NIHRDataInsights/HRCSData huggingface dataset:
Title: Transforming visual images to cognitive maps
Funder: Wellcome Trust

Abstract: Memory is a fundamental aspect of our selves, defining who we are and where we have been. The seemingly inevitable impairment of memory, due to pathologies such as Alzheimer’s disease, or normally during aging, will afflict large segments of the human population. Therefore, understanding how memories are created and used represents a major frontier of neuroscience research. One form of memory that has been the subject of intensive research is spatial memory, which is both the knowledge of an environment and sensing where we are while we navigate. How does the brain use external visual images to create an internal spatial memory for navigation? While brain regions involved in vision and memory have independently been the subjects of intense research, we do not know how they work together. My goal is to understand how images of visual scenes are transformed into a spatial memory. To this end I will take advantage of new experimental tools to investigate this question: rodent virtual-reality, large-scale electrical recordings, and optogenetic interventions of neural circuits. Specifically, I will investigate the circuits and computations by which visual signals are transformed into spatial signals, and how the hippocampus combines visual information with other inputs.


Research activity codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Memory across multiple time-scales
Funder: Wellcome Trust

Abstract: Some memories last for a lifetime and others last only a few hours. For example, one typically remembers a travel to an exotic country for many years, but one remembers Monday’s lunch menu for only a couple of days. We aim to better understand how the long memories can last and how the brain achieves that. When learning, we change the connections between the main elements of our brain, the neurons. This process can lasts for different amounts of time: it is as if each connection could choose to listen to one of multiple clocks that all tick at different rates: fractions of seconds, hours, years. We hypothesize that the imbrication of these clocks helps memories to last. Moreover, not all memories are equal. If they are connected to exciting or rewarded events (for example your wedding), they will last for longer. Reward in the brain is encoded by a substance called dopamine. We therefore will study how dopamine influences learning strategies and memory duration.


Research activity codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: How curiosity enhances hippocampus-dependent memory
Funder: Wellcome Trust

Abstract: In today’s world, it is most desirable to optimize cognitive capacities, such as learning, across the lifespan. One fundamental, yet poorly understood, method is via a person’s intrinsic curiosity. Despite the ubiquity and importance of curiosity in everyday life, we have a very limited appreciation of the exact neural mechanisms of curiosity-enhanced learning. Because initial curiosity studies have relied on the passive encoding of material, one fundamental aspect of curiosity – active exploration to acquire further knowledge – remains to be investigated. I, therefore, propose a new virtual reality paradigm to characterize the neural mechanisms of how active curiosity enhances memory. Across three principal approaches, I will ask how separate stages of memory (orientation vs. initial learning vs. different modes of consolidation) contribute to curiosity-related memory enhancements and why curiosity-based learning might vary between healthy individuals. I will uncover whole-brain mechanisms and ‘zoom in’ on specific curiosity- and memory-related brain structures using complementary state-of-the-art measures and analyses. Combining such approaches is vital if we are to understand how curiosity enhances memory, but may also aid crucial translation of laboratory-based findings on learning and memory to real-world issues (e.g., influence on educational policies and implications for cognitive resilience in the elderly).

Lay abstract: In today’s world, life-learning learning is vital in many aspects of life. For example, teachers try to ignite their students’ curiosity to improve learning. But why does curiosity enhance learning? Despite the importance of curiosity in real-life, we do not have a precise understanding of the brain mechanisms that support curiosity and curiosity-based learning. In this proposal, I will use complementary neuroimaging methods to investigate which brain mechanisms support curiosity-related memory enhancements. I will focus on the brain mechanisms during the exact time periods when we are in an actual ‘curiosity state’ (i.e., when we highly anticipate information), when we learn the actual high-curiosity information, and when our brain consolidates curiosity-related information (i.e., during awake rest periods and sleep). Understanding the precise neural mechanisms underlying curiosity will help us to optimally spark curiosity in real-life.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Contextual determinants of surprise in health, development and disorder.
Funder: Wellcome Trust

Abstract: The goal of this research proposal is to build a theoretical and experimental framework to understand the contextual determinants of “surprise” (expectation violations/prediction errors) in health, development, and disorder. I have the following three aims: 1) To exploit high-field neuroimaging and pharmacological manipulations in healthy adults to reveal the precise neural mechanisms that alter surprise processing in response to volatility, and validate different pupil metrics as a window into central neuromodulatory function. 2) To conduct model-based neuroimaging in infants, for the first time, to predict risk for the dimensional symptoms of autism, and reveal the computational neurodevelopment of probabilistic and volatility learning in infants. 3) To develop a unified computational framework of surprise-driven learning that has the specificity to reveal separable mechanisms of psychopathology in different neuropsychiatric conditions and the potential to be used as a clinical tool. To achieve these objectives I will utilise the same cognitive tasks, pupillometric measurements and computational models of learning across three research themes. This ensures that while the individual projects are strongly hypothesis-driven the findings can be directly translated across developmental, adult, and disordered states. Key words: autism, neurodevelopment, predictive coding, surprise, computational models, 7T fMRI, pharmacology, noradrenaline, psychosis.

