NIHRDataInsights/HRCSData huggingface dataset:
Title: Cerebro-cerebellar interactions during learning of cognitive tasks
Funder: Wellcome Trust

Abstract: A substantial part of animal, including human, behaviour is goal directed. Learning how to achieve a defined goal requires the interplay between higher brain centres involved in planning and decision making and subcortical structures that coordinate the desired movements. However, there is growing evidence suggesting that subcortical structures such as the cerebellum play a much wider role by also being directly involved in higher cognitive functions. Although much information exists about the cerebellum and neocortex individually, little is known about how the connections between these areas are involved in complex behaviours. In this project I propose to study how the learning mechanisms in these brain structures support each other to give rise to complex behaviours. First, I will develop a computational model of cerebellar-neocortical interactions based on recent developments from deep learning. Next I will test the predictions of this model using electrophysiological recordings during goal-directed behaviours which require higher cognitive functions. This research will provide a better understanding of the neural mechanisms through which the cerebellum controls high-level, non-motor functions. Ultimately this will be of clinical interest for cognitive pathologies like autism and schizophrenia and will have implications for both cognitive sciences and computer science.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Control of cortex-wide neural activity maturation by local and long-range GABA signalling
Funder: Wellcome Trust

Abstract: Animal behavior is generated by the collective activity of many neurons, and thus constitutes an emergent property of the brain, which might not be apparent at the individual level of anatomical regions and single cells. Moreover, these collective interactions and patterns of activity across neuronal populations are not fixed but dynamically shaped by many different processes, such as learning, over multiple timescales. These features suggest that the behavior of such complex dynamical system cannot be fully understood by independently analyzing each of its constituents. For this reason, I aim to examine the role and dynamics of two distinct neuronal populations across early brain development, the most critical learning period, by following a whole-brain imaging approach. This will allow me to investigate how the cross-talk between distant brain regions and cell populations influences the formation of a mature brain. Specifically, by simultaneously assessing the spatial and temporal dynamics of excitatory and inhibitory cell activity patterns across the cortex, I would like to study the interplay between both types of neuronal populations during functional maturation of brain circuits, and after senses come online. This is critical to understand normal brain development and subsequently, potential dysfunctions associated with neurodevelopmental disorders.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Role of Golgi cells in the cerebellar granule cell layer
Funder: Wellcome Trust

Abstract: The cerebellum is a brain structure that contains over half of the mammalian brain's neurons. The majority of inputs of the cerebellum enter the granule cell layer, which is therefore called the input layer of the cerebellum. Within this layer, two neuronal populations exist: excitatory granule cells and inhibitory Golgi cells. The latter play a fundamental role in balancing granule cell responsiveness, driven by pre-cerebellar inputs. Understanding the contribution of these inhibitory neurons to granule cell layer activity is indispensable to unveil cerebellar functions. To do so, we will manipulate activity of neurons within this network, by chemical means, in behaving mice. During these manipulations, we will be recording neural activity as well as behavioural parameters. From these data, it will be possible to better understand how inhibition controls excitatory neuron activity, what is the processing of cerebellar inputs operated by the granule cell layer, and cerebellar cortex computations. We will substantiate our work with tools of computational neuroscience that will allow us to formalise our findings.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Investigating synaptic plasticity and chronobiology underlying memory consolidation
Funder: Wellcome Trust

Abstract: Memory consolidation, the process by which novel experiences are gradually transformed into stable memories, is a fundamental neurobiological phenomenon. Current models suggest that interactions between where the memories are initially encoded (hippocampus) and subsequently stored for long-term (neocortex) are crucial. During an experience, inputs from the hippocampal region are thought to “tag” groups of neurons in the neocortex, which allows their reactivation during sleep or rest subsequently changing the neocortical circuit architecture. We hypothesize that this initial tagging of neocortical neurons is a result of structural changes in the very connection points, synapses, between the hippocampus and its target neurons in the neocortex. To test our hypothesis, we will implement state-of-the-art molecular-genetic methods to mark synapses of hippocampal neurons in the neocortex and investigate whether these have undergone learning associated structural changes and whether these are dependent on hippocampal output. A further angle of our study will be to test if the changes in synapse structure we discovered are affected by disturbances in circadian rhythms which is highly influential on effective learning and remembering. These studies will help to identify the neural substrates for long-term memories and to explain how disparate cortical areas generate coherent cognitive states.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: LONGITUDINAL NEUROIMAGING AND BEHAVIOURAL STUDY OF COMPLEMENT 3A RECEPTOR KNOCKOUT MICE TO MAP PATHOGENETIC ANXIETY AND MEMORY NETWORKS
Funder: Wellcome Trust

