Neuroscience

Serum Amyloid A-1 (SAA-1), a crucial acute-phase protein, is significantly upregulated during inflammation, associating with high-density lipoprotein (HDL) and modulating immune responses and tissue repair. Elevated SAA-1, however, is implicated in chronic inflammatory diseases and neurodegenerative conditions. This project investigates the role of SAA-1 in neuroinflammation and cognitive deficits following traumatic brain injury (TBI), particularly in Alzheimer’s-like pathology. We will use targeted siRNA within liposomes to selectively inhibit hepatic SAA-1 production, isolating peripheral SAA-1 effects on neuroinflammatory markers and behavior in TBI models. Parallel experiments will use adeno-associated viral vectors to knock down brain-derived SAA-1, assessing neuroinflammation and behavior to differentiate peripheral versus central SAA-1 contributions. Additionally, we will combine both liver and brain-specific knockdowns to evaluate potential synergistic effects in mitigating neuroinflammatory damage. Complementary studies will track exogenous, radiolabelled SAA-1-HDL complexes crossing the blood-brain barrier to elucidate SAA-1’s brain entry mechanisms and impact on neuroinflammation. This project aims to clarify SAA-1’s contributions to delirium post-TBI, potentially guiding targeted interventions to mitigate neurocognitive symptoms.

The scholar will work on a project integrating neuroimaging and genetics across the entire lifespan with the goal of gaining a more fine-grained understanding of the biological mechanisms driving brain morphological changes across the lifespan in health and disease.

A major goal in systems neuroscience is to connect the activity of populations of neurons to specific behaviors. However, large scale recordings of neural activity during the execution of learned tasks and during the experience of familiar stimuli have revealed that neural activity patterns continually change over extended periods. This so-called Representational Drift is not accompanied by obvious alterations in behavior, learning or systemic physiology, which raises profound questions about its origin and its implications for learning and memory. For example, textbook theories of learning and memory assert that stable memories require stable relationships between neural activity and learned associations. Representational drift brings these theories into question, while raising practical problems for understanding neural data, designing experiments and developing technology such as brain-machine interfaces.  

This project uses a mix of data science, computational modelling and theory, and collaboration with experimentalists to understand the causes and implications of Representational Drift. We use a variety of statistical methods as well as modelling and analysis of artificial neural networks to generate and test hypotheses. We work closely with experimentalists in Harvard Medical School and UCL, and wish to find experimental partners in the NIH to further this research.  Key skills include proficiency in numerical methods, simulation, strong coding skills and a working knowledge of advanced statistical methods, including generalized linear models and Bayesian inference.  

Key recent publications include:  
Micou, C., & O'Leary, T. (2023). Representational drift as a window into neural and behavioural plasticity. Current opinion in neurobiology, 81, 102746. https://www.sciencedirect.com/science/article/pii/S0959438823000715  Rule, M. E., & O’Leary, T. (2022). 

Self-healing codes: How stable neural populations can track continually reconfiguring neural representations. Proceedings of the National Academy of Sciences, 119(7), e2106692119. https://www.pnas.org/doi/abs/10.1073/pnas.2106692119

Adult neurogenesis, the process of generating new neurons in the adult brain, is a rare occurrence in mammals, confined mainly to the olfactory bulb and the hippocampus. Unlike the body's ability to repair most tissues, the limited scope of neurogenesis in the brain restricts our capacity to recover from neurological damage, a limitation that profoundly impacts the treatment of brain disorders.  In the olfactory system, ongoing neurogenesis supports the regeneration of key neuron types, including dopaminergic cells, granule cells, and olfactory sensory neurons, all of which are essential for sensory processing and adaptability. Recent studies have revealed that dopaminergic neurons born during embryonic development differ significantly from those generated postnatally, suggesting that they perform distinct functions rather than acting as simple replacements.  Our project aims to expand on these findings by exploring whether these differences extend to other regenerating neuron populations in the olfactory system. Using a combination of transgenic mouse models, in vivo calcium imaging, immunohistochemistry, electrophysiology, and behavioral testing, we will investigate the specific roles of embryonic versus adult-born dopaminergic neurons in olfactory processing.  By addressing these questions, our research will contribute to a deeper understanding of the unique contributions of adult neurogenesis to brain function, with the potential to inform new approaches for treating neurological disorders.

The ability to sense and respond to environmental cues is vital for the survival of all organisms. This process hinges on the integration of sensory information to generate appropriate behaviors, a capability rooted in neuronal plasticity. Neuronal plasticity encompasses structural, synaptic, and intrinsic modifications within neurons. However, these mechanisms are often studied in isolation, leaving their collective impact on behavior poorly understood.  Our lab aims to bridge this gap by exploring how mice adapt to olfactory stimuli. In this project, we will manipulate the olfactory environment of mice through sensory deprivation (akin to experiencing a mild cold) or olfactory enrichment (comparable to exposure to a perfume shop). Using advanced genetic tools, we will label neurons responsive to specific odors. Our approach integrates immunohistochemistry, in vivo calcium imaging, and patch-clamp electrophysiology to examine how olfactory bulb neurons adjust their synaptic connections, morphology, and intrinsic properties in response to varying durations of sensory alteration.  To link these cellular changes to behavior, we will employ automated behavioral testing to evaluate the mice's ability to detect and differentiate odors. This will allow us to assess how adaptive plasticity influences learning and behavioral flexibility. By combining cellular and behavioral analyses, this interdisciplinary project aims to uncover the complex neural mechanisms underlying behavioral adaptability in response to changing olfactory environments.

The Mughal Laboratory (The Neurovascular Research Unit) studies the neurovascular coupling mechanisms involved in regulation of blood flow in the brain and clearance of metabolic by-products. Along with providing the basic understanding of these mechanisms in physiology, the research also extends to the vascular cognitive impairment and dementia (VCID) including stroke and CADASIL. By using pre-clinical models and cutting-edge imaging approaches, the Mughal laboratory provides a thorough understanding of different neurovascular mechanisms along with the contributions of different vascular compartments (arteries—capillaries— veins) with the aim to extend this knowledge from physiology to the disease models.

The research program is supported by multiple on-going projects. Students will have the option to work on any project in the lab, and to take it in new directions. 
 