Lay abstract: At a cost of £35 billion per year, autism is now the most expensive medical condition in the UK. A new hypothesis suggests that people with autism might struggle to make sense of the world because their brains don’t form the correct expectation for a given situation, resulting in constant mild surprise. Imagine, for example, how surprising first tasting a lemon might be if you expected it to taste sweet like other fruits. Encouraging new evidence suggests this problem might be explained by mathematical models that describe how surprises are computed and the action of brain chemicals, called neuromodulators, which signal when something unexpected has happened. However, more work is needed to understand the brain processes that underpin surprise, how these brain differences develop and also how they differ across disorders. This research project has three goals. First, to use cutting-edge brain imaging methods to better understand how neuromodulators signal surprise in healthy volunteers. Second, to measure surprise responses in the brains of babies to see if this can predict emergence of autism symptoms. Finally, to examine whether tests of surprise responses are able to distinguish autism from related neuropsychiatric conditions.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: State of the art MEG-TRIUX-neo for advancing multi-modal neuroimaging techniques in Scotland
Funder: Wellcome Trust

Abstract: Magnetoencephalography (MEG) is an advanced technology using super-conducting quantum interference devices (SQUIDs) for measuring the tiny magnetic fields produced by the coherent electrical activity in groups of neurons. MEG is the only neuroimaging technology that enables non-invasive recordings with both excellent temporal and good anatomical resolutions. Such spatiotemporal accuracy is instrumental for discovering the mechanisms underlying mental functions and deficits in healthy and impaired brains. We seek Wellcome Trust funding to replace our 12-year old MEG system with a state-of-the-art TRIUX-neo from MEGIN Ltd. The TRIUX-neo is an ultra-sensitive system based on new technology that combines MEG recordings with high-density EEG, online head-motion tracking and a helium recycling mechanism now essential with worldwide helium shortage. With the TRIUX-neo, our multi-user MEG group (with significant Wellcome Trust funding, Investigator, Innovator, Seed and Sir Henry Wellcome Fellowship) will keep enhancing its cutting-edge, unique, cohesive and collaborative research and pioneer new methods and techniques across our extensive platform of in-house imaging facilities (i.e. EEG, MEG, NIRS, 3/7T fMRI). Key MEG innovations will focus on understanding brain network dynamics and oscillations in health and disease, using information theory and advanced network analyses and unique data fusion of EEG and 3/7TfMRI and neurostimulation (TMS, tES).

Lay abstract: Cognition is the product of our dynamic brains. To understand it, researchers need to measure the dynamic activity of brain regions in different cognitive tasks. Magnetoencephalography (MEG) is an advanced technology using super-conducting quantum interference devices (SQUIDs) that measures tiny magnetic fields, with both excellent temporal accuracy (~1 ms) and good resolution of brain structures (~1-2 cm). CCNi researchers have developed new mathematical tools to analyse dynamic cognition via MEG measurements. We seek to renew our equipment with a state-of-the-art TRIUX-neo from MEGIN Ltd. The TRIUX-neo is an ultra-sensitive system based on new technology that combines MEG recordings with high-density EEG, online head-motion tracking and a helium recycling mechanism. This will enhance measurement capabilities within our existing cutting-edge platform for brain imaging and foster a hub of neuroimaging excellence in Scotland in collaboration with our multiple regional, national and international partners.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Uncertainty in the hippocampus
Funder: Wellcome Trust

Abstract: Hippocampal neurons are tuned to abstract, behaviourally highly relevant variables, such as the location of the animal ("place cells"), or particular memories being recalled ("memory cells"). However, it is unknown how these neurons represent a behaviourally equally important kind of information: the uncertainty about location or memory. Building on recent advances in the neural coding of perceptual uncertainty in neocortical sensory areas, we will develop computational models to study hippocampal population codes for uncertainty in location and memory. These models will unify a diverse set of empirical data, including place field stability and neural oscillations, under a coherent functional account. Moreover, as neocortical findings suggest that response variability may provide crucial clues about the neural coding of uncertainty, we will also make explicit predictions about this almost entirely neglected aspect of hippocampal representations: response variability, and its modulation under conditions associated with different levels of uncertainty. We will test these predictions by conducting novel analyses of hippocampal recordings in rats and humans. Our work will thus reveal how the "GPS system" of the brain achieves what any truly well-functioning GPS must: to not only represent a single point estimate of location but also the uncertainty about it.