Abstract: Complement cascade is an important part of the immune system that also plays a role in development and brain function. We are interested in a specific complement protein that is increased in emotionality disorders such as depression and autism-spectrum disorders. One way of studying a molecule's function is to see what happens in the absence of it. Indeed, mice lacking this molecule have profound innate anxiety and a memory deficit. Preliminary work in our laboratory has shown that these mice also have reduced synapse density in an area related to both anxiety and memory—the hippocampus. However, the exact role of this molecule in regulating emotionality and cognition is not known. I will use longitudinal structural and functional resting state magnetic resonance imaging and behavioural testing to understand the role of this part of the complement cascade in the maturation of anxiety and memory networks. I will then use single cell gene expression analysis to see which cell types are responsible for the changes observed in brain imaging. Understanding immune signalling in pathological memory and anxiety is clinically relevant because the studied molecule is a pharmacologically accessible receptor, making it a potentially useful target in treating psychiatric disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Testing the synaptic theory of working memory
Funder: Wellcome Trust

Abstract: Despite over 70 years of research on the neural basis of working memory (WM), it is still not understood how information is maintained in the brain over short periods of time (seconds to minutes). Classical neurophysiological studies since the 1970s have posited that the sustained firing of neurons in the cortex could explain how information is held in WM. There have been alternative theories for maintenance of information via synaptic changes. However, because electrophysiology dominated most of neuroscience research in the 20th century and made it relatively easy to record the firing rate of neurons, the study of these alternative mechanisms has remained somewhat unexplored. With the advent of new techniques such as two-photon calcium imaging, optogenetics and computer generated holography, it is now possible to record and manipulate the activity of single neurons in awake behaving rodents. Using an auditory parametric WM (PWM) task in head-fixed mice, we aim to implement a closed-loop ‘all-optical’ setup to probe whether the maintenance of cues in WM is accompanied by changes in the functional connectivity between neurons in the cortex. This research will provide fundamental insights into the neural mechanisms underlying PWM and the nature of the neural code.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Explaining the heterogeneity and topography in inferior temporal cortex with deep neural networks
Funder: Wellcome Trust

Abstract: Object recognition is accomplished by the ventral visual pathway, also known as inferior temporal (IT) cortex. IT contains regions that respond preferentially to faces, color, and places. However, we still do not understand the principles underlying the emergence and organisation of these regions. Currently, there are no computational models that take into account the heterogeneity of IT, including the spatial clustering of neurons with similar selectivity and the spatial organisation of these clusters on the cortical surface. Therefore, we would like to answer two questions regarding IT: 1) Does the heterogeneity of IT simply emerge from exposure to many images, or are specialized mechanisms and/or innate constraints involved in its development? 2) What are the organisational principles reflected in IT topography? We will determine whether the heterogeneity of populations of units, like that empirically observed in IT, can emerge spontaneously in deep neural networks (DNNs) without specialized architecture, or whether we need an architecture that specifically accounts for it. We will then build a DNN that incorporates the spatial information about selective populations of units and assigns these populations to topographical maps. We will test the models’ predictions using electrophysiology and fMRI data.

Lay abstract: Humans recognize objects almost immediately: for instance, a brief glance is sufficient to recognize the face of a friend. Our everyday actions and interactions (e.g. talking to people, shopping, driving) depend on object recognition. Yet object recognition depends on a complex neural architecture within the visual cortex. A particularly important part of the brain for object recognition is the inferior temporal (IT) cortex. IT contains regions that respond preferentially to faces, color, and places. Despite a recent period of extensive study, we still do not understand how the selectivity of these regions emerges and how they are organized. Here I propose to use state-of-the-art computational models (called deep neural networks) to understand why IT cortex has the structure it does. I will test whether similar structure emerges in our models compared against brain activity measured in monkeys and humans. I aim to reveal the basic principles of object recognition, which are essential for human cognition and everyday life.