Research keywords: Neurovascular, Ion channels, Calcium signaling, Blood flow in the brain
 

Mechanisms of perception and cognition 
Section on Perception, Cognition, and Action, Laboratory of Sensorimotor Research (NEI/NIMH)

Students would have the option to work on any project in the lab, and to take it in new directions. Current projects in the lab aim to understand the normal brain processes by which physical signals that impinge on the sensory apparatus (eyes, ears) are transformed into perceptions, thoughts, and actions. Work in the lab has been especially invested in developing color as a model system. The advantage of color is that its physical basis (wavelength) is well characterized, yet these chromatic signals support not only low-level visual abilities such as color matching but also high-level cognitive processes such as categorization, memory, social cognition, and emotion. This variety of phenomena provides a rich opportunity for investigating the full scope of perceptual and cognitive computations that make human vision such an important source of information about the world. The lab uses many research techniques, including psychophysics and non-invasive brain imaging (MRI, MEG) in humans, along with fMRI-guided microelectrode recording, fMRI-guided pharmacological blockade, microstimulation, tract-tracing, and computational modeling in non-human primates (NHPs). Work in the lab is organized around Four broad approaches:

First, the use of MRI in humans and NHPs to investigate homologies of brain anatomy and function between these species, to support the applicability of neurophysiology from NHPs to the human case, and to test hypotheses about the fundamental organizational plan of the cerebral cortex in the primate.

Second, the use of well-controlled psychophysics (including longitudinal experiments) combined with microelectrode recording in NHPs to show on a mechanistic level how populations of neurons drive behaviors such as perceptual decisions, categorization, and concept formation and memory.

Third, comparative psychophysical studies in humans and NHPs, as part of a program of neuroethology to understand the relative computational goals of perception/cognition in different primate species. In addition to studies of vision, the lab conducts experiments using auditory and combined audio-visual stimuli, to understand common principles of sensory-cognitive information processing, and to determine how signals across the senses are integrated into a coherent experience.

Fourth, large-scale neurophysiological experiments combined with cutting-edge analysis methods including machine learning, to determine the mechanisms of high-acuity visual perception at the center of gaze. We have developed several eye-trackers that afford photo-receptor resolution, providing an unprecedented look at fine-scale spatial and chromatic processing of the foveal representation in primary visual cortex. 
 

This collaboration will provide the opportunity to work on malignant brain tumors in the laboratories of these three investigators with complementary expertise. The Zhuang laboratory (NIH) has an interest in the investigation of hypoxia (HIF-2a) signaling and tumor development as well as the pathogenesis of brain tumors and development of therapeutics. The Bulstrode laboratory (Cambridge) has an interest in neural stem cell identity and microenvironment interactions in brain development and in brain tumors. The Lathia laboratory (Cleveland Clinic) has an interest in cancer stem cells, tumor microenvironment interactions, immune suppression, and sex differences in brain tumors. The prospective student will have access to mentorship, infrastructure, and resources across all three laboratories. 

Patients with neurological diseases often have difficulty in evaluating, planning and initiating actions. This can lead to disorders of motivation, such as apathy and impulsivity. My group studies the cognitive neuroscience of goal-directed action, in the context of disease. Some patients have difficulty evaluating a particular plan in a given context. For example, they might revert to habitual actions which were previously associated with reward, or may be unable to think beyond their current situation. We take a multimodal approach, with behavioural studies, eye tracking, drug studies in healthy people and patients, EEG and neuroimaging. I have also developed computational models – both in the form of abstract cognitive models, and neural network simulations, to understand what the brain computes when determining actions.

My group has found that dopamine plays an important role in energising goal-appropriate actions. We hypothesise that prefrontal goal representations act through corticostriatal loops, being amplified or attenuated by dopamine.  In this project, the student will study patients with Parkinson’s disease and the effects of dopaminergic drugs on cognition, together with neuroimaging (which can include MEG or fMRI), to understand goal-directed action selection and energisation. The student will design their own behavioural tasks to separate out the component processes involved in maintaining and using goal information to energise actions. The student will test patients on their task, test drug mechanisms using a within-subject neuroimaging design, and  deploy appropriate analysis methods with help from a postdoctoral researcher.   The project will also include the opportunity to learn computational modelling if the student is keen.

Sex differences often represent the most dramatic intraspecific variations seen in nature. Although males and females share the same genome and have similar nervous systems, they differ profoundly in reproductive investments and require distinct morphological, physiological, and behavioural adaptations. Animals determine sex early in development, which initiates many irreversible differentiation events that influence how the genome and environment interact to produce sex-specific behaviours. Across taxa, these events converge to regulate sexually dimorphic gene expression, which specifies sex-typical development and neural circuit function. However, the molecular programs that act during development remain largely unknown. 

We aim to understand the gene regulatory networks underlying sexually dimorphic neuronal development in the brain of the genetically tractable vinegar fly Drosophila melanogaster. We are using single-cell technologies to compare the molecular profiles of both males and females in the developing central brain to understand the mechanisms underlying sexual dimorphism in the nervous system. The fly's central brain is a remarkably complex tissue composed of approximately 100,000 interconnected neurons, forming the intricate networks necessary to coordinate complex cognitive and motor functions. Tightly regulated molecular programs act over a broad developmental window leading to the diversity of cell types found in the brain. The proposed experiments will paint a detailed picture of cellular and molecular diversity in a developing central nervous system. Our data will answer the longstanding question: How are neuron types associated with sexual behaviours born and wired?

Lab website: 
http://www.oxfordcircuits.com/

Contact: Stephen F. Goodwin stephen.goodwin@cncb.ox.ac.uk 

The sensory nervous system is a target for recognition by various immune factors after painful nerve injury (Davies et al., 2020; PMID: 32153361). While we know a great deal about immune mechanisms causing pain, we are only just beginning to understand the role it plays in its resolution. We have previously shown that nerve injury upregulates the stress ligand RAET1 that signals to natural killer (NK) cells via the immune receptor NKG2D. This neuro-immune interaction results in the pruning of intact primary sensory axons within the injured nerve (Davies et al., 2019; PMID: 30712871), that are otherwise a significant risk factor in neuropathic hypersensitivity (Kim et al., 2023a; PMID: 37366595). This neuro-immune interaction raises the possibility of an immune-based therapy for the treatment of neuropathic pain (Kim et al., 2023b; PMID: 37385878).

