in populations of neurons. Networks of neurons work together to produce different neural activity patterns that drive learning and movement. The possible patterns that can be produced thus depend on the structure of the network, and this can be affected by existing skill sets. We will use artificial neural networks to computationally model motor learning. We will train the model on different motor tasks and see how they adapt to learning new ones. This will be coupled with experimental data that measure neural activity in monkeys and mice during motor tasks. By understanding how the brain learns new movements, we can gain insight into applications of assistive devices and therapies for motor function.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL;MENTAL HEALTH
Title: Effects of lifestyle and phylogeny on occipital lobe organisation across primate species
Funder: Wellcome Trust

Abstract: The way a brain is organised stems from a combination of evolutionary and environmental influences. I aim to understand how these factors have shaped how different primate brains are organised. Specifically, I am interested in how visual experience and evolutionary adaptations have shaped the organisation of the occipital (visual) lobe.To study occipital lobe organisation, I will reconstruct white matter tracts from MRI scans of primate brains. I will then use computational approaches to compare these tracts, finding which tracts differ between species. Using our knowledge of phylogenetic relationships and different animals’ lifestyles, I can test hypotheses about which tracts diverged at different points in evolutionary history, and about which adaptations are unique to different ecological niches. Afterwards, I will explore how ecological specialisations affect connectivity on a cellular level, in finer-grained detail than MRI can offer, by staining brain slices for axons and their myelin and analysing the innervation patterns of specific white matter tracts.This work will yield insights into the evolution of the primate visual system and illuminate how it evolved to subserve uniquely human functions like reading. This work will additionally help us understand principles of brain diversity, with implications for evolutionary biology and translational neuroscience.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL;MENTAL HEALTH
Title: The present is saturated with the past and pregnant with the future: continuous temporal integration of past and future events in the brain
Funder: Wellcome Trust

Abstract: The environment is continuously changing. Our nervous system is capable of integrating these changes over time, facilitating an adaptive interaction with the world. At any moment, our brains are retaining past experiences and estimating future events. In the words of the philosopher Gottfried Leibniz: the present is saturated with the past and pregnant with the future. For example, when two people are having a conversation, retentions of what has just been said are needed in order to construct what will be said in the immediate future. During my doctoral research, I will try to answer the question of whether retention of immediately past events and anticipation of future ones influences present perception both in the visual and in the auditory domains. By manipulating task demands, I also hope to explore whether such effects are flexible and context dependent. To explore how different brain regions across the visual and auditory systems allow for retention and anticipation, I will record electrical brain activity of participants while they observe learned and unlearned sequences of stimuli, such that we can manipulate their anticipation of what is coming . This work will advance the understanding of how events in the environment are integrated in time.


Research activity codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: NEUROLOGICAL;MENTAL HEALTH
Title: Mapping the neurocomputational landscape of obsessive-compulsive disorder
Funder: Wellcome Trust

Abstract: Obsessive-compulsive disorder (OCD) is diagnosed purely based on its symptoms, without regard for underlying neurocognitive causes. This practice entails the likely risk that distinct neural illnesses are diagnosed as a single disorder. The analogy is Parkinsonism, where multiple conditions cause the same symptomatology. This project investigates distinct neurobiological disorders within OCD and determines their neurocognitive phenotypes. In my previous work, I have identified two candidate cognitive phenotypes in OCD, indecisiveness and impaired metacognition. In this fellowship, I will investigate (i) the neural processes underlying these impairments, (ii) the role of neurotransmitter noradrenaline therein, and (iii) determine whether they constitute separable neurocognitive subtypes in OCD. To answer these questions, I will combine simultaneous electroencephalography and functional MRI with pharmacological manipulations, both in healthy volunteers and OCD patients. In addition, I will use large smartphone-based data collection to investigate how indecisiveness and impaired metacognition relate to other cognitive deficits in OCD and to integrate them in a broader landscape of cognitive subtypes in OCD. This project will reveal the neural processes that underlie indecisiveness and metacognitive impairments in OCD. I will determine whether these are separable neural disorders, and whether noradrenaline blockade holds potential as treatment for one of the subtypes.

Lay abstract: Psychiatric patients, such as obsessive-compulsive disorder (OCD) patients, are diagnosed purely based in their symptoms. However, it is likely that what we call OCD is in fact an assembly of several distinct neural illnesses. The analogy is Parkinsonism, where entirely different conditions can cause the same symptoms. Knowing the underlying causes is critical if we want to develop targeted treatments for OCD. In this project, I will explore neural disorders that underlie OCD. I will employ multimodal neuroimaging, pharmacological manipulations, computational modelling, and smartphone-based big data collection in OCD patients and healthy volunteers. These techniques will allow me to determine which neural deficits can cause OCD symptomatology, whether they form distinct subgroups in OCD, and whether neurotransmitter drugs have the potential to treat these subgroups. The ultimate goal of my research is to go beyond symptomatic disorder classification, thus helping advancements towards a more personalised treatment in OCD.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;MENTAL HEALTH
Title: Pre-configured and learned properties of hippocampal circuits
Funder: Wellcome Trust