Research activity codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Flexible task representations for intelligent behavior
Funder: Wellcome Trust

Abstract: A long research tradition in cognitive neuroscience has investigated the role of the prefrontal cortex (PFC) in flexible goal-directed behaviour. This work has yielded important insights, e.g., that the PFC’s coding properties flexibly adapt when task demands change to prioritise goal-relevant information. However, it relies primarily upon the use of familiar and explicitly instructed tasks that provide poor fit to human behaviour in naturalistic and open-ended environments, and likely miss essential aspects PFC function. I therefore propose to study the representations that form within PFC as humans learn to perform complex categorisation tasks with only minimal external instruction. I hypothesise that during learning the PFC will form abstract representations of the task’s latent structure, that support not only performance in the given task, but also provide provides a scaffold for learning in similar environments. Using representational similarity analyses, in combination with multiple brain recording techniques (fMRI, MEG, ECoG), I will measure how stimulus-evoked neural responses change adaptively during learning, and test if these changes generalise to novel task environments with similar structure. These findings will provide important new insights about the coding mechanisms by which PFC supports flexible behaviour in complex, naturalistic environments.

Lay abstract: The ability to adapt quickly to novel tasks and environments is a hallmark of intelligent behaviour. Humans are remarkably proficient at this, due to their capacity to generalise existing knowledge from related past experience. For instance, when traveling abroad, we can quickly work out how to operate an unknown train ticket machine. I want to understand the brain mechanisms that allow us to form these flexible mental programs that can be re-deployed under completely different circumstances. Combining brain recordings with pattern classification techniques, I will study the rapid formation of knowledge representations in the prefrontal cortex as humans learn to perform novel categorisation tasks. This work will reveal fundamental biological mechanisms that underlie complex goal-directed behaviour, and will also provide new insights that will be of help in building more intelligent machines.

Research activity codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: The Efficacy of, and Mechanisms underpinning, Pramipexol as an Antidepressant
Funder: Wellcome Trust

Abstract: I will be investigating the mechanisms by which Pramipexole, a drug which mimics the neurochemical dopamine, alters depressed people's reactions to positive and negative feedback. I will be doing this so that we can increase our understanding about the brain mechanisms that underlie the ways in which depressed people perceive and react to the world. My hope is that understanding these mechanisms will help us to make more effective, targeted and individualized treatments for depression.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Working memory impairment in temporal lobe epilepsy
Funder: Wellcome Trust

Abstract: This project examines how temporal lobe epilepsy (TLE) disrupts specific memory processes, through the integrated study of behaviour, neurophysiology, and multi-modal imaging . This is important because, within the peak age group 60–90 years of developing TLE, up to 60% of individuals demonstrate objective memory dysfunction, before starting anti-seizure medication. At present, there are no specific treatment targets for this significant problem. Two factors which are associated with memory problems in TLE are higher number of seizures and co-existing cerebrovascular disease. However, it remains unknown how these two factors impact memory, whether they interact, and whether they both act by disrupting function of the hippocampus- our memory organ. I plan to: • use a novel cognitive task to assess how TLE perturbs two specific facets of memory that are known to be less efficient with ageing and Alzheimer’s disease. • establish the mechanistic contributions of electrical disruption and structural white matter abnormalities to memory impairment. These cognitive processes, if affected, could explain memory deficits caused by acute and long-term effects of seizures. Ultimately, this project may help inform clinical assessment and guide specific management of sub-clinical seizure activity and vascular risk factors, to improve memory co-morbidity and quality of life in TLE.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Catatonia: Neuroimaging, Immunology and Psychopathology (CAT:NIP)
Funder: Wellcome Trust

Abstract: Background: Catatonia is a severe psychiatric illness in which individuals have difficulties in moving and speaking. I aim to understand what brain changes occur during catatonia. Approach: Patients with catatonia are usually effectively treated using medications from the benzodiazepine class, which increase the activity of pathways relying on the neurotransmitter GABA. In addition, 88% of patients with a form of brain inflammation known as NMDA receptor encephalitis have catatonia, which suggests that the neurotransmitter glutamate might also be relevant. To investigate the roles of these neurotransmitters, we have two main experiments: 1. We will take blood samples from patients with catatonia to examine whether they have antibodies to cell surface components associated with GABA and glutamate transmission. We will use these blood samples to investigate whether any new antibodies or other proteins that bind to the brain or affect brain function can be found. 2. We will conduct a form of brain scan called magnetic resonance spectroscopy on patients with catatonic features. This will allow us to examine the levels of GABA and glutamate in their brains and to compare these to other patients without catatonic features. Impact: We hope to identify what causes catatonia in order to appropriately target future treatments