We use a combination of cell culture and mouse models to interrogate the receptor-ligand interactions between the peripheral nerve and killer immune cells injury and disease. We work closely with clinicians to collect and analyse relevant human samples and perform translational mechanistic studies using humanised cell culture models. Students will have the opportunity to learn animal behaviour, stem cell technology, live-imaging and high-dimensional flow cytometry, among other techniques, to understand the cellular and molecular interactions involved in cytotoxic neuro-immunity and its consequences for neuronal function and pain.

We are at an exciting turning point in neuroscience. New technologies now allow us to measure and control neural activity and behaviour with unprecedented detail (Landhuis et al. Nature 2017, Lauer et al. Nature Methods 2022). At the same time, new theoretical frameworks are starting to reveal how rich behaviours arise from synaptic, circuit, and systems computations (Richards et al. Nature Neuroscience 2019). We are contributing directly to the latter by aiming to understand how we learn. To this end, we are developing a new generation of computational models of brain function guided by deep learning principles. We focus on understanding how a given behavioural outcome ultimately leads to credit being assigned to trillions of synapses across multiple brain areas – the credit assignment problem. To survive and adapt to dynamic and complex environments animals and humans must assign credit efficiently. Recently, we have shown that the brain can approximate deep learning algorithms (Sacramento et al. NeurIPS 2018, Blake et al. Nature Neuroscience 2019, Greedy et al. NeurIPS 2022, Boven et al. Nature Comms 2023). In this project, you will build on our state-of-the-art computational models of AI-like credit assignment in the brain and contrast it with recent experimental observations at the behavioural, systems, and circuit levels.

The spinocerebellar ataxias (SCAs) are a complex group of neurodegenerative diseases that affect the cerebellum and result in the loss of motor coordination. No effective treatments exist for the SCAs, and there is a pressing need for better models in which to study the underlying disease-causing mechanisms and to identify potential therapies.

The aim of this project will be to develop novel stem cell-derived models to identify common pathological mechanisms in SCA that could be targeted therapeutically. The Becker group has identified several novel SCA mutations that highlight mGluR1-TRPC3-IP3R1 signaling as a key pathway affected in disease. Both research groups have developed complementary stem cell-derived and primary cerebellar models that provide unique systems to investigate the functional consequences of disease gene mutations in cerebellar Purkinje cells, which are the neurons that are primarily affected in SCA. 

The project will employ human induced pluripotent stem cells (iPSCs) that will be differentiated into cerebellar neurons and three-dimensional organoids and deeply phenotyped using a combination of functional experiments including calcium imaging, super-resolution imaging, and morphological analyses. In addition, functional analyses will be carried out in primary Purkinje cells. Identified disease phenotypes will subsequently be screened for potential therapeutics.

Becker Group website: 
https://www.ndcn.ox.ac.uk/research/cerebellar-disease-group

Hammer Group website: 
https://irp.nih.gov/pi/john-hammer 

The student will explore a fundamental question in cognitive neuroscience, inspired by state of the art computational models of episodic memory. Their project will include collection of new empirical data, modelling the data computationally, and then testing a joint neural-cognitive model of memory recall using fMRI, where analysis will use RSA techniques.

Over the last 10 years, genome wide association studies (GWAS), exome and short-read genomic sequencing have enabled a revolution in our understanding of the genetic basis of neurodegenerative diseases, their progression and disease pathways. Despite this progress, our molecular understanding of the genes and loci that cause neurodegeneration remain limited, evidenced by the near absence of disease-modifying treatments for these diseases. In part this is because we have lacked the technology to fully characterise these important genomic regions. Short reads cannot fully assemble complex genomic rearrangements especially repetitive sequences, nor can they accurately and unambiguously identify or quantify different expressed isoforms. Therefore, the hypothesis underlying this PhD project is that significant inaccuracies in our knowledge of the genomic structure and transcript annotations at neurodegenerative disease loci have limited our understanding of disease pathogenesis.

To address this knowledge gap, the student will generate and analyse high quality paired long-read DNA and RNA-sequencing data to accurately investigate and annotate loci of interest in human brain samples, and in purified cell populations, across a range of neurodegenerative diseases. The student will use this new genomic and transcriptomic map to re-assess both GWAS risk SNPs at these loci and the pathogenicity of rare variants identified through WGS of patients with hereditary forms of neurodegeneration, so leveraging data generated within this project and that already available publicly. Thus, the student will help generate a core resource of annotated pathogenic loci to drive the identification of novel disease mechanisms, genetic causes and therapeutic targets in neurodegeneration.

Synaptic plasticity is fundamental to nervous system development and function.  Our labs have been studying BMP and reactive oxygen species (ROS) signalling as key regulators of synapse development, growth and plasticity. For example, during critical periods of nervous system development, metabolic ROS generated in mitochondria specify the functional ‘baseline’, including through setting the size and composition of synaptic terminals. The mechanisms by which this is achieved can now be explored. Specifically, we are now investigating:
 -    novel facets of BMP signalling, and their roles in regulating synapse size, composition and transmission properties;
 -    how transient critical period experiences in the late embryo lead to dramatic, lasting changes in gene expression and neuronal function.  

This project will combine biochemical and genetic approaches with electrophysiology and methods for high-end imaging. We expect this project to redefine our understanding of how multiple signalling pathways, working at different time scales and regulating distinct elements of plasticity, integrate at the synapse.

The student will take a clinical informatics or bioinformatics approach to investigate causes and/or outcomes in mental disorder and/or related brain phenotypes. This could involve using GWAS summary statistics for metabolomics, genomics and proteomics and relating these to mental disorder and /or brain phenotypes, using techniques such as statistical genomics and mendelian randomisation. It could also or alternatively involve clinical data from electronic health records, in combination with biomarker data,, with a focus on psychosis and/or depression and possible relation to physical health (cardio-metabolic or immune mechanisms).

