NIHRDataInsights/HRCSData huggingface dataset:
Title: Mapping the energetic pathways of the brain: Ultra-high-field MRI of cerebral oxygen and glucose utilisation
Funder: Wellcome Trust

Abstract: Aerobic glycolysis (AG) plays a vital role in brain disease, development, and ageing. Elevated AG has been linked to axonal elongation and synaptogenesis in childhood, synaptic plasticity in adulthood, and is a hallmark of cancer. There is also evidence of a significant reduction in AG in older age and in neurodegeneration. The development of a non-invasive method for imaging AG has the potential for significant impact in basic neuroscience and clinical practice. For example, in cancer therapy, post-treatment mapping of AG is anticipated to be a sensitive measure for assessing recurrence and for the planning of salvage therapy. I propose to develop ultra-high field (7T) MRI methods to safely and non-invasively map aerobic glycolysis and tissue oxygen availability in the human brain, providing a new window into brain metabolism and metabolic dysfunction. The methods development involves two main paths. 1) Glucose labeled deuterium imaging to directly map cerebral AG. 2) Development of vascular imaging methods, including deuterium perfusion and blood volume imaging. The combination of these two methods will enable calculation of cerebral glucose metabolism, oxygen metabolism, and tissue oxygen availability. These methods will be validated experimentally using a controlled pharmacological modulation of aerobic glycolysis with sub-anaesthetic ketamine administration.

Lay abstract: In the healthy adult brain approximately 90% of its energy is produced via oxidative metabolism of glucose, with the remaining 10% produced via non-oxidative metabolism of glucose. Uncoupling in the ratio of oxygen-to-glucose utilisation is a hallmark of cancer and is fundamental to brain development, ageing, and neurodegeneration. In this fellowship I will develop non-invasive methods for mapping brain oxygen-to-glucose utilisation and tissue oxygen availability using ultra-high field magnetic resonance imaging. The ability to image these fundamental aspects of brain physiology is expected to have a significant impact on our understanding of brain function, and will provide vital information for tracking disease progression and treatment response. For example, the ability to make a comprehensive assessment of brain physiology post cancer treatment is anticipated to greatly enhance our ability to detect disease progression and provide swift rescue therapy.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Modulation of circuit dynamics by noradrenergic signalling in the annelid model Platynereis
Funder: Wellcome Trust

Abstract: In nervous systems, a large number of neuromodulators regulates the activity of every neural circuit. The monoamine noradrenalin (norepinephrine) is a major neuromodulatory transmitter that promotes wakefulness and arousal and regulates autonomic functions. Until recently, noradrenalin signalling was considered to be specific to vertebrates. Our discovery of functional noradrenalin signalling in marine invertebrates has overturned this long-held view. In this project, we propose to investigate noradrenergic signalling in the larval stages of the marine annelid Platynereis dumerilii, a laboratory animal and powerful new model for connectomics and circuit function. We will take advantage of the Platynereis system to obtain novel cellular-level insights into noradrenergic signalling through a systems-neuroscience approach. To analyse the functions of noradrenalin and its regulators at single-cell resolution, we will generate transgenic constructs and CRISPR-induced knockout lines and analyse wild-type, knockout and transgenic larvae with whole-brain activity imaging and various behavioural paradigms. We will establish whole-body wiring diagrams through serial EM reconstruction and map the components of noradrenergic signalling to the connectome. The use of this simple and accessible invertebrate genetic model will thus allow us to study noradrenergic signalling in unprecedented detail in a fully-mapped nervous system.

Lay abstract: In nervous systems, the activity of every neuron is tuned by a large number of chemical substances. One of these substances is noradrenalin, a molecule that promotes wakefulness and regulates heart rate and other functions. Noradrenalin so far was only found in vertebrates, but my team has recent discovered this molecule in some marine invertebrates. My aim is to study noradrenergic signalling in such a marine animal, the ragworm Platynereis. Platynereis is a powerful new laboratory model to study the function of neural circuits. I aim to understand the details of noradrenergic signalling at a single-neuron resolution by taking a multidisciplinary approach. I will use whole-brain imaging, transgenesis and CRISPR technology and study ragworm larvae in various behavioural assays. I will also use high-resolution microscopy to reconstruct the noradrenergic circuits. These studies will allow us to understand noradrenergic signalling at unprecedented detail in a simple and fully-mapped nervous system.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: The roles of modern and ancestral visual pathways in the mammalian brain, for defensive behaviours and spatial navigation
Funder: Wellcome Trust

