NIHRDataInsights/HRCSData huggingface dataset:
Title: Ribosome function in plasticity and neurodevelopmental disorders
Funder: Wellcome Trust

Abstract: Protein synthesis is essential for the strengthening and weakening of synaptic connections between neurons, and it is pathologically altered in multiple genetic models of Autism Spectrum Disorders and Intellectual Disability (ASD/ID). The identities of the mRNAs translated to sustain changes in synaptic strength are not known, nor is the mechanism linking aberrant translation to functional changes in ASD/ID. This proposal will address two key questions: (1) How does dysregulated translation lead to altered synaptic function in Fragile X Syndrome (FX), the most common monogenic cause of ASD/ID? And (2) How are specific mRNAs translated to support opposite changes in synaptic strength? I will test the predictions that reduction of ribosome production can correct neurological phenotypes in the Fmr1-/y mouse model of FX, and that mRNAs translated to support synaptic strengthening (LTP) and weakening (LTD) are differentially regulated by ribogenesis. To do this I will use Translating Ribosome Affinity Purification (TRAP) and RNA-seq along with electrophysiological and behavioral assays. These studies will identify the link between excessive protein synthesis and synaptic disruption in FX and explain how translation is specified to support opposing changes in synaptic strength.

Lay abstract: Learning involved long-term changes in the strength of specific synaptic connections between neurons. The translation of new proteins from existing mRNAs is required to sustain these changes. In Fragile X Syndrome (FX) and other single-gene disorders linked to autism and intellectual disability (ID), too much protein synthesis in neurons causes disruptions in synapses that may contribute to impaired learning. My goal is to understand how this occurs. I will test whether abnormal production of ribosomes, which translate mRNA into protein, is causing neurological deficits in the Fmr1-/y mouse model of FX. I will also test whether changing ribosome production can alter the synaptic strengthening that occurs during learning. This will be done using advanced molecular strategies that can measure translation in specific neurons, combined with assays of synaptic function and behaviour. These studies may help to explain why too much protein synthesis causes neurological problems in FX and autism.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Circuit mechanisms that command and pattern behavioural sequences
Funder: Wellcome Trust

Abstract: Animals accomplish goal-directed behaviours by performing sequences of motor actions. A central goal of neuroscience is to understand how neural circuits regulate behaviour in accordance with external events and internal drives and precisely choreograph diverse actions for a successful outcome. To meet this challenge, I will exploit the unique accessibility of the larval zebrafish and focus on a conserved behaviour – hunting – in which a sequence of discrete, specialised actions mediates pursuit and capture of prey. I will use a powerful experimental strategy that combines cellular-resolution calcium imaging, behavioural analyses, optogenetic circuit manipulations, neuroanatomical tracing and computational modelling to discover how brain-wide circuits operate at the cellular level to flexibly control the expression and coordination of behaviour. This paradigm will enable me to discover (1) how sensory and internal state information are integrated to control the sensorimotor decision to hunt, (2) how specific hunting actions are generated and (3) how command signals operate alongside dynamic sensory inputs to assemble a goal-directed sequential behaviour. Overall, the project will produce a mechanistic, cellular-resolution circuit model that explains how the brain controls and patterns multi-component behaviour. I expect this will reveal fundamental principles about the operational logic of the nervous system.

Lay abstract: Animals accomplish complex behaviours such as building a nest, hunting for prey and caring for their young by coordinating sequences of simpler movements. The brain weighs sensory information alongside internal drives to decide when to take action and then dynamically controls sequences of movements to keep pace with changing events (for instance during pursuit of fleeing prey). In this project, I will examine how neural circuits function to achieve this flexible control. By using larval zebrafish, which have tiny, transparent brains, I will monitor the activity of entire neural networks at single-cell resolution during hunting sequences. Optogenetic techniques will enable me to precisely manipulate brain activity using light and thereby test and refine computational models of circuit function. This will allow me to discover how brain circuits make the decision to initiate behaviour and how they choreograph a sequence of precise manoeuvres to accomplish a goal.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: The typology and function of an integrated spatial and visual cortical system
Funder: Wellcome Trust