Extensive work from the Blouet lab has recently characterised the high level of myelin plasticity in the median eminence (ME), with rapid local turnover of myelin in healthy adult rodents. The ME is a region of the hypothalamus essential for various homeostatic functions, neuroendocrine output and energy balance regulation. Both weight loss, achieved through caloric restriction, and weight gain, obtained by feeding with a high fat diet, reduce ME myelin turnover, leading to local hypo- or hypermyelination, respectively. However, the contribution of changes in ME myelin plasticity and myelination to the behavioural, metabolic, or neuroendocrine adaptations engaged during energetic challenges remains unclear and how these adaptations might be impaired in aging is unknown. Investigating whether similar changes occur in humans requires novel strategies to image ME myelin in vivo in humans with high resolution and sensitivity. In this project, we propose to develop advanced magnetic resonance imaging (MRI) methodologies to perform longitudinal quantifications of ME myelination in young or aged rodents exposed to a variety of genetic or environmental perturbations modifying energy balance and adult myelin plasticity. We will also translate protocols to image and quantify ME myelin in human participants and determine the effect of age and variations across the spectrum of body mass index on ME myelin density. This project will benefit from the expertise available in Dr. Bouhrara in myelin imaging using advanced MRI methodologies to quantify ME myelination in the rodent brain in vivo and in human participants with high neuroanatomical resolution and sensitivity. These optimized protocols will be used in the Blouet lab to investigate long term changes in myelination during homeostatic and metabolic challenges. This is a unique opportunity to bridge the gap between molecular neuroscience and MR physics to address outstanding mechanistic questions regarding metabolic dysfunctions and myelination patterns. We expect that this synergetic work will form the basis for further preclinical investigations and clinical trials of targeted metabolic interventions. 

CADASIL is a hereditary cerebral small vessel disease caused by mutations in the NOTCH3 gene. Small vessel diseases affect the small penetrating arteries and brain capillaries and patients often suffer of migraine, ischaemic stroke, and cognitive decline. Despite its severity, no disease-modifying treatments are available to date. Classical pathogenic mechanisms are associated with cysteine gain or loss in NOTCH3 extracellular domain, but recent studies suggest that mutation site and other polygenic influences may affect disease severity.  In the lab, we have developed a human in vitro model using induced pluripotent stem cells (iPSC) from CADASIL patients to identify new modifying factors which can be targeted therapeutically. The main aim of the project is to establish iPSC models of CADASIL patients with mild and severe phenotype recruited at the Cambridge Stroke clinic and use these models for omics analysis, mechanistic studies, and drugs screening. The project includes a number of techniques: 2D and 3D iPSC-based neurovascular unit models, transcriptomic, proteomic, phenotypic and functional cell assays and high-throughput screening.

Mitochondria are present in every nucleated cell and perform many essential functions. Their primary role is the efficient generation of adenosine triphosphate (ATP) which is required for all active cellular processes including protein synthesis, cell growth and repair. Mitochondrial dysfunction is seen in many common and rare diseases, but given their central role in cell homeostasis, it remains puzzling why this targets some cell-types and not others. We have developed new single-cell methods allowing us to address this question by studying tens of thousands of cells in the brain over the life course. This will cast light on the role of mitochondria in human ageing and neurodegenerative diseases.

The laboratory of Prof. Bridge in Oxford uses multi-modal MRI to understand the pathways in the human visual system, and how they are affected by vision loss early or late in life.

The laboratory of Dr. Nienborg at the NIH combines behavior, neurophysiology, and videography in mammalian animal models to better understand how the visual system processes information depending on the animal’s behavioral and cognitive state. 

Visual processing during natural behavior requires subjects to distinguish between changes in visual information caused by a subject’s own body movements (e.g. by walking along a street), and those caused by changes in the external world (e.g. a car driving by). How the brain achieves this is fundamental to understanding visual perception. Moreover, the degree to which their own body movements affect processing in visual cortex in normally sighted and blind subjects has direct implications for the development of neural prostheses targeting the visual cortex.

The project will have two objectives:

1. Identify how spontaneous body movements affect processing in the visual cortex in a mammalian animal model during head-free, naturalistic behavior.
2. Compare the modulations in the visual cortex by a subject’s own body movements in sighted and blind human participants.

This project will allow students to learn wireless electrophysiological recordings in mammalian animal models (e.g. non-human primates or a highly visual rodent species) combined with videography during naturalistic behavior. Students will also be able to learn how to leverage recent machine learning approaches for the analysis of the video and neural data. Additionally, students will have the opportunity to learn how to acquire and analyze functional MRI data in sighted and blind human subjects, using a variety of tools.  

What sets the brain apart from other organs is its complex connectivity. In order to study brain function, we need techniques for measuring brain connections with high precision in living humans. The goal of this project is to develop new methods for measuring brain connections using magnetic resonance imaging (MRI).

The project focuses on the cortex, a thin sheet of grey matter surrounding the brain. The cortex is well developed in primates, particularly humans, and plays a key role in cognition. It has a characteristic layered structure; each layer containing different varieties of neurons and connections. The input and output of a cortical region is determined by the connections of the layers. Thus, measuring layer connectivity can give us key insight into information flow in the brain. But these detailed anatomical patterns have only been studied in animal brains, where it is possible to precisely delineate connections.

This project aims to develop new methodology to study layered connectivity in the human brain using MRI. The incredible flexibility of MRI allows us to sensitise the measured signals to multiple aspects of tissue microstructure. We will use this flexibility to create MRI measurements that are sensitive to cortical lamination and integrate these measurements with computational models of laminar connectivity.

This project will open the door to addressing new questions about human brain organisation, such as whether brain areas are organized hierarchically, how information flows across the brain during cognition, learning, and memory; and what happens in diseases that disrupt brain connections

The laboratory of Prof Bridge in Oxford focusses on understanding the pathways in the human visual system that can process residual vision after someone has had a stroke that affects the primary visual cortex.

The laboratory of Prof Leopold combines neuroimaging, behaviour and neurophysiology in a non-human primate model to better understand computation in the visual system, particularly relating to conscious perception.

The proposed PhD project would have 3 main objectives:

1. Quantitatively compare changes in retinotopic maps and population receptive fields in humans and non-human primates with damage to primary visual cortex.
2. Determine the visual pathways in the two species that are necessary and/or sufficient to provide residual vision within the blind region of the visual field.
3. Investigate the neural changes that occur as a result of visual training following the damage to the visual system in order to inform rehabilitation programmes for people who have suffered a stroke to the visual system.
   
   During the training programme, the student would have the opportunity to learn about multi-modal human neuroimaging approaches applied to both the healthy and the damaged visual system. This would be complemented by training in both neuroimaging and neurophysiology in the non-human primate.

