NIHRDataInsights/HRCSData huggingface dataset:
Title: The Human Brain Synaptome Project
Funder: Wellcome Trust

Abstract: We will create the first atlas of the human brain showing the location, molecular composition and physical features of trillions of single synapses at the whole-brain scale. The Human Synaptome Atlas will reveal the distribution of excitatory and inhibitory synapse subtypes in all major areas of the brain in three normal individuals and in the prefrontal cortex of 100 normal individuals (20-80 years of age). Toward this, we have reported a breakthrough technology pipeline enabling mapping of billions of individual synapses to generate the mouse brain synaptome (PMC6117470). To address the challenges and opportunities presented by the human brain, we will: 1. Establish the next-generation synaptome mapping pipeline – SYNSTAR – scalable to the size and complexity of the human synaptome. 2. Generate novel reference resources and tools for analysis and interactive visualisation of human synaptomes. 3. Integrate the atlas with international strategic programmes mapping human brain anatomy and function from the molecular and cellular scale to whole-brain networks. The Human Synaptome Atlas and SYNSTAR will provide a foundation for the study of the normal and diseased brain including the many genetic disorders, neurodegenerative conditions and brain injuries that damage synapses. Keywords: Human, Brain, Synapse, Synaptome, Postsynaptic, Proteome, Atlas

Lay abstract: A hallmark of the vast complexity of the brain is the immense number of synapses – the connections between each nerve cell. We have been developing new ‘synaptomics’ tools that can map these billions of synapses and identify their protein components. This has revealed unprecedented organisation and diversity in synapse types among the different regions of the mouse brain. To fully understand how these ‘synaptome maps’ contribute to brain development and function, we need first to adapt our tools to overcome the challenges presented by the size and complexity of the human brain. We will then generate a synaptome atlas of the whole human brain and also examine key functional areas in detail. This will provide entirely new insight into how the normal human brain works, but also novel tools and resources that can be used to uncover how the synaptome maps go awry in schizophrenia, autism and depression.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Towards personalized cognitive brain stimulation for depression
Funder: Wellcome Trust

Abstract: Non-invasive brain stimulation is a new family of treatments for depression. Efficacy is established for TMS to dorsolateral prefrontal cortex and under evaluation for tDCS. Recently efficacy has emerged for two additional targets: dorsomedial prefrontal (DMPFC) and lateral orbitofrontal cortex (LOFC). In the current state of the art, resting-state neuroimaging is being tested to personalize TMS target selection. My vision is to further improve treatment by targeting stimulation based on cognitive function. My project aims to lay the scientific foundations to achieve this. In depression, cognition and emotion are biased towards negative information. According to theory, when drugs and cognitive therapies work, they do so by rapidly reducing negative bias. I will test if this cognitive mechanism mediates TMS treatment and explains individual differences in clinical response. With repeated treatment, people gradually experience the world more positively, which slowly improves mood. This is thought to depend on reinforcement learning. Using tDCS I will stimulate DMPFC to increase learning from positive outcomes. I will stimulate LOFC to reduce inappropriate self-blame for negative outcomes. My scientific aim is to establish proof of concept that this cognitive targeting will improve DMPFC and LOFC stimulation. My long-term goal is to improve treatment.

Lay abstract: Depression is the leading cause of adult disability. Depressed people suffer low mood, lack of motivation and a high risk of suicide. Current treatments, drugs or psychotherapy, are slow and only work for some people. So better treatments are needed. Non-invasive brain stimulation is a promising new treatment. Patients' brains are stimulated safely and painlessly while they rest. I aim to improve stimulation by using the fact that depressed people focus on negative information. While people play simple computer games, I will stimulate the brain areas that control negative focus. I predict better results than stimulating during rest. I will test this in scientific experiments. In the clinic, I will test if stimulation treats depression by reducing negative focus. I predict that patients who show less negative focus after one week of treatment will get better within six weeks. My work aims to explain and improve how stimulation treats depression.

