NIHRDataInsights/HRCSData huggingface dataset:
Title: Functional organization of midbrain circuits for target selection
Funder: The Francis Crick Institute

Abstract: In order to determine behavioural priorities, the brain must integrate sensory information from multiple modalities with motivational and contextual information. Many situations require a fast evaluation of the salience and the relevance of the sensory information, for example during orienting to relevant targets. However, it is not clear how target priority is determined by the brain. The superior colliculus (SC) is an evolutionary conserved structure, present in all vertebrates, involved in orienting and escape behaviours and it has been implicated in spatial attention and target selection. The SC has access to a wide range of multisensory inputs, as well as non-sensory information from primary and association areas of the neocortex, and hypothalamus. In turn, the SC projects to the thalamus (mainly to the lateral posterior /pulvinar complex), the dorsolateral periaqueductal gray and to the motor systems in the brainstem and spinal cord. This extensive afferent and efferent connectivity suggests that the SC serves as a hub for linking brain circuits carrying information concerning the location of high-priority targets for an immediate re-orienting response. Thus, the SC provides a unique opportunity to investigate how, within a single brain structure, signals from the different senses are combined with non-sensory information and used to guide motor responses. At present, however, it is not clear how functional microcircuits within the SC integrate and assess the relevance of sensory information from different modalities to generate an attentional shift or a motor response. To understand this, we record activity from hundreds of neurons from the superior colliculus of mice while they perform visual-auditory localization tasks using two-photon microscopy and performing extracellular electrophysiological recordings. The use of genetic markers and optogenetic approaches allows us to identify different neuronal populations and determine their role during behaviour. Finally, we study the rules that determine how these different cell types communicate by performing multiple patch clamp recordings in brain slices to study the strength and probability of their synaptic connections. My long term goal is to elucidate the relationship between the architecture and physiological function of the neuronal circuits underlying the selection of a behaviourally relevant target.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: MICA Cryo-chronobiology: how do cold-inducible chaperones maintain neural clock function under brain temperature fluctuation?
Funder: Medical Research Council

Abstract: Molecular clocks drive cellular circadian rhythms to run with a consistent ~24h period, despite changes in body temperature. This temperature compensation remains unexplained, especially for the brain where temperature varies with neuronal activity. Cold-inducible chaperones (CICs) regulate clock transcripts in the nucleus and are themselves circadian-regulated. I predict that CIC-clock interactions are critical to temperature-compensated neural timekeeping, and that failure of this mechanism underlies circadian disruption in chronic brain disorders. This proposal tests whether CIC-clock interactions are required to maintain neural clock function as brain temperature changes. Data from brain-injured patients, magnetic resonance spectroscopy imaging of healthy volunteers and radiotelemetry in mice will determine how brain temperature varies with circadian time. The human neural clock and its circadian proteome will be characterized in stem cell-derived neurons and glia expressing bioluminescent CIC/clock reporters, complemented by quantitative protein mass spectrometry. By inducible and conditional exogenous regulation, CIC/clock proteins will be reversibly trapped in the cytoplasm to uncouple CIC-clock interactions during temperature shift. Mechanistically this will reveal which CIC is most important to neural timekeeping, and which neural cell type is most vulnerable to CIC-clock disruption. Finally, a transgenic mouse lacking this CIC in the key cell type will be generated for radiotelemetric monitoring, alongside existing CIC and clock mutants. Together, these experiments will establish a basis for modulating CIC-clock interactions in neurodegenerative disease models. This work will deliver new tools, resources and knowledge with far-reaching applications for chrono/neurobiologists and immediate translational relevance to critical care patients. The goal is to transform molecular understanding of CIC-clock interactions into treatments for chronic brain disorders.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: NeuroNex2: Enabling Identification and Impact of Synaptic Weight in Functional Networks; NSF reference 2014862
Funder: Medical Research Council