Our aim is to understand the sensory circuits that govern normal (protective) touch and pain, and how following injury or disease to the nervous system, pain can become chronic (neuropathic pain). Sensory neurons are heterogeneous neurons that innervate sensory targets (such as the skin), and extend central terminals which enter the dorsal horn of the spinal cord. We are interested in the role of molecularly defined subpopulations of sensory neurons, and how they contribute to the development and maintenance of neuropathic pain. We utilise chemogenetic and optogenetic strategies to selectively silence or activate sensory neuron function in mice. Combining this with behavioural paradigms to assess evoked and spontaneous pain, allows us to identify key populations of sensory neurons in pain processing, with the hope of identifying new druggable targets for future development. Further validation is undertaken in human iPSC derived sensory neurons. Students will learn and use a wide range of techniques including (but not limited to); Chemogenetics, optogenetics, viral vectors, mouse transgenics, animal behaviour, electrophysiology and calcium imaging.

All memories, including social memories, are encoded in neuronal ensembles. Neuronal ensembles are small populations of sparsely distributed neurons selected by specific stimuli. We recently developed and published a mouse model of volitional social learning using a custom-made apparatus. This model provides a unique opportunity to study the neurobiological substrates of volitional social learning and memory. Previous studies have shown that the hippocampus, in particular the CA2 region, is critical for encoding social memories. However, almost all prior studies on the neurobiological basis of mouse social interaction fail to account for the volitional aspect of social interaction. The project we propose entails a collaboration between our lab at University of Oxford and Dr. Hope’s lab at NIDA IRP to investigate the role of hippocampal neuronal ensembles in volitional social learning and memory. Dr. Hope and Dr. Ramsey have developed and implemented the volitional social learning task, and my lab regularly performs in vivo recordings in neuronal ensembles of the hippocampus.  Thus, we will co-mentor a graduate student through the NIH OxCam program to investigate activity in the hippocampus that encodes volitional social memories.

To date, neurodegenerative diseases have no cure and the clinical diagnosis is very challenging due to considerable overlap in the pathology and clinical symptoms. Thus, there is a strong unmet need for objective and sensitive diagnostic methods that can aid clinicians in early identification and differential diagnosis.

We have developed seed amplification assay (SAA) that detects alpha-synuclein (aSyn) aggregation in CSF of patients with synucleinopathies with much higher sensitivity and specificity than previously possible. Our findings also show that aSyn SAA is able to distinguish between Parkinson’s disease and multiple system atrophy and identify patients at high risk with REM sleep behaviour disorder prior to their conversion. Here, we suggest to build a “multiplex” SAA to detect multiple aggregating proteins (aSyn, tau and TDP-43) and test its ability to stratify between dementias of different aetiologies. We are in an exceptional position to deliver this goal because we have the necessary technical knowledge to build robust SAAs combined with access to unique clinico-pathological cohorts with longitudinal CSF and donated brain, where our assay can be tested and validated.

This proof-of-concept data will be used to further evaluate early and accurate diagnosis in larger longitudinal cohort of patients with mild cognitive impairment (MCI) and dementia. The proposed work aims to accelerate clinical trials by providing a “personal protein signature” that can be targeted by therapies tailor-made for individual patients aiming to lower the burden of these specific proteins (e.g. cocktail of vaccinations) and superior means to measure the efficacy of such treatments.

Parkinson’s disease is typically considered to impact motor functions. However, non-motor symptoms, such as visual hallucinations, increase disease burden. Developing therapies for hallucinations in Parkinson’s disease has been challenging, since we do not fully understand what causes them to occur. In the healthy brain, successfully interpreting what one sees involves different neurotransmitters like GABA and Acetylcholine; hence it is possible that pathological processes involving these brain chemicals relate to the generation of visual hallucinations.

The project will investigate the role of neurotransmitters GABA and Acetylcholine in sensory processing in the healthy and Parkinsonian human brain. It will combine pharmacological interventions with human neuroimaging (functional MRI, MR Spectroscopy) and non-invasive brain stimulation, to provide putative targets for therapeutic interventions to alleviate visual hallucinations in Parkinson’s disease.

Research in Oxford will take place at the Wellcome Centre for Integrative Neuroimaging (https://www.win.ox.ac.uk) and the MRC Brain Network Dynamics Unit (https://www.mrcbndu.ox.ac.uk), hosted by the Physiological Neuroimaging Group (https://www.ndcn.ox.ac.uk/research/physiological-neuroimaging-group).

The brain is continuously bombarded with visual input but has limited processing capacity. Learning to selectively process visual features relevant for behaviour is therefore crucial for optimal decision-making and thought to rely on activity of GABAergic inhibitory interneurons. Altered inhibition is linked to perceptual and learning impairments and associated with neurodevelopmental disorders including schizophrenia and autism.

The aim of this project is to understand the precise role of different types of GABAergic inhibitory interneurons during visually-guided learning and decision-making. Mice have a similarly organized visual cortex and show complex decision-making behaviours. Mouse brain circuits can be measured and manipulated during behaviour in ways not possible in humans.

Our approach is to train mice, including pharmacological and genetic mouse models of neurodevelopmental disorders and healthy controls, in visual decision-making tasks. We measure activity in visual cortex in specific cell types using 2-photon imaging and electrophysiology and use optogenetics to activate or inactivate activity of specific interneuron cell types. We will also apply two new innovative methods to optically measure the inhibitory neurotransmitter GABA (developed in the Looger lab, UCSD) and to locally pharmacologically manipulate GABA levels in the brain (collaboration with Malliaras and Proctor labs, Dept of Engineering, Cambridge) during visual learning and decision-making.

The PhD project is associated with a Wellcome Trust funded Collaborative programme with a cross-disciplinary international research team to investigate the role of GABAergic inhibition in both mice and humans at different scales, from local circuits to global brain networks.

Lab website: https://www.pdn.cam.ac.uk/svl
Contact: Jasper Poort jp816@cam.ac.uk

During development, brains grow rapidly as behaviors develop. Impairment in early brain development often leads to neurodevelopmental conditions, including a number of neuropsychiatric disorders. From early postnatal period throughout adulthood, learning leads to important and dynamic changes in brain circuitry, and in an animals’ behaviors to adapt and sense the environment. The hierarchical yet reciprocal interaction between thalamus and cortex is one of the key brain circuits that are involved in learning-related changes from early development to adulthood.

To investigate the development of thalamocortical connection in the context of sensory learning, this project aims to understand 1) the specificity and plasticity in the interaction between thalamus and cortex during both early development and later life, and 2) how the impairment in this functional connection during early development results in long lasting effects on the capacity for learning in the adult brain. Specifically, we will study how different neuronal types and neuromodulators play a role in the developmental and adult plasticity of thalamocortical connectivity.