Research activity codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Can cortical reorganisation support adaptive behaviour?
Funder: Wellcome Trust

Abstract: It is well established that the sensorimotor cortex can reorganise throughout life. In the adult human brain, reorganisation has been suggested to both support and hinder rehabilitation, and thus is an important mechanism to characterise. Previous human reorganisation research is largely based on net changes in activity levels (cortical remapping), and thereby provides an incomplete estimate of reorganisation. Contrary to textbook and clinical understanding of sensorimotor reorganisation, I hypothesise that, once organised sensorimotor maps have formed, opportunities for reorganisation in the adult brain will be limited, or even blocked, by pre-existing organisational constraints. To test this, I propose to implement advanced neuroimaging approaches and brain stimulation protocols in individuals with congenital or acquired limb loss, to interrogate the information content underlying cortical remapping and its relationship with rehabilitation. In addition, I will track longitudinal brain and behavioural changes from the early stages of reorganisation in handless children and in adults before and after arm amputation. Finally, I will examine the contributions of afferent versus efferent inputs in driving reorganisation versus maintaining persistent representation. By crystallising the representational and behavioural consequences of brain remapping across development, my research will identify opportunities and barriers for guiding rehabilitation and assistive technology interfaces.

Lay abstract: Our brain’s capacity for reorganisation is considered a key mechanism for supporting recovery from injury. The sensorimotor cortex is perhaps the most influential model for reorganisation in the adult brain. For example, following arm amputation, the missing-hand cortex becomes responsive to inputs from other body parts. However, once a cortical territory had become specialised (e.g. to support hand function), it is unclear whether it can actually change to support new functions (e.g. of other body parts). I plan to characterise the conditions under which behaviourally-meaningful reorganisation can occur. I will use neuroimaging and brain stimulation to interrogate the information content being stored in the missing-hand cortex of children and adults with upper-limb deficiencies. I will use high-resolution neuroimaging and computational modelling to determine how reorganisation occurs. A more complete understanding of the opportunities and barriers for sensorimotor reorganisation will be crucial for future development of rehabilitation and assistive technology interfaces.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: The mammillary bodies and memory: from encoding to consolidation
Funder: Wellcome Trust

Abstract: The mammillary bodies (MBs) are critical for memory but their specific functions have remained largely elusive. Historically, the MBs were associated with memory encoding, however, our recent findings suggest an as yet unexplored role in memory consolidation, both at the cellular and at the systems level. The proposed research will use multi-level, comparative approaches to investigate the contribution of the MBs to post-encoding processing, during wakefulness and sleep. The combined rodent/human methodologies will take advantage of the unique benefits provided by each line of research. The application of convergent techniques with rodents (inactivation, calcium-imaging, electrophysiology, behaviour) will interrogate the contributions of the MBs to different stages of memory processing, both in an intact system and when the system is disrupted. Complementary research with humans will address similar questions. fMRI will help to assess diencephalic contributions in the intact system. The impact of damage to the MB system on aspects of sleep-related consolidation will also be assessed. Together, this research will provide a comprehensive analysis of post-encoding memory processes and support the development of wide-reaching models of MB function.

Lay abstract: The devastating effects of conditions such as Alzheimer’s disease underline the importance of our memories. Understanding how our brains support memory remains one of the greatest scientific challenges. A network of brain structures that includes the mammillary bodies (MBs) are required for normal memory. The MBs are typically linked to memory encoding, i.e. the processing of online information, but very little is known about their contributions to memory beyond this point. My recent research suggests that the MBs may also be necessary for aspects of memory consolidation. I will test this prediction using a number of complementary techniques and a cross-species approach. My research will examine how the MBs contribute to memory formation beyond the encoding stage, with a particular focus of sleep-related consolidation. In doing so, the research will help generate better models of memory function in both healthy and diseased states.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Inhibitory Mechanisms Of Homeostatic Plasticity In Vivo
Funder: Wellcome Trust

Abstract: Homeostatic plasticity is the compensatory mechanisms that regulate activity levels in the brain during ongoing changes, for example following learning or input loss. To date, homeostatic plasticity studies have largely focused on changes in excitatory neurons; however, inhibitory neurons also play an important role in regulating overall network activity. Given the known connectivity of excitatory and inhibitory neurons in mouse visual cortex, changing activity in different inhibitory subtypes would have drastically different effects on network activity, but the role of specific inhibitory subtypes in homeostatic plasticity is unclear. We will use in vivo two-photon imaging in behaving adult mice expressing genetically encoded calcium indicators to measure the activity levels of inhibitory subtypes during the homeostatic recovery of activity that follows the loss of sensory input to the visual cortex. We will then use optogenetic tools to change activity levels in these inhibitory subtypes, to determine: 1) their causal role in the maintenance of activity after homeostatic activity recovery, and 2) their interactions with homeostatic plasticity mechanisms that facilitate homeostatic recovery. These experiments will identify which inhibitory subtypes are critical for homeostatic plasticity.