Abstract: When we move within an environment, our visual system is bombarded with visual stimulation from the outside world while, at the same time, the head and eyes are also moving. The brain is nonetheless able to integrate these competing inputs into a stable perception of the world. I will investigate two brain regions that are likely to be key players in this process of visuospatial integration: the visual cortex and the retrosplenial cortex (RSP), which processes information essential for navigation such as location, speed, direction and the angular velocity of the head. Recent physiological evidence suggests that the visual cortex integrates signals from the RSP that indicate the motion velocity of the head. This suggests that visual representations in the cortex are context dependent and incorporate egocentric signals to generate a coherent representation of visual motion events in the external world. To develop a biologically realistic model of how the brain performs this computation, we will generate a detailed connectivity map at cellular resolution of the major pathways within these brain areas. By mapping their functional response properties, we will obtain a physiological understanding of how egocentric visual representations are generated and then translated in the RSP for visually-guided behaviour.

Lay abstract: When we move, our brains are bombarded with moving visual stimuli from the outside world while, at the same time, our heads and eyes are also moving. To navigate the world, our brains must piece all this information together to form a coherent picture. This project aims to understand this process by unravelling the functional connectivity between two brain areas, one involved in spatial navigation and memory and the other in visual processing. Using cutting-edge neuronal tracing, recording and live brain imaging technology, we will discover how these two areas distinguish between information that comes from movements of the head and eyes, and information which comes from the movement of an object in the external environment. Findings from this research could shed light on the mechanisms of this computation in the healthy and diseased brain, including potentially in conditions such as Alzheimer’s disease, in which this spatial system become dysfunctional.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Inhibitory control of visually-guided behaviour
Funder: Wellcome Trust

Abstract: The brain utilises cortical and subcortical pathways to transform sensory information into action, giving rise to learned and instinctive sensory-guided behaviours. How these pathways interact to generate flexible behaviour, allowing animals to react differently to the same environmental stimuli depending on circumstance, remains poorly understood. We propose that inhibitory circuits in the thalamus are essential for flexible control of sensory-guided actions. Our pilot data show that the ventral lateral geniculate nucleus (vLGN) - a prethalamic structure composed of different classes of inhibitory projection neurons - provides inhibitory control of an instinctive visually-evoked behaviour. We will identify the neural circuit mechanisms of this control and determine when it is engaged. Moreover, since the vLGN is extensively connected with visual circuits in the neocortex and the midbrain, we will test if and how this nucleus can coordinate these visual pathways to guide both instinctive and learned visually-guided behaviours. We will achieve these aims by combining genetic tools with calcium imaging, electrophysiological recordings, cell-type specific optogenetic manipulations and quantitative behaviour in animals performing visually-guided tasks. This work will generate detailed understanding of mechanisms by which the brain can orchestrate behavioural responses to environmental stimuli.

Lay abstract: Cognitive control of behaviour is a remarkable ability of the brain, enabling flexible selection of actions in response to the same environmental challenges depending on circumstance and prior knowledge (for example, whether to run away from or investigate a potential threat). How such behavioural flexibility is achieved by the brain remains unclear. We aim to uncover new mechanisms by which behavioural responses to sensory stimuli are controlled and regulated. We will focus on novel candidate brain circuits in the thalamus, which can inhibit or promote automatic visually-guided behaviours. We will identify which neurons and connections enable this effect, by recording and manipulating their activity during different behaviours in mice, and will determine if these circuits implement cognitive control over visually-triggered actions. Understanding neural circuit mechanisms of behavioural control is fundamental for providing a basis for identifying causes of inappropriate or impulsive responses in psychiatric disorders.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Organising knowledge for flexible behaviour in the prefrontal-hippocampal circuitry
Funder: Wellcome Trust