Abstract: In order to survive, animals need to avoid predators and skillfully navigate the environment. These behaviors critically depend on the sense of vision. In mammals, two distinct systems process visual information: the evolutionarily ancient "superior colliculus" and the modern "visual cortex". We will define their relative functions in two natural behaviors essential for survival: (1)innate defensive responses and (2)spatial navigation. 1)We will study the visual cortex's role in controlling innate defensive behaviors triggered by the superior colliculus. We will focus on the mouse postrhinal-cortex (POR), capitalizing on my discovery that the superior colliculus has, through POR, a dedicated cortical space from which it receives direct excitatory feedback.(Beltramo,Science,2020). We will test the hypothesis that POR, relaying contextual information about the estimated threatening nature of visual stimuli, controls collicular function's plasticity. By silencing distinct cortico-collicular projections, we will determine how the visual cortex shapes the flexibility of colliculus-mediated innate behaviors. 2)We will investigate the contributions of the two visual pathways in spatial navigation, studying how visual input is transformed into the spatial maps found in the entorhinal/hippocampal formation. Perturbing the activity of distinct visual streams, we will establish how the superior colliculus and visual cortex influence the internal maps that guide navigation.

Lay abstract: Our brain is the result of a long evolution. Over time, new brain regions superseded functions originally performed by preexisting areas. Newer structures did not replace older ones but rather integrated with them, increasing circuit complexity. What roles ancient and modern, functionally similar brain regions play in behavior? The visual system offers an ideal model for studying this question. Mammals have two coexisting brain structures processing visual information: the ancient “superior colliculus” and the phylogenetically newer “visual cortex”. We will determine their relative roles in two natural behaviors crucial for survival: (1)innate defensive responses and (2)spatial navigation. Visually-evoked innate defensive behaviors, such as freezing upon detection of distant predators, critically increases survival chances. Equally important is the ability to navigate adroitly, creating internal “spatial maps” of the environment. This project will provide crucial insight into how evolutionarily ancient and modern visual pathways interact to generate complex behaviors essential for survival.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Synaptic Neurology
Funder: Wellcome Trust

Abstract: The overarching theme is to understand how the properties of defined classes of neurons underpin circuit computations and pathological activity patterns in the brain. 1. We will investigate the potential role of NMDA receptor-mediated dendritic supralinearity in parvalbumin-positive interneurons, and how this may help to stabilize neuronal assemblies. 2. We will apply closed-loop optogenetic drive to manipulate gamma oscillations in the visual cortex, and ask whether this can bias perception. 3. Chloride shifts and depolarization block of interneurons have been proposed to underlie seizure perpetuation. We will investigate their roles using closed loop optogenetics, KCC2 overexpression, single unit recordings, and simultaneous imaging of extracellular GABA and glutamate, in awake head-fixed animals. 4. Finally, we will investigate the role of neurogliaform cells, a relatively poorly understood neuronal subtype, in seizures, using Ndnf-Cre mice to target them.

Lay abstract: Much is known about the properties of distinct types of neurons and their connections, but how they underlie normal and abnormal circuit behaviours is poorly understood. In particular, it is widely speculated that network oscillations (rhythmic fluctuations in neuronal firing detectable at the population level) are important for communication among brain areas, although direct evidence is lacking. Furthermore, an imbalance between excitation and inhibition can lead to seizures, but many questions surround the roles of different subtypes of inhibitory neurons. The proposal addresses whether network oscillations have a causal role in information transmission. It also aims to resolve a controversy about the relative importance of failure of inhibitory neurons to fire and failure of excitatory neurons to be inhibited during seizures. A further line of research addresses the roles of a hitherto inaccessible population of inhibitory neurons in seizure initiation and propagation.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Behavioural role and neural representation of temporal dynamics in sensory stimuli.
Funder: Wellcome Trust