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Neurobiological foundations of flexible social behaviour
Funder: Wellcome Trust

Abstract: A core aspect of healthy social function is the ability to map our private beliefs onto those that we express publicly according to the social context. It may be socially appropriate to express gratitude for a gift we do not want, or remorse for an action we do not regret. My goal is to understand the neurocognitive mechanisms supporting context-appropriate social behaviours and how they are altered in neuropsychiatric conditions. I will use a novel social interaction task which requires subjects to learn a repertoire of context-dependent mappings from private to public beliefs. I will first apply computational modelling to reveal how subjects solve this problem, identifying ‘prediction-error’ signals that drive changes in ‘private-public’ mappings. I will then relate these time-varying components to voltammetric recordings of dopamine and serotonin in human striatum during task performance. These neuromodulators are relevant because they are known to support learning and are implicated in neuropsychiatric conditions with prominent social dysfunction. Finally, I will complement the voltammetric recordings with non-invasive whole-brain OPM-MEG recordings, to identify neural areas which provide contextual ‘inputs’ for updating private-public mappings and are the ‘targets’ of such updates. This work promises to enhance our understanding of possible routes to social dysfunction.

Lay abstract: Social situations often require us to ‘misrepresent’ what we truly think or feel in order to gain benefits or avoid harm. This ability to act in a context-sensitive manner is, however, impaired in several neurological and psychiatric conditions, leading to great distress for the individual and their family and friends. Yet, despite being essential for healthy social function, we know little about how the brain supports context-sensitive social behaviour. I will give people social tasks which allow me to characterise how they learn which contexts are relevant for behaviour and which behaviours are appropriate in a given context. I will use these tasks in conjunction with novel brain imaging technologies which offer a window onto the neurochemistry and the neurocircuitry supporting context-sensitive social behaviour. This work will significantly advance our understanding of the neurobiological foundations of flexible social behaviour and the routes to social dysfunction in disorders of mental health.

Research activity codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: MENTAL HEALTH;NEUROLOGICAL
Title: Auditory structured sequence learning on multiple timescales
Funder: Wellcome Trust

Abstract: Regularities play an important role in analysing auditory scenes; for example, by exploiting the predictable sounds of the car engine, a driver can effortlessly ignore this irrelevant noise, freeing cognitive resources to focus on the road. Regularities also play an important role in language, dictating the relationship between syllables in word or the order words in a sentence, and have been studied to better understand language acquisition and evolution. Despite the critical importance of regularities to both language-motivated and auditory scene-motivated research there are few direct interactions between them. Integrating these previously separate fields, this fellowship will test the hypothesis that sequencing abilities studied within the context of scene-motivated and language-motivated sequence learning will depend on common brain mechanisms. Creating novel stimuli consisting of sequences of rapid (scene-motivated) and slower (language-motivated) stimuli, governed by the same complex relationships, sensitivity to regularities will be assessed using behavioural, pupillometry and electroencephalography studies. Sequence processing proficiency will then be compared to other cognitive abilities and used to explore neurodevelopmental language disorders, e.g. dyslexia. This work will develop novel avenues for understanding the role of sequence processing in the brain and provide potential insights into how these neural processes are disrupted in language disorders.

Lay abstract: The brain is highly sensitive to the regularities present throughout the auditory environment, and uses them in many ways; for example, if the brain learns the predictable order of sounds made by a car engine, it can efficiently identify it as a source of irrelevant noise, freeing cognitive resources for other tasks such as driving. Regularities also play an important role in language, dictating the relationship between syllables in word or the order words in a sentence. These regularities have been studied to better understand language acquisition and evolution. However, there are few interactions between language-motivated and scene-motivated research. With this fellowship I intend to integrate these fields, to assess if these separate research areas tap into the same, or different brain mechanisms. The outcomes of this fellowship will further illuminate the role of sequence learning across cognitive processes, and have the potential to advance our understanding of language disorders.

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