Lay abstract: When you use the GPS in your phone, or search with Google, not only you get the system's single best answer to your question (where am I?, which page has this information?) but you also get a report of the system's uncertainty about that answer (a shaded area for location, and a ranked list of sites that may be relevant). The hippocampus is a brain area that plays a central role in navigation and memory. While we have detailed knowledge of how the activity of its cells encodes location and memory, we know very little about how these activities represent uncertainty. Using computational models and model-based analyses of neural data, we will investigate how neural populations represent uncertainty in the hippocampus. This will help us understand how information retrieved by the hippocampus can be used for decisions and updated based on new information.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: The predictive basis of intensity and loudness processing
Funder: Wellcome Trust

Abstract: Generative models of perception, such as predictive coding, are mainstays of contemporary neuroscience. Whilst there is abundant evidence and theory concerning what is predicted and when it is expected, little is known about how predictive models influence how strongly sensations are received (i.e. their intensity, or its perceptual counterparts such as loudness). This proposal builds upon the handful of studies demonstrating the existence of predictive processing of intensity, and on my own published work demonstrating that pathological states of perception (i.e. tinnitus) can be understood, and objectified, as pervasive states of aberrant sensory predictions. Its goal is a clear picture of the function and neurobiological basis of predictive intensity processing, which might subsequently lead to diagnostic and therapeutic avenues for clinical disorders such as tinnitus, chronic pain and fibromyalgia. The investigative approach is multifaceted, examining a range of hierarchical levels through a progression of paradigm complexity, and using complementary neuroimaging modalities, including electroencephalography (EEG), magnetoencephalography (MEG), electrocorticography (ECoG) and functional MRI. The predominant focus is auditory intensity (and loudness) in normal-hearing controls, with a subset of successful paradigms being run in clinical populations (to demonstrate the practical relevance of measures obtained), and in the somatosensory system (to demonstrate modality-independent commonalities).

Lay abstract: Our brains' predictions dramatically affect what we perceive, including how strongly we feel physical sensations (i.e. their intensity), with a common example being placebo analgesia. Furthermore, many clinical disorders of sensation (including tinnitus, hyperacusis, chronic pain and fibromyalgia) may have anomalies of predictive intensity processing at their heart. However, little is known about predictive processing of intensity, compared to other aspects of perception. Here, I propose to systematically study, in human volunteers, the brain mechanisms underlying predictive processing of intensity, mainly in the auditory system but also in tactile sensation, across a range of scales from local neural circuits to brain-wide connections, and in both normal functioning and a limited range of clinical disorders of sensation. Outcomes will be a coherent understanding of the normal functioning of these systems in the brain, with methods and knowledge immediately transferrable to the study, understanding, diagnosis and treatment of common disorders of sensation.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Neural and genetic control of path integration
Funder: Wellcome Trust

Abstract: Darwin was among the first to propose that animals probably use self-motion cues when navigating in featureless environments, a mode of navigation known as path integration. While an extensive literature supports the role of path integration in navigation, the cellular and circuit algorithms of this process remain unmapped. Such knowledge is critical for understanding one of the most fundamental features of our brain: representation of 'self' and 'surround'. I will use a genetic screen in Drosophila to identify the neural circuit of path integration and characterise how the central complex neurons integrate self-motion cues. I will then test how olfactory and motion information streams are combined during olfactory navigation. Finally, I want to check whether transcription factors like FoxP act as 'behavioural toolkit' genes, subserving general roles in processes requiring that information is integrated at seconds to minutes timescales. I will address these questions in Drosophila using a combination of genetic screens, behavioural assays, functional imaging under virtual reality arena, whole-cell recordings and transcriptional profiling. My work will shed light on the neural basis of the 'sense of direction' and contribute to the wider questions of sensory coding and temporal integration.