Abstract: Traditionally, synapses have been treated as on or off switches, that is, one-bit machines. Recent models, based on synapse size as a proxy for synaptic weight, show that this assumption is wrong. In fact, the information content can be much higher, for example, being >4 bits at hippocampal synapses. Synaptic weight is controlled over broad temporal and spatial scales that are dynamically regulated by activity in neural circuits. New evidence points to subcellular resources (endoplasmic reticulum, mitochondria, endosomes, ribosomes) that broker and drive synaptic efficacy and plasticity through mechanisms that regulate local protein synthesis. Thus, an understanding of synaptic weights needs to be addressed at both subcellular and circuit levels. We hypothesize that synaptic weight is defined by the differential composition and co-occurrence of key proteins and subcellular resources. We will use multidisciplinary approaches to assess these features in well-defined states. Comparisons will be made across neural circuits involving multiple cell types, brain regions, and diverse behaviors in several species. Mapping consistent predictors of synaptic state arising from these analyses onto neural connectomes will enhance tremendously our understanding of the roles of synaptic weight in circuit organization and function. To achieve these goals, new technologies are needed to bridge multiple scales in image resolution and to collect sufficiently large tissue volumes to perform circuit level analyses. An important new approach involves conical tilt tomography on the scanning electron microscope operating in the transmission mode (tomoSEM). TomoSEM aims to fill the current resolution-to-volume gap between methods used for structural biology (high resolution, small volumes) and connectomics (relatively low resolution, large volumes). TomoSEM provides the axial (~15 nm) and in-plane (~2 nm) resolution needed to identify and quantify subcellular components in large volumes.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: NEUROLOGICAL
Title: Advanced Pain Discovery Platform (APDP) Programme Director
Funder: Medical Research Council

Abstract: The Programme Director will have a key role in providing leadership for the initiative of The Strategic Priorities Fund (SPF) research programme for an Advanced Pain Discovery Platform (APDP), which aims to deliver an interdisciplinary consortium-based platform of national scale, generating discovery and early translational science that will break through the complexity of pain and reveal new biological, cognitive and psychosocial treatment approaches to address a wide spectrum of chronic and debilitating conditions. The Programme Director will be working with the funders, research community, people with lived experience of pain, investments and broader stakeholders to maximise potential impacts of the APDP.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: NEUROLOGICAL
Title: MAGNETO: Magnetic Actuators and Neural Engineering for TMS Optimisation
Funder: Medical Research Council

Abstract: The overall aim of this collaborative project is to integrate the 'extended' transcranial magnetic stimulation (xTMS) research tool, built in the MRC Brain Network Dynamics Unit, with research at the MRC Cognition and Brain Sciences Unit and MRC Centre for Neurodevelopmental Disorders. The xTMS system provides unrivalled opportunities to perturb physiological systems in the living human brain in health and disease (as highlighted as a key research tool needed in the 2021 MRC Unit and Centre Portfolio Review), and catalyses interdisciplinary projects spanning engineering, fundamental biomedicine and clinical application across the UKRI ecosystem.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: NEUROLOGICAL
Title: MURIDAE – Modalities for Understanding, Recording and Integrating Data Across Early life
Funder: Medical Research Council

Abstract: MURIDAE aims to significantly improving the translatability of mouse models for neuropsychiatric and neurodevelopmental disease by integrating multiple, longitudinal experimental measures of early-life in individual animals, while identifying time-critical interventions for therapeutic benefit. To address this challenge, we have an ambitious plan of work encompassing a number of experimental modalities that are required to effectively address this aim. Working closely with the Mary Lyon Centre (MLC) at MRC Harwell and other cluster Partners, we will first establish a new, standardised platform of home-cage behavioural monitoring, integrating these data with brain structure and physiology measures in mouse early postnatal life relevant to human neurodevelopmental trajectories. We will then apply our pipeline to multiple hypothesis-driven mouse genetic models of neuropsychiatric disease. As proof of principle, we will first use an existing model that has been previously been characterised both as an adult and on a limited number of early life measures. Guided by clinical partners, new MLC-created mouse models representing critical and tractable genetic targets will be studied using our pipeline. Overall, we will improve translatability by exploiting the predictive power of our data to define clinically relevant prodromal biomarkers. This in turn will help in defining key developmental intervention points for genetic rescue and identifying new therapeutic targets and their optimal developmental timing. This systematic, standardised approach will facilitate a better understanding of the shared mechanisms leading to neuropsychiatric disorders and, by linking with partners studying adult phenotypes, our platform will be applied across the Network to inform multiple model systems where early life events are crucial, yet under-studied in vivo.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Small molecule modulators of lncRNA NEAT1_2: A novel approach to enhancing the endogenous neuroprotective response in amyotrophic lateral sclerosis
Funder: Medical Research Council