Lay abstract: Neuroplasticity is the brain’s ability to learn and change in response to novel environments or following injury. There are many forms of neuroplasticity, including homeostatic plasticity, which describes the balancing mechanisms that ensure that brain activity never becomes extreme during synaptic changes following learning or input loss. The disruption of homeostatic plasticity is implicated in diseases such as epilepsy, Alzheimer’s disease and schizophrenia; however, the cell-types involved in this plasticity are unclear. Here we will measure activity levels of specific inhibitory neuron subtypes during the homeostatic recovery of activity that follows input loss. We will then use optogenetic tools to change the activity levels in these inhibitory subtypes to determine their causal role in the homeostatic activity regulation at spatial scales of synapses, cells and cellular networks. These experiments will identify candidate inhibitory neurons that can be targeted for therapeutic intervention when homeostatic plasticity is disrupted in disease.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: The development of neural circuits for episodic and general memories
Funder: Wellcome Trust

Abstract: This proposal aims to understand how neural networks for memory emerge during post-natal development, both during normal development and following early-life brain damage. Episodic memories (memories of events and their spatio-temporal context), and generalised learning such as semantic memories (factual world-knowledge) are supported by different brain networks. Episodic memories are thought to be encoded initially by the hippocampus, whilst general knowledge would be extracted by integrating across experiences via hippocampus-neocortical interactions. However, the ontogenetic unfolding of memory runs counter to this framework. Early development is characterised by the rapid acquisition of general knowledge, despite amnesia for specific events. Furthermore, sustaining early-life hippocampal damage results in dense amnesia for specific episodes, but general learning is relatively preserved. We aim to resolve this apparent paradox by studying neural circuit activity in vivo, in conjunction with behaviour, in developing rodents. Our goals are to: 1) Understand the development of hippocampal mechanisms supporting the generation of memory traces of specific events; 2) Understand the neural mechanisms that enable the association of items with their spatio-temporal context (episodic memory processing); 3) Discover how neural coding for generalised knowledge emerges across cortical-hippocampal networks during normal development, and identify networks supporting preserved learning after early-life hippocampal damage.

Lay abstract: Memories can be divided into two types: memories of specific events, which retain a feeling of when and where they happened (‘episodic’ memories), and general knowledge, not linked to a time or place it may have been learnt. Many theories of memory assume that we learn by example: all memories are first episodic, then time and experience lead to their integration into general ones. However, the development of memory in young animals runs counter to these theories: during development, learning general knowledge about the world precedes the ability to make episodic memories. Furthermore, damage to the hippocampus (a structure essential for episodic memory) early in life has relatively little effect on general knowledge acquisition. By recording neural activity from developing rodents, these experiments will investigate the neural mechanisms that support general and episodic memory during development, and investigate how these are affected by early-life damage to the hippocampus.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: The retention of memory and creation of knowledge
Funder: Wellcome Trust

Abstract: Memories are often formed automatically, selectively retained and then some information becomes incorporated into the networks of knowledge that each of us possess. A key challenge is to identify the neural mechanisms responsible for the selective retention of recent hippocampal-dependent memory traces and those mediating the incorporation of this information into existing knowledge networks in the neocortex. Phase 1 concerns selectivity: Guided by predictions of the synaptic-tagging-and-capture hypothesis of protein synthesis-dependent memory consolidation, we would use a novel everyday-memory task to follow up our observations that certain parameters of learning, including peri-event novelty, enhance memory retention. Experiments using genetically modified animals that involve neurotransmitter imaging and endoscopic Ca2+ imaging would explore the potentially critical role of a neural circuit from the locus coeruleus to the hippocampus in selective retention. Phase 2 addresses knowledge assimilation: This work would be conducted in the context of the new schema theory of semantic-like memory that presupposes that prior knowledge guides memory updating. It would follow up our original experiments on schema learning, introduce a new method for doing such experiments, explore endoscopic imaging in both hippocampus and neocortex, and the network contributions of distinct neocortical regions using a disconnection approach.