To address these questions, we will use the rodent whisker-related sensory-motor system because it is ecologically relevant and critical to the animal’s abilities to navigate and engage in goal-directed behavior. We will apply a multidisciplinary approach that combines molecular and genetic techniques with in vivo intracellular and extracellular electrophysiology, in vivo longitudinal calcium imaging, viral tracing, optogenetic and pharmacogenetic methods, and quantitative behavior and anatomical analyses.

Lee’s lab at NIH will focus on early developmental studies and Bruno’s lab at Oxford will focus on adult plasticity. The two labs will use complementary approaches. A student working with Drs. Lee and Bruno will have a unique opportunity to learn conceptual perspectives from both labs, as well as a wide range of experimental and analytical methodologies in the field of system neuroscience. 

The laboratory investigates the interactions between episodic memory formation and brain dynamics during sleep. How are memories strengthened (‘consolidated’) overnight? What is the role of specific brain rhythms during sleep? Can we use sleep to experimentally control the extent of forgetting? To tackle these questions, a range of techniques including intracranial EEG, scalp EEG, MEG, fMRI, non-invasive brain stimulation (NIBS), and behavioural testing are used.

Multisensory learning helps an individual learn through more than one sense. However, the underlying neural mechanism is unclear. In this study we aim to pursue this question in a spatial learning regime. We will focus on the medial entorhinal cortex (MEC), which plays a critical role in spatial learning and the dysfunction of which is closely related to Alzheimer’s disease. We will record neural dynamics of the MEC using two-photon imaging approach when mice navigate in virtual environments, in which multisensory spatial information will be precisely delivered. The goal of the project is to deeply understand how the neural response of the MEC contributes to multisensory learning.

Repetition priming (RP) is a basic form of memory, whereby prior exposure to a stimulus facilitates or biases subsequent responses to that stimulus. From a neuropsychological perspective, RP is interesting because it can occur without awareness, and despite the damage to the medial temporal lobe (MTL) system that produces amnesia. Many functional neuroimaging studies using fMRI and MEG/EEG have investigated the brain regions and neuronal dynamics associated with RP. However, the results are complex, depending on several important variables, and suggesting multiple underlying neural mechanisms. Recent computational models provide some insight, and the proposed project will extend these models to a broader range of neuroimaging data, including existing data from intracranial recording in human and non-human primates.

1. Models of ion channel regulation in single cells and small circuits
2. Modelling robust neuromodulation
3. Regulation and control of neural activity and circuit dynamics

Mitochondrial DNA (mtDNA) mutations have emerged a major cause of neurological disease and may also contribute to the ageing process – but their origin is not well understood. Remarkably, we have shown that most humans harbour a mixture of mutant and wild-type mtDNA (heteroplasmy) at very low levels. Our aims is to understand how mtDNA mutations arise, how they are inherited, and how they accumulate in specific tissues, particularly in the nervous system. Harnessing this knowledge, we will develop new treatments targeting the mitochondrion.

The cerebellum is a fascinating brain structure. While it has traditionally been regarded solely as a regulator of motor function, recent studies have demonstrated additional roles for the cerebellum in higher-order cognitive functions such as language, emotion, reward, social behaviour and working memory. Accordingly, cerebellar dysfunction is linked to motor diseases such as ataxia, dystonia and tremor, as well as cognitive affective disorders such as autism spectrum disorders and language disorders.

We understand surprisingly little about the molecular processes that underlie the formation of the cerebellum and that, when disrupted, lead to disease. The goal of our research is to provide fundamental insights into the genetic, molecular and cellular mechanisms that govern the development and different diseases of the cerebellum with the  ultimate desire to develop novel treatment options for these disorders.

The project will focus on the functional characterization of novel gene mutations causing cerebellar disorders, with particular emphasis on the effects of disease genes on the dendritic arborisation of developing Purkinje cells in the cerebellum. The approach will be multi-disciplinary and employs a variety of methods including functional experiments in cell lines and primary neurons, as well as modelling of identified patient mutations and their effects using stem cells combined with genome engineering. The project is supervised by two experienced investigators with complementary expertise. Research in the Hammer group at NIH will focus on introducing mutations of interest into primary Purkinje cells and to investigate dendritic phenotypes. Research in the Becker group at Oxford will include further functional analyses in Purkinje cells from mutant mouse models, as well as in human induced pluripotent stem cells.

Becker Group website:
https://www.ndcn.ox.ac.uk/research/cerebellar-disease-group

Hammer Group website:
https://irp.nih.gov/pi/john-hammer

A balance between neuronal excitation and inhibition is crucial for normal brain physiology; upsetting this balance underlies various brain pathologies. To shed light on the molecular underpinnings of this regulation at the synapse level, this project will investigate the dynamics of glutamate- and GABA-A synapses and receptors in CA1 hippocampus under baseline conditions and in response to synapse potentiation. Specifically, using structural, functional and imaging approaches we will study both, spiny glutamatergic and aspiny GABA-ergic CA1 synapses and associated receptor complexes (AMPA-type glutamate and GABA-A) and how these change at the synapse- and receptor levels in response to LTP (long-term potentiation) induction. Our aim will be to monitor changes of glutamatergic and GABAergic synapses and receptors at pyramidal neurons (glutamate) and/or parvalbumin-positive (PV+) interneurons at various points after LTP induction. We will monitor changes in synapse size and receptor composition using advanced imaging and electrophysiological approaches.

Inherited neurological disorders are disabling, progressive, often fatal conditions, representing an enormous unmet medical need with devastating impacts on affected families, the healthcare system, and the economy. There are no cures and the limited therapies available treat symptoms without addressing the underlying disease.

Next-generation sequencing has facilitated a molecular diagnosis for many inherited neurological disorders, such as mitochondrial diseases and other neuromuscular diseases, which are the focus of this research. The development of targeted therapies requires detailed laboratory investigation of molecular and mutational mechanisms, and a systematic evaluation of well-chosen agents as well as gene and transcript directed strategies using standardized experimental systems. Our research is focusing on understanding the molecular pathogenesis of childhood onset inherited neurological diseases, such as mitochondrial disease and other neuromuscular diseases to develop targeted therapies.