Abstract: The unmet need Amyotrophic lateral sclerosis (ALS), the most common form of motor neuron disease, is a fatal neuromuscular condition. The two drugs approved for ALS, riluzole and edaravone, extend patient survival by only a few months. Hence, novel disease-modifying therapies that are efficacious across different ALS subtypes are urgently needed. Paraspeckles are a protective mechanism in ALS ALS is aetiologically heterogeneous, with most cases being sporadic while the minority of cases that have a genetic cause can be divided into >25 genetic subtypes. However, an increase in the number of paraspeckles in the nuclei of motor neurons occurs irrespective of the cause of ALS. Paraspeckles are intranuclear membraneless ribonucleoprotein organelles (RNP granules) that have a protective function, and multiple structural proteins of paraspeckles are affected by ALS-causative mutations. The lncRNA NEAT1_2 is a key component of the paraspeckle Long noncoding RNA (lncRNA), NEAT1 (Nuclear Paraspeckle Assembly Transcript 1) exists in two isoforms, NEAT1_1 and NEAT1_2. The latter is the stress-induced isoform essential in the recruitment of RNA-binding proteins and the formation of paraspeckles (i.e., NEAT1_2 "seeds" the formation of paraspeckles). Project hypothesis Small molecules that stabilise NEAT1_2 will augment paraspeckle assembly within the motor neurons in ALS. This in turn will enhance their resilience and survival. Project aim To identify small molecules that interact with the triple helix (TH) structure at the 3' end of NEAT1_2. This TH is the NEAT1_2's stability element that is sufficiently complex to support small molecule binding. Progress to date This proposal describing a robust fluorescence displacement assay using NEAT1_2 TH RNA is based on work conducted by CoI Shelkovnikova when she worked with PI Atack and CoI Ward at the MDI. Secondary assays are established in CoI Shelkovnikova's new lab in Sheffield.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: Neurons and biological timing: Molecular Neurobiology of the Circadian Clock
Funder: Medical Research Council

Abstract: Our daily rhythms of sleep and wakefulness, hormone secretion and metabolic activity are driven by the brain s circadian pacemaker: the suprachiasmatic nuclei (SCN) of the hypothalamus. The current molecular model of the circadian oscillator within the SCN is one of interlocked transcriptional/post-translational feedback loops, which sustain autonomous 24 h cycles of gene expression. Notwithstanding its success, our knowledge of its components is far from complete and the model is heavily based on evidence and inferences of the properties and behaviour of clock factors in heterologous systems, far removed from the SCN. Our objective, therefore, is to conduct a series of definitive experiments to identify novel components of the clockwork and to test the predictions of the model, both in the context of the SCN neuronal environment, the principal neural oscillator, and in primary fibroblasts which also have pacemaking ability. We exploit a combination of neurobiological, molecular genetic, biochemical and behavioural approaches, both in vitro and in vivo. An important feature is extensive use of genetically modified mice- for real-time imaging of fluorescent and bioluminescent clock gene products, targetted and random mutations of clock genes and as genetic models of diseases with a pronounced circadian disturbance. Specifically, we aim to define the nature of dynamic interactions between oscillator components, both protein and DNA regulatory sequences, in the SCN. A particular focus is the development and application of real-time imaging of circadian gene expression at the level of tissues and cells by reporter transgenes. If our model is correct, it should be possible to accelerate or slow down the clock, to control circadian phase, and indeed to stop and start the cycle at will, by temporally regulated expression of core components of the loop. The second aim of the work will be to elucidate the molecular and cellular mechanisms downstream from the core oscillator that are responsible for circadian regulation within the SCN neuron and within SCN targets in the brain, and thence to peripheral, tissue-based clocks. Our analysis has revealed unanticipated biochemical and genetic links between the daily clock and the cell division cycle that underpins normal growth and cancer. Finally, with growing knowledge of circadian molecular neurobiology, it will be possible to explore the relevance of circadian timing to neurological disease, in particular by examining circadian function in animal models of such diseases, including Huntington s disease (HD) and Alzheimer s disease (AD), as well as disorders arising from genetic (several sleep disorders) or environmental (e.g. shiftwork) disturbance of circadian physiology. It is in this regard that new knowledge of the circadian timing system offers considerable scope for translational development.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Circuit Mechanisms of Learning and Action-Selection
Funder: Medical Research Council