Abstract: Humans and animals can find new solutions to existing problems, and generalise existing knowledge to new situations. This flexibility relies on internal models of the relationships and causes that govern our world. Despite the importance of world-models to a wide class of behaviours and thus likely relevance to psychiatry, little is known about how they are represented in the brain. Recent evidence suggests rapid progress can be made by comparison to the field of spatial cognition. Specific neuronal mechanisms are shared between spatial and non-spatial model-based behaviours, and new theories suggest links between spatial and non-spatial knowledge. We will study and manipulate hippocampal, entorhinal and prefrontal activity in rodents performing model-based tasks bridging spatial and non-spatial domains. Using unusually rich but precisely specified tasks, we will characterise neuronal representations of world models quantitatively, enabling formal mathematical description. We will therefore provide new data describing how internal-models are represented in neuronal activity in service of flexible behaviour, and how these representations generalise knowledge across different tasks. These data will be crucial for developing theories of how our brains represent and generalise knowledge for flexible behaviour, and will lay essential groundwork for studies of how these representations go awry in clinical populations.

Lay abstract: If you burn a cake you know how to change the recipe, even if you have never done so before. You have an understanding, or a "model" of cake-baking: The chocolate comes before the oven, but the oven causes the burning. This project will try to understand what such models might look like and how they are built in your brain. In order to do this, we will record from many cells in key brain regions as mice use such models to guide their behaviour. We have developed behavioural tests in mice which require rich complex internal models, but models that we understand mathematically. This is important as it will allow us to interrogate general principles about how models are represented, rather than just how particular models are represented in particular circumstances. We hope these principles will lay the groundwork for understanding how these mechanisms go wrong in psychiatric populations.

Research activity codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Distributed brain systems for motivation and action
Funder: Wellcome Trust

Abstract: The overarching aim is to understand the neural mechanisms of learning, decision-making, and motivation in humans. We will examine how they emerge from distributed patterns of activity across networks of subcortical nuclei such as the basal forebrain and dorsal raphe nucleus. While we know about such subcortical areas from animal studies, they have been under-investigated in humans. New imaging and uni- and multivariate analysis methods now make it possible to examine the distributed patterns of activity that arise in these areas. We have recently shown that we can record from these areas of the human brain using ultra high field magnetic resonance imaging. In addition, we know that these nuclei interact with cortical areas, especially in orbitofrontal, anterior cingulate, and insula cortex (regions that are especially prominent in humans and other primates). We aim to record from both cortical and subcortical areas and to understand how they interact during learning, decision making, and motivation. The final aim is to assess whether new ultrasound stimulation tools that make it possible to alter neural activity in a minimally invasive manner even in brain areas far from the surface can be used to manipulate brain activity in these circuits in humans.

Lay abstract: The brain is important for learning and deciding what it is good to do. For example, when we decide between visiting a restaurant or museum or not even bothering to leave the house at all. These mechanisms may not work optimally in psychological illnesses such as depression. As a consequence people may evaluate their opportunities incorrectly and feel apathetic. Because these learning, decision-making, and motivation problems are so important, they depend on complex, coordinated neural activity between subcortical nuclei (groups of cells deep in the brain) and prefrontal cortex (more recently evolved brain regions especially prominent in humans). Recently, it became possible to measure and even alter activity levels in the brain circuits we think are important in humans. We seek to exploit these new techniques to understand how these circuits enable learning about costs and benefits of courses of action and to make decisions between them.

Research activity codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Memory and motivation in human health and disease
Funder: Wellcome Trust

Abstract: Many brain diseases are associated with disabling cognitive and behavioural syndromes, which are currently poorly understood and have few effective treatments. Here, I propose that we need a systems level account to develop new therapies which target syndromes at the systems or network level, across diseases – regardless of underlying pathology. To test this transdiagnostic approach, I focus on two model syndromes: one cognitive (short-term memory deficits) and the other behavioural (apathy or lack of motivation). My aim is first to deconstruct the cognitive and behavioural components underlying these syndromes using carefully designed, sensitive behavioural measures. Then to relate behavioural performance to brain networks using a multimodal neuroimaging approach, including structural and functional connectivity measures. To identify whether there are robust brain imaging signatures of component deficits that are common to different diseases, we shall examine patients with Alzheimer’s disease, Parkinson’s disease, stroke and small vessel cerebrovascular disease. To determine whether we can detect these signatures at the earliest stages of disease (in their preclinical phase) we shall apply these methods also to groups at high risk of developing neurodegenerative disorders. Finally, we shall examine whether it is possible to modulate component deficits using cholinergic and dopaminergic drugs.