Using a translational approach, we aim to
1. understand the clinical course of patients in relation to the underlying disease mechanism
2. delineate the mutational and molecular mechanisms of the molecular defect in the appropriate cell types by developing model systems such as induced neuronal progenitor cells (in vitro) and zebrafish (in vivo)
3. improve the treatment options for patients by developing novel therapies that are directed at these mechanisms, including directly at the genetic mutation or resulting transcript.

We use a combination of exome sequencing, genome sequencing, and other omics technologies to identify novel disease genes and disease mechanisms. By functional evaluation in vitro (induced neuronal progenitor cells) and in vivo (zebrafish) we confirm pathogenicity and uncover molecular mechanisms of disease. To address the mutational mechanisms, we use gene transfer, splice modulation, allele silencing and CRISPR/cas systems.

Primary progressive multiple sclerosis (PPMS) is a chronic demyelinating disease of the central nervous system, which currently lacks restorative therapies. Transplantation of neural stem cells (NSCs) has been shown to promote healing of the injured CNS, but previous work has demonstrated that NSCs from patients with PPMS are prematurely senescent. Cellular senescence causes a pro-inflammatory cellular phenotype that impairs tissue regeneration. Senescence in PPMS NSCs was found to be associated with increased secretion of HMGB1, a pro-inflammatory alarmin found to inhibit oligodendrocyte differentiation, and also found increased within white matter lesions of PPMS autopsy tissue. This project aims to understand the role of HMGB1 in PPMS NSC senescence using techniques such as CRISPR-Cas9, RNA sequencing, and functional NSC assays. The longterm goal of this project will be to determine the cause of senescence in NSCs from patients with PPMS and if these cells are suitable for therapeutic use.

Andrew Holmes’ Lab (NIH/NIAAA) and Armin Lak’s Lab, Oxford University

Several decades of research has shown that medial frontal cortical neurons, as well as the neuromodulatory system that innervate the medial frontal cortex, notably the dopamine system, are important in reward valuation and decision making. However, it is not known whether different regions of medial frontal cortex play distinct roles in guiding decisions. Moreover, the role of frontal dopamine signals in shaping and regulating decisions has yet to be established. To address these questions, this project will use a combination of large-scale Neuropixels recording across the medial frontal cortex, as well as optical measurement of dopamine release in the medial frontal cortex during decision making in mice. At Oxford, the project will use Neuropixels probes to record the activity of many neurons across different regions of medial frontal cortex while mice perform a task that systematically manipulates the value of choice options. This data will allow us to investigate the relation between frontal neuronal activity and decision-making variables, and characterize distinct roles of different medial frontal regions in choice behavior. At NIH, the project will take advantage of optical and genetic methods to measure the dynamics of dopamine release in frontal cortical regions identified in the electrophysiological recordings. These experiments will reveal the roles that frontal dopamine play during decision making. In analyzing the electrophysiological and optical data, we will use computational models of learning and decision making to relate neuronal signals with trial-by-trial model-driven estimates of decision variables. The project is primarily experimental in nature but will provide an opportunity to develop computational skills. Together, the project will provide fundamental insights into behaviorally-relevant computations that neurons across the medial frontal cortex perform during decision making, and will reveal the roles of frontal dopamine signals in shaping choice behavior. For more information please visit: https://www.niaaa.nih.gov/laboratory-behavioral-and-genomic-neuroscience and https://www.laklab.org.

*This project is available for the 2021 Oxford-NIH Pilot Programme*

The Domingos laboratory researches neuroimmune mechanisms underlying obesity. We discovered the sympathetic neuro-adipose junction, a functional synapse-like connection between the sympathetic nervous system and white adipocytes (Cell 2015). We found that this neuro-adipose junction is necessary and sufficient for fat mass reduction via norepinephrine (NE) signaling (Cell 2015, Nature Comm 2017). We then discovered Sympathetic neuron-Associated Macrophages (SAMs) that directly import and metabolize NE. Abrogation of SAM function promotes long-term amelioration of obesity independently of food intake (Nature Medicine, 2017). Given the recent discovery of SAMs, virtually nothing is insofar known about the cell biology of these cells or what other immune cells populate the SNS to cross talk with SAMs.

This PhD project aims to uncover  biological mechanisms of SAM biology. Using single cell sequencing methods, the student will unravel the heterogeneity of the sympathetic neuro-immune cross talk involving SAMs. By identifying novel immune cell mediators, we will have a better understanding of how SAMs are regulated, and pave the way to the identification of cellular and molecular targets that would then be amenable to drug delivery. We will be guided by singe cell sequencing dataset for formulating hypothesis that model fundamental aspects regarding the biology of these cells. The interactions between SNS axons and SAMs, or other resident cells identified by single cell sequencing, will be resolved by super resolution microscopy and 3D reconstruction, for a better understanding of the intricate topology of SAMs’ morphology in relation to SNS axons (Nature Medicine 2017). The PhD candidate can also use optogenetics to probe neuro-immune interactions (as in Nature Medicine 2017), as well as 3DISCO imaging for mapping the distribution of the aforementioned cells in adipose tissues. This project will give a candidate a tremendous opportunity to apply cutting-edge methods in the growing field of neuroimmune biology.

Alzheimer disease (AD), dementia with Lewy bodies (DLB) and Parkinson disease (PD) are the most common neurodegenerative diseases that create an enormous public health burden with a rapidly aging population. There is currently no definitive test that allows doctors to determine if someone has or will get one of these disorders. At present, the diagnosis is purely based on the symptoms, but by the time this is made the disease process is already too advanced for any therapies to have full impact. There is a clear and urgent need for reliable diagnostic tests that can identify early signs of dementia and movement disorders, and methods that can distinguish between the different types of neurodegeneration e.g. AD / DLB / PD so that drug treatment can be prescribed in a patient specific manner. Early, sensitive and reliable diagnostics will inevitably open an invaluable window for not only to early treatment but also towards finding a cure.