Abstract: Scientific abstract (around 400 words — max. 3,500 characters including spaces) Our goal is to understand the relationship between the structure ofthe nervous system and its function and to discover the basic principles by which neural circuits implement fundamental computations. A major focus of our research is the circuit implementation of learning and decision-making. For the nervous system to select appropriate responses to multiple, often conflicting cues present in the environment it must be able to l) learn which sensory cues are associated with rewards and punishments; 2) compute the "predicted value" of each action based on the learnt information; 3) select one action and suppress other physically incompatible competing actions; 4) update memories when predicted and actual outcomes differ to improve future decision-making. We aim to discover the circuit motifs that implement these four functions, the comprehensive set of structural changes in the brain that are involved in storing specific memories, and the genes required in specific neurons for these computations. One obstacle to progess in the field has been the problem of identifying underlying structural motifs with synaptic resolution, and causally relating these structural motifs to their proposed function. Furthermore, learning and action selection often emerge from parallel and distributed computation across many interconnected brain areas, requiring comprehensive analysis of structure and function across multiple areas. To overcome these obstacles we are exploiting recent advances in connectomics and in large-scale imaging of neural activity with light-sheet microscopy in the tractable genetic model system, the Drosophila melanogatser larva. The larval nervous system has the same ground-plan as the adult Drosophila and other insects, but contains fewer (ca. 12,000) and smaller neurons, most of which are uniquely identifiable based on morphology. We can therefore image its entire nervous system at synaptic resolution with electron microscopy (EM), and map complete circuits with synaptic resolution. We can record from individual uniquely identified neurons with atch-clamp. We can also image the activity of all neurons in the nervous system in intact animals (through the transparent cuticle), before, during, and after learning, at high spatial and temporal resolution with lightsheet microscopy while monitoring memory-based decisions. Finally, we can use powerful genetic tools for selective manipulation of individual neuron es to causall relate their activi to s ecific com utations and behaviours.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Experimental and Comparative Connectomics
Funder: Medical Research Council

Abstract: Scientific abstract (around 400 words — max. 3,500 characters including spaces) Animals sense the local environment, learn and remember past events, predict future ones, and combine current and past information to choose and coordinate 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. These operational patterns depend on the synaptic-level structure of the wiring diagram of the central nervous system (CNS). We imaged the complete CNS of the Drosophila larva with synaptic resolution using electron microscopy (EM), and devised methods to efficiently map and analyze its circuits, and functionally characterized them with a combination of electrophysiology, optophysiology, behavioral assays and theoretical modeling. The stereotypy and unique identity of most of the 12,000 larval neurons are key to our success in relating circuit structure to function. Genetic driver lines that label a single pair of left-right homologous identified neurons are pivotal in relating circuit structure to circuit function and behavior. On this basis, we are now entering experimental connectomics: mapping the wiring diagrams of animals where select neurons are mutant for a gene of interest (such a genes for synaptopathies or associated with mental disease), or of animals that have formed specific associative memories. We then map the synaptic wiring diagram of the experimentally modified circuits, observe their neural activity during behavior, and formulate models of circuit function that explain the behavioral modifications on the basis of structural circuit changes. Finally, with novel technical advances in EM and computational methods, we can now approach the synaptic wiring diagram of small vertebrate brains, towards discovering the fundamental circuit architecture of the cerebral cortex. In examining the cortical circuit architecture of a single species, we lack a basis for discerning, a priori, what is fundamental for neural computation and what is inessential. We will therefore exploit ancestral homologies of the amphibian pallial surface with the amniote cerebral cortex to distil fundamental cortical circuits and their loops with basal ganglia. The complete, nanometer-resolution volumes of an amphibian and an amniote forebrains will serve as public resources for subsequent studies on the neurons and circuits of the vertebrate brain beyond cortical microcircuits. In summary, our lab work will lead us to understand how a brain operates as an integrated whole, the effect of genes and experience in shaping neuronal circuit structure and animal behavior, and the fundamental architecture of vertebrate cortical circuits.


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