Lay abstract: Navigation is one of the most impressive feats of the natural world: Humpback whales travel from polar feeding grounds to specific locations in tropics for breeding; monarch butterflies fly across vast distances following specific migratory routes. Navigating animals often encounter environments devoid of prominent landmarks; a sailor lost in the Pacific or a desert ant foraging in the Sahara faces the same problem of knowing where they are going. How best to solve this problem without a map? One of the simplest ways of calculating where you are going is to use a compass to calculate the direction of the travel and an odometer to measure the travel distance. My work will focus on deciphering how a tiny insect brain uses a neural compass and an odometer to calculate where they are going, unveiling fundamental mechanisms through which our brain synchronises direction, movement and time to keep us on track.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Adaptive myelination in learning and memory
Funder: Wellcome Trust

Abstract: We found that production of new oligodendrocytes (OLs) is stimulated by, and required for, motor skill learning in mice. New OL production was required within 2-3 hours of mice engaging with the motor task, seemingly too soon for full myelin wrapping. We will therefore investigate how, at the cellular level, OLs contribute to early-stage learning, by interfering genetically with pre-myelinating functions of OLs including process outgrowth and ensheathment, or metabolic coupling between OLs and axons. We will also investigate signalling between axons and OLs to ask whether AMPA receptor-mediated synaptic input to OLs selects electrically active axons for myelination over their inactive or less-active neighbours, and whether this contributes to learning. Recently, we found that active OL generation is required for non-motor, "cognitive" learning in a T-maze test, which relies on short-term working memory and longer-term reference memory in a spatial context. We will use additional maze tests to dissociate working and reference memory and test the hypothesis that adult OL genesis is a general requirement for goal-directed learning and memory processes. We will also perform a genetic test of the idea that myelinating OLs, which are extremely long-lived, are required for preserving long-term memories.

Lay abstract: How we learn and retain skills and abilities is a major unanswered question in neuroscience. For a long time attention has been focussed on neurons, the brain’s electrically active cells. During learning, communication among neurons becomes strengthened at "synapses", the tiny physical and electrical contacts between one neuron and another. This allows learned patterns of activity to be preserved and re-activated (remembered) more easily in the future. Another way of strengthening communication among neurons is to insulate and protect their "axons" – the long thread-like extensions of neurons that allow them to reach out to one another across the brain. The insulation is provided by "myelin", spiral wraps of fatty membrane made by oligodendrocytes, another type of brain cell. We will study how oligodendrocytes detect and respond to electrical activity in axons during learning, and how this modifies myelin and changes the properties of neural circuits – so-called "adaptive myelination".

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Circuit mechanisms of cognitive control
Funder: Wellcome Trust

Abstract: In order to survive, an animal's behaviour must be flexible. This flexibility allows animals to react differently to the same stimuli depending on the context. How the brain selects different actions in response to the same stimulus remains a mystery. Here I propose to understand the neural mechanisms of behavioural flexibility in mice. Specifically, I will study the prefrontal cortex (PFC), given its crucial role in generating flexible cognitive behaviour in rodents, primates and humans. I have developed a novel attentional switching paradigm, wherein mice switch between responding to and ignoring the same visual stimuli, and have combined this behaviour with 2-photon imaging and optogenetic manipulation of neurons from identified cell classes in visual cortex. Here I hypothesise that PFC cells projecting to sensory and motor areas bias the processing in these target areas in a context dependent manner, enabled through transiently reduced inhibition from specific interneurons. I will thus address the following specific aims. 1) Identify the neural population dynamics in PFC associated with attentional switching, 2) Determine the interneuron classes involved in the reorganisation of neuronal dynamics during attentional switching. 3) Determine the role of projection-specific PFC neurons targeting sensory and motor regions during this behaviour.

Lay abstract: In order to survive, an animal's behaviour must be flexible. This flexibility allows animals to react differently to the same stimuli depending on the context. For example, the smell of smoke will probably elicit very different behavioural responses if one is at home or near a barbecue. How the brain selects different actions in response to the same stimulus remains a mystery. Here I propose to understand the neural mechanisms of such behavioural flexibility. Mice are capable of performing highly flexible behaviours as well. Furthermore, they are ideal for studying the brain because powerful techniques exist for measuring and manipulating the activity of neurons in the mouse brain. In this project I will study a flexible behaviour in which mice are trained to change their responses to the same stimulus every few minutes. The mice will be in a virtual reality environment, and under a microscope where I will combine state-of-the-art methods to study the brain during this flexible behaviour. I will study the prefrontal cortex, which has a crucial role in generating flexible behaviour. I will test if the prefrontal cortex acts as a switchboard, routing information to different brain regions at different times, depending on the current context.

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