Abstract: Understanding how the brain represents and processes information is one of the most fundamental questions in neuroscience. Investigating the function of normal brains is also crucially important for understanding neurological disorders and psychiatric diseases. Sensory neuroscience provides a direct way to investigate the relation between activity and function. The simplicity and accessibility of the early olfactory system in turn presents an opportunity to not only correlate but causally link c ircuit computation with brain function and thus get a mechanistic understanding. The world is a dynamic place. While true in many ways, it is particularly so for smells: Air turbulences impose a rich temporal structure onto smells as one can appreciate from e.g. watching smoke meandering. Here, I will explore what this temporal structure is, what information it contains, how it is represented in the brain and how it is used to extract critical knowledge about the world, such as the location o f odour sources. Through electrical recordings in mice, images of brain activity and perturbation of specific cells we will understand how stimulus dynamics governs behaviour and thus unravel mechanisms of how information about the external world is represented and processed in neural circuits.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Transforming brain recordings with next-generation probes
Funder: Wellcome Trust

Abstract: Thanks to the Wellcome Trust and other leading international institutions, we have developed and proved the viability of a new generation of recording probes that will transform electrophysiology. These “Neuropixels” probes transcend past approaches, recording hundreds to thousands of neurons simultaneously. Several key steps are now necessary to maximize the impact of this new technology, enabling its widespread use in the neuroscience community. We must develop radically new recording equipment and software, provide training, and build a collaborative community of users (Aim 1). To allow this community to fully exploit the potential of this technology, we must extend it to a larger range of applications: multi-shank probes, wireless recording for freely moving animals, and optrodes for use with optogenetics (Aim 2). Meanwhile, we will obtain ground-truth data to calibrate error rates, and begin the development of a tool to automatically identify brain regions based on electrophysiological characteristics (Aim 3). This project integrates software and hardware engineering, fabrication efforts, neurophysiology tests, and behavioral and anatomical techniques. It thus requires a collaboration between laboratories with different skill sets, and a unique nanoelectronics research partner, IMEC. The results of this collaboration will transform the field of neuroscience.

Lay abstract: Thanks to the Wellcome Trust and other leading international institutions, we have developed and proved the viability of a new generation of recording probes that will transform electrophysiology. These “Neuropixels” probes transcend past approaches, recording hundreds to thousands of neurons simultaneously. Several key steps are now necessary to maximize the impact of this new technology, enabling its widespread use in the neuroscience community. We must develop radically new recording equipment and software, provide training, and build a collaborative community of users (Aim 1). To allow this community to fully exploit the potential of this technology, we must extend it to a larger range of applications: multi-shank probes, wireless recording for freely moving animals, and optrodes for use with optogenetics (Aim 2). Meanwhile, we will obtain ground-truth data to calibrate error rates, and begin the development of a tool to automatically identify brain regions based on electrophysiological characteristics (Aim 3). This project integrates software and hardware engineering, fabrication efforts, neurophysiology tests, and behavioral and anatomical techniques. It thus requires a collaboration between laboratories with different skill sets, and a unique nanoelectronics research partner, IMEC. The results of this collaboration will transform the field of neuroscience.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: The complete synaptic-level connectome of a nervous system and experimental connectomics
Funder: Wellcome Trust

Abstract: Animals sense the local environment, learn and remember past events, predict future ones, and combine current and past information to choose appropriate motor responses. Underlying these capabilities is the nervous system, which continuously integrates multiple sources of information and chooses one response in exclusion to all others. Our vision is to study neural circuit function on the basis of known synaptic-level wiring diagrams. In Aim #1, we propose to map the complete wiring diagram of an insect, the Drosophila larval central nervous system, using serial electron microscopy. With the knowledge of the circuits formed by the identified and genetically accessible larval neurons we can study how circuits change either by experience or in disease. In Aim #2 we propose to read out the engrams, the persistent yet reversible structural circuit patterns that form in response to learning and that underlie long-term memories, using associative memory in the larval mushroom bodies as the model system. For circuits to assemble correctly while remaining plastic, hundreds of genes need to work in concert. In Aim #3, we will study the effects of mutations in select genes associated with neural diseases on the synaptic-level circuit structure, causing the disease phenotype.