Lay abstract: Common disabling brain diseases such as Alzheimer’s, Parkinson’s or stroke, often lead to changes in thinking or in behaviour. We don’t understand many of these well and current treatments aren’t very effective. My aim is to examine two common problems that patients can suffer from across brain diseases: deficits in short-term memory and in their motivation to do things (apathy). By using carefully designed tests, we can assess specific aspects – component processes – of short-term memory or of motivation. Then by scanning patients in different ways using MRI (magnetic resonance imaging) we can see if a particular component of short-term memory or motivation is associated with changes in structure or function in a particular brain network. By doing this in Alzheimer’s, Parkinson’s and stroke we can determine whether there are common changes in brain networks associated with specific components across diseases. If that’s the case, that provides a potential target for treatments. We’ll also examine whether our tests can pick up early signs in people who at high risk of developing a brain disease. And finally, we’ll test drugs that affect two brain chemicals to see whether they can improve components of short-term memory and motivation.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: A high-quality connectome of the complete female adult Drosophila central nervous system
Funder: Wellcome Trust

Abstract: We previously proposed to generate a complete connectome for the adult male Drosophila central nervous system (CNS), comprising both brain and nerve cord. Capitalising on that investment, this discretionary award would allow us to deliver a second, high-quality, female connectome just one year later, at a fraction of the cost. This would be the first full CNS connectome, bilaterally complete and with sensorimotor circuits intact, of an adult female animal with complex behaviours. It would immediately allow comparisons of neuronal number, morphology, and connectivity across 1) hemispheres (this animal), 2) sexes (with the male CNS), and 3) three same-sex individuals (with partial datasets FAFB and the hemibrain) and global estimates of intra-individual, inter-sex, and inter-individual variation. The PIs will use this joint resource to investigate circuitry underlying sexually dimorphic behaviours such as decision-making (e.g., mating receptivity and egg-laying), aggression, sensory integration and descending control of motor programmes, memory formation and recall, and sleep. We will make both datasets available with a range of analytic tools for use by the >200 labs studying Drosophila neurobiology worldwide. Moreover, we expect the technology and pipelines developed for obtaining and comparing these connectomes to facilitate future studies in other organisms, ultimately including humans.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Mechanisms of perceptual decision-making in premotor cortex
Funder: Wellcome Trust

Abstract: Decisions require integration of sensory evidence and prior knowledge before committing to a chosen action, but the neural mechanisms of decision-making remain poorly understood, partly because they involve the interaction of multiple brain structures and timescales. We have developed a change-detection task in mice, which separates covert antecedents of choices from motor-execution-related activity, to probe mechanisms of decision-making. Pilot data reveal that secondary motor cortex (MOs) is selectively and persistently activated by behaviourally-relevant sensory evidence when animals expect a stimulus change, and is the earliest cortical area recruited prior to executing a behavioural choice. We will determine how neural dynamics in MOs unfold as mice commit to a decision, map these dynamics on genetically and anatomically identified populations of neurons, and test their necessity for behaviour. We will identify how MOs representations are updated by sensory evidence and how this is influenced by temporal expectation. We will test specific hypothesis about circuit mechanisms that drive decision-related dynamics in MOs, using targeted optogenetic inactivations of multiple brain regions to assess their impact on behaviour. This work will identify the contribution of cortical and subcortical pathways to transforming sensory evidence into decision, and how temporal expectation influences this transformation.

Lay abstract: Making decisions is an essential part of life. For example, deciding whether to go for a run in England requires us to infer whether it has stopped raining or this is just a temporary lull—we must integrate external information with prior knowledge before committing to an action. In this project, we will investigate how different parts of the brain contribute to deciding how and when to act. We will focus on how activity in a key decision-making area in the frontal neocortex contributes to animals' choices, using a new task designed to probe mice's decision-making. Using mice, we can pinpoint which types of cells and pathways in the brain are involved, by recording and manipulating their activity at specific times during the decision process. Determining how brain circuits compute decisions is fundamental for understanding how animals make appropriate and inappropriate judgements, and may inform the development of intelligent artificial agents.

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