Abstract: Despite recent advances in systems and computational neuroscience, very little is known about how the brain’s functional complexity arises during ontogenesis and which developmental mechanisms determine the emergence of complex behaviour. The proposed research aims to bridge this gap between developmental neurobiology and systems neuroscience by defining the relative roles of early embryonic events and post-natal learning in the development of spatial and non-spatial coding in the hippocampal formation. Our key goals are to: 1) establish whether the functional diversity in hippocampal place cells is defined by early embryonic divergence; 2) test whether ‘non-place’ coding in the hippocampus is intrinsic to the network (as place coding appears to be), or whether it requires late post-natal learning; 3) discover the relative contributions of experience-dependent and independent processes in creating the specific neural architecture (‘continuous attractor') underlying codes for direction and distance. We will deliver these goals using chronic in vivo recording of neural activity (high density electrophysiology and calcium imaging) in developing animals coupled with neuronal birth tagging, behavioural testing and functional inactivation of crucial targets, to discover which self-organised embryonic events and instructive signals are necessary to organise hippocampal circuits.

Lay abstract: Recent technical advances have led to a rapid growth in our understanding of the molecular and anatomical diversity of the nervous system, and how information is stored and manipulated by neural circuits. However, we still have a limited grasp of how the brain’s staggering structural and functional complexity emerges during development. Our research aims to fill this knowledge gap and address the following questions: how are the neural circuits required for complex behaviours assembled during development? Which aspects of brain development rely on intrinsic, experience-independent process, and which, instead require extensive learning about the world? We will focus on the neural circuits of the hippocampus, a brain structure we know is important for learning, remembering events, and spatial orientation. We will monitor and manipulate neural activity during early development, to define the relative roles of early embryonic events and post-natal learning in the expression of memory and spatial navigation.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL;MENTAL HEALTH
Title: An investigation of distributed cortical neural circuit mechanisms for memory storage
Funder: Wellcome Trust

Abstract: Long-term memory involves interactions dispersed across cortical circuits, but how these interactions are coordinated is not known. Because of its input from the hippocampus and wide ranging projections to cortical systems, the medial entorhinal cortex might play a pivotal role in the formation and coordination of cortical memory networks. However, organising principles for distribution of entorhinal projections to the cortex have not been established and how these projections play roles in the formation and shaping of cortical network activity is unknown. Here I proposed to investigate these unknowns at a circuit level using advanced anatomical, electrophysiological, optogenetic and live imaging methods. I will address three aims: to determine whether entorhinal inputs to cortex support parallel or divergent processing models; to identify and establish the relationship between cortical neurons receiving MEC inputs and associational neurons that mediate interactions between cortical areas; and to investigate cortical memory-related neural activity and roles of MEC inputs during learned visuospatial behaviours. Together these experiments will reveal principles for control of distributed memory networks by the entorhinal cortex and may contribute a framework for future investigation of how disparate brain areas generate coherent cognitive representations. Keywords: memory, cortex, entorhinal, circuit, behaviour.

Lay abstract: Memories are thought to be stored as traces distributed across the brain. How these memory traces are coordinated is a fundamental unsolved problem. I aim to address this problem by investigating outputs from a brain structure called the entorhinal cortex. This structure is of great interest as it receives signals from the hippocampus, which is important for initial learning, and sends outputs to diverse cortical targets that together are important for long-term memory. I will carry out experiments using advanced genetic and physiological methods to establish organising principles by which the entorhinal cortex coordinates neural activity within and between cortical regions. I will also use microscopic cameras to monitor cortical activity during visuospatial learning and will then test influences of projections from the entorhinal cortex. These studies will help to identify the neural substrates for long-term memories and to explain how disparate cortical areas generate coherent cognitive states.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL;MENTAL HEALTH
Title: Dissecting the neural circuits for visual perceptual learning
Funder: Wellcome Trust

Abstract: Visual perceptual learning (VPL) is an improvement of performance of a visually guided task as a result of visual experience. However, it is not well understood whether improvements are due to changes in lower-level visual or in higher-level association brain areas, and whether improvements can transfer to untrained visual features and tasks. Here I propose to dissect the neural circuits of VPL in mice and test the theory that VPL consists of both: 1) enhanced task-independent encoding of sensory features in low-level areas in cells with selective feature-preference, generalising poorly to different features. 2) enhancement of task-relevant features, initially in higher level areas with broad feature-preference, generalising to a broader range of features. Mice can quickly learn a visual discrimination task, which I will combine with cell-type specific 2-photon calcium imaging and optogenetic manipulation of neural activity. I hypothesize that PV interneurons are necessary for task-independent learning, while SOM interneurons can gate feedback from high-level areas to boost task-relevant features. I will address the following specific aims: 1) identify the changes during VPL in visual and association areas during learning 2) determine the role of task-engagement in VPL 3) determine how VPL generalises to untrained or previously irrelevant features.

Lay abstract: The capacity to learn is essential to adapt to our environment. Visual perceptual learning (VPL) is the improved performance of a visual task after training. However, it is poorly understood whether improvements are due to changes in specialised visual brain areas or in more generalist decision-making areas, and whether improvements can transfer to untrained visual features and tasks. I will study the neural mechanisms of VPL in mice. These animals can quickly learn to discriminate between visual features. Powerful research methods for mice will allow me to monitor and manipulate neural activity at different stages of learning. I will study how learning modifies responses in different visual and decision-making areas and test how these effects depend on the similarity of the visual features and task to the training context. This will reveal how we become experts on specific tasks, but also how learning can transfer to novel conditions.

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