Lay abstract: The nervous system enables animals to sense their surroundings and respond appropriately to specific events using prior experiences and innate biases as a guide. The building blocks are neurons: cells that integrate incomming inputs from external stimuli or from other neurons, and then communicate them to other neurons or to actuators such as muscles. The only complete map of neural connections was produced for a nematode with only 300 neurons. Now, with modern tools contributed by us and others we propose to map the pattern of connections of the far more numerically complex nervous system of the fruit fly maggot, an organism whose embryonic development and overall architecture of its nervous system shares numerous parallels with us humans. But neural circuits are dynamic, and changing connections between neurons is one way by which memories can be stored. Building on prior work, we will train animals to like an odor and others to dislike it, and we will compare how the exact same circuit differs in its connections, revealing what neuroscientists call the "engram": a persistent alteration that represents a memory. Finally, we will study the changes to neural circuits caused by genetic mutations related to neural diseases.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: The role of glia and the cerebral vasculature in dementia
Funder: Wellcome Trust

Abstract: The cerebral vasculature and glial cells play crucial but poorly understood roles in initiating Alzheimer’s disease (AD) and related dementias, contributing to cognitive decline via a loss of synapses and neurons. We have shown that: (i) a major reduction of cerebral blood flow occurs early in human AD because oligomeric amyloid beta (Aß) evokes constriction of brain capillaries by contractile pericytes; (ii) the blood flow reduction in AD may reflect microglia controlling pericytes; (iii) microglia-mediated phagocytosis, which removes both Aß and synapses, is regulated by ion channels and receptors; (iv) decreased blood flow and AD alter node of Ranvier length in myelinated axons, which will change axonal conduction speed and thus neural circuit function. Now, focusing on Aß and decreased blood flow, we will investigate how vascular and glial function contribute to dementia, by: (A) defining the mechanisms underlying Aß-evoked capillary constriction, and developing therapeutic approaches to restoring blood flow; (B) characterising how microglia and astrocytes remove Aß and synapses, and investigating how to control this; (C) studying how Aß and decreased blood flow damage myelin and nodes of Ranvier, and how to prevent this. Together, this work will identify novel non-neuronal therapeutic targets for treating dementia.

Lay abstract: Alzheimer’s disease (AD) and related dementias involve a loss of nerve cells, and the connections between them (synapses), in the brain. However, early in the disease process, the blood supply which provides energy to nerve cells is greatly reduced and supporting cells (so-called glial cells), which help the nerve cells to process and transmit information, change their function. We will examine how: (1) brain blood flow is deleteriously reduced early in AD, and whether this can be reversed; (2) the brain’s glial cells protectively remove a molecule (amyloid beta) that triggers dementia, but also remove synapses and thus evoke cognitive decline; and (3) how rapid long-distance transmission of signals in the brain is affected in AD. By examining the important but less-studied blood vessels and glial cells in the brain, we hope to understand brain function and dementia better, and to devise new therapeutic targets for treating dementia.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Spinal circuits underlying pathological pain
Funder: Wellcome Trust

Abstract: Allodynia and hyperalgesia occur in neuropathic and inflammatory pain states, and depend on circuits involving dorsal horn excitatory interneurons. Recent studies have identified several neurochemical/transcriptomic populations among these cells. We will use a multi-disciplinary approach, involving molecular-genetic targeting of these populations, to investigate their involvement in pain mechanisms at circuit and behavioural levels. We have found that neurons expressing gastrin releasing peptide receptor (GRPR) correspond to vertical cells, which transmit information to lamina I projection neurons, and are implicated in both neuropathic and inflammatory pain. We will use anatomical, electrophysiological and behavioural approaches to determine whether the GRPR cells fulfil this role. If not, we will investigate another population defined by expression of neuropeptide FF. Cells with PKC&gamma; are critical for neuropathic allodynia, but these can be assigned to two populations that express neurotensin or cholecystokinin. We will determine whether these are functionally different, and whether both contribute to allodynia. Finally, we will establish whether any other excitatory interneurons are interposed between PKC&gamma; cells and vertical cells in the pathway for tactile allodynia. The study will provide important information about synaptic circuits for pain, and the roles of different interneuron populations. Keywords: pain, spinal cord, neuronal silencing, chemogenetics, optogenetics

Lay abstract: Nerve injury and tissue inflammation often cause exaggerated pain, which results from abnormal activity in nerve circuits in the spinal cord. These circuits include a class of nerve cells, known as excitatory interneurons, which activate other cells. Recent studies have identified several distinct excitatory interneuron populations, and our aim is to determine the roles of these different populations in normal and pathological pain. We will use a multidisciplinary approach involving genetically-modified mice in which different interneuron populations can be specifically targeted. Anatomical and physiological techniques will be used to define the nerve circuits that involve these cells. We will also test the effect of activating or silencing different populations, both at the cellular level, and on the behavioural responses in models of nerve-injury and inflammatory pain. These studies will define the neurons and circuits that underlie different forms of pain, which is essential for the development of new treatments.

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