Lay abstract: As we go about our daily life, we automatically form memories of the events of the day. Too many, as it happens, such that a key job of the memory system is to filter out unnecessary information and just keep the important or interesting stuff. These memory traces are then either retained as they are, such as memories of special events (such as the birth of a child), while others are stripped of information about where and when they happened so that merely factual information is added to our knowledge base. A great deal of research is currently investigating memory selectivity and the accumulation of knowledge in humans, but it is impossible to do mechanistic causal research in people. Using animal memory tasks, this project investigates these issues using state-of-the-art molecular engineering tools in conjunction with new cognitive tasks for laboratory animals that mimic well the typical events of daily life in humans. We hope to secure definitive information about the neurotransmitters involved in enhanced memory retention, and the networks of neurons that must communicate for new information to be assimilated with what we already know.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Non-local computations in hippocampal circuits: neural mechanisms
Funder: Wellcome Trust

Abstract: The overall goal of this proposal is to build a neural-level understanding of how non-local cortico-hippocampal communication mediates memory consolidation and spatial computations. The well-studied network of spatially modulated neurons in the hippocampus and associated regions provides the pre-eminent cellular-model of memory for events and places. However, the activity of these neurons mainly encodes local information, that is, the current configuration of an animal in its environment. Work conducted by us, and others, have identified transient reactivations of hippocampal neurons and cortical counterparts as a key mechanism supporting systems consolidation and spatial planning. These brief ‘non-local’ events provide a means by which remembered experiences can gradually update memory networks, equally they are theorised to support the calculations necessary for route planning. Our aims are: 1) to understand how hippocampus and cortex interacts during reactivations; 2) determine how reactivated information affects existing representations; 3) precisely define the spatial computations that guide navigation; 4) investigate how neuromodulation controls the occurrence of reactivations. To this end, our approach is to combine computational modelling, machine learning, and state-of-the-art experimental techniques. Developing a basic understanding of these processes opens the way to understand how they fail in disease and may ultimately deliver tremendous therapeutic benefits.

Lay abstract: Past experiences, in the form of memory, guide the way in which we understand the world and plan for the future. In the brain, a region called the hippocampus is known to be important for forming memories about events and places that have been encountered. Research in humans and animals has identified neurons in the hippocampus and related brain areas that contribute to this process by representing self-location. However, it is clear that these representations alone are insufficient to explain how mammals form and use long-term memories. We will build on theoretical work and promising pilot data to study how the hippocampus interacts with the rest of the brain to: 1) extract common themes from recent experiences, 2) guide planning for the future. Mechanistic insights into these functions may, in the future, allow us to derive novel therapies for neurogenerative diseases such as Alzheimer’s which directly impact mnemonic abilities.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Neurophysiology of nutrient rewards
Funder: Wellcome Trust

Abstract: Optimal human food intake goes beyond reactive consumption and involves sophisticated behaviours that fine-tune food acquisition to our specific needs. Every day, we form decisions and consumption-plans to pursue our favourite foods, and model food choices from our social partners. This proposal develops a novel translational approach to study the neural mechanisms for realistic food-intake behaviours involving planning, decision-making, and social learning. We perform single-neuron recordings in amygdala, hypothalamus, and orbitofrontal cortex during feeding behaviour for clinically relevant nutrients, including fats and sugars. Separate research aims focus on two aspects of food intake: (1) planning and decision-making for specific nutrient rewards; (2) social influences on food choice. Neuroimaging with identical foods and behaviours extends single-cell data to brain networks, functional connectivity, individual differences, and real-life eating phenotypes. We advance the field by identifying explicit neuronal signals that underlie formation and pursuit of nutrient consumption-plans; by formalizing behavioural conditions for social nutrient-reward learning; and by identifying neuronal signals that underlie such learning and related social influences on food choice. By studying sophisticated, typical food intake in single neurons, neural systems, and behaviour, we aim to uncover basic neurophysiological mechanisms and lay foundations for clinical studies in obesity.

Lay abstract: No Data Entered

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