The intention of this DPhil project is to develop such a diagnostic method where samples taken from patients can be  interrogated using a highly sensitive and specific clinic-ready technique/ “kit” called Real-Time Quaking-Induced Conversion (RT-QuIC). An RT-QuIC method, which detects multiple sticky proteins in cerebrospinal fluid (CSF) as a surrogate marker of brain pathology has already been established by the Parkkinen lab to identify signs of early onset Parkinson’s disease (http://www.bbc.co.uk/news/health-37196619). Our aim here is to develop complementary RT-QuIC methods for AD and DLB patients. We anticipate that this will serve as a powerful predictive tool for patients at high risk of developing dementia i.e. patients with mild cognitive impairment, and enable a personalised test that can identify specific variants of the disease. In addition, we are using the RT-QuIC method to understand the disease pathogenesis, particularly the role of different conformational variants, or “strains” of proteins that may contribute to the tremendous heterogeneity of neurodegenerative diseases by showing different morphology, seeding and/or cross-seeding propensities, strain-specific neuropathology and different levels of neurotoxicity.

The proposed project will require vast biochemical, biophysical, molecular neuroscience and pathological skills and knowledge provided by the unique translational training environment formed by Dr. Parkkinen and her local and international collaborators who are all experts on the field. Dr. Parkkinen’s Molecular Neuropathology research group is based at state-of-the-art facilities at the Academic Unit of Neuropathology (AUN) and Oxford Brain Bank which are part of the Nuffield Department of Clinical Neurosciences (NDCN) in the University of Oxford. Research into neurodegenerative diseases has a high priority and profile within the University of Oxford and especially NDCN. Dr. Parkkinen is also an integral part of the Oxford Parkinson’s Disease Centre (https://www.dpag.ox.ac.uk/opdc) which is a multidisciplinary group of internationally recognised scientists with strengths in genomics, imaging, neuropathology, biomarkers and cell and animal models. Regular meetings are arranged for all post-graduate students within AUN/NDCN, and feedback and guidance is provided to ensure completion of the degree within the allocated time. All the necessary funding is provided by Dr. Parkkinen’s successful Weston Brain Institute and Parkinson’ UK grants.

Patients with neurological diseases often have difficulty in evaluating, planning and initiating actions. This can lead to disorders of motivation, such as apathy and impulsivity. My group studies the cognitive neuroscience of goal-directed action, in the context of disease. Some patients have difficulty  evaluating a particular plan in a given context. For example, they might revert to habitual actions which were previously associated with reward, or may be unable to think beyond their current situation. We take a multimodal approach, with behavioural studies, eye tracking, drug studies in healthy people and patients, EEG and neuroimaging. I have also developed computational models – both in the form of abstract cognitive models, and neural network simulations, to understand what the brain computes when determining actions.

My group has found that dopamine plays an important role in energising goal-appropriate actions. We hypothesise that prefrontal goal representations act through corticostriatal loops, being amplified or attenuated by dopamine.  In this project, the student will study patients with Parkinson’s disease and the effects of dopaminergic drugs on cognition, together with neuroimaging (which can include MEG or fMRI), to understand goal-directed action selection and energisation. The student will design their own behavioural tasks to separate out the component processes involved in maintaining and using goal information to energise actions. The student will test patients on their task, test drug mechanisms using a within-subject neuroimaging design, and  deploy appropriate analysis methods with help from a postdoctoral researcher.   The project will also include the opportunity to learn computational modelling if the student is keen.

There are few examples of tractable overlaps between the fields of neurodegeneration and neuroimmunology. Yet, an immunological basis for a subset of patients with neurodegeneration would identify a group whose condition may be modified with the use of available immunotherapies. Dr Nath’s group have identified oligoclonal immunoglobulin bands in the cerebrospinal fluid of ~10% of patients with amyotrophic lateral sclerosis (ALS, also termed motor neuron disease). Further, endogenous retroviruses are observed to be activated in about 50% of ALS brains at autopsy. These observations mandate a search for the targets of the cerebrospinal fluid IgGs, to include retroviruses.

To identify antigenic targets, the DPhil candidate will use a variety of immunoassays established in both Dr Irani’s and Nath’s labs. These include B cell immunoglobulin heavy-light chain cloning, single cell RNA sequencing, western blotting, phage display screens and cell based assays.

In addition, these techniques will be applied to the cerebrospinal fluid of patients with Alzheimer’s disease to take an agnostic mass spectrometry based approach to identify antigenic targets of B cells and cerebrospinal fluid IgG in this cohort.

Overall, there will be excellent exposure to neuroimmunology and neuroinfection focused laboratories with the opportunity to learn multiple clinically applicable techniques to link common forms of neurodegeneration with a neuroinflammatory component.

The human brain is astonishing: it is the source of our thoughts, actions, memories, perceptions and emotions. It confers on us the abilities that make us human, while simultaneously making each of us unique. Through deepened knowledge and understanding of how human brain works, we will comprehend ourselves better and treat brain diseases more incisively. Over recent years, neuroscience has advanced to the level that we can envision spanning molecules, cells and neuronal circuits in action. In particular, there is an emerging view that subtle aspects of presynaptic dysfunction are implicated in an increasing number of brain disorders such as neurological and neurodegenerative diseases.

We are particularly interested in exocytosis, a process of vital importance for neuronal cells that is controlled by a set of both positive and negative regulators. While promotors of exocytosis are well studied, negative regulators are poorly understood. We discovered that a small SNARE protein amisyn (STXBP6) acts as a vertebrate-specific competitor of synaptobrevin-2, a key player in exocytosis. Amisyn contains an N-terminal pleckstrin homology domain that mediates its transient association with the plasma membrane by binding to phospholipid PI(4,5)P2. Both the pleckstrin homology and SNARE domains are needed to inhibit exocytosis. Of note, amisyn is poorly studied despite several studies have emphasized its importance for exocytosis and reported the occurrence of amisyn mutations in autism, diabetes and cancer.

This PhD project aims to study mechanisms of exocytosis with a focus on amisyn. The candidate will study how lack or impaired function of amisyn modulates exocytosis, synaptic transmission and behavior. We have generated a mouse model without amisyn to be employed for these studies. In addition, our collaborative team has expertise in a wide variety of interdisciplinary techniques to support and facilitate the proposed PhD project, such as biochemical, (electro)physiologal and life confocal microscopy techniques.

Light exposure profoundly affects human physiology and behaviour. Light at the wrong time can shift the internal circadian rhythm and suppress the production of the endogenous hormone melatonin. These non-visual effects of light are largely mediated by the recently discovered melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs), which are sensitive to short-wavelength (blue) light.

Chronic exposure to light at night can also have long-term consequences for health and well-being. Importantly, however, recent evidence shows that daytime light exposure can improve alertness and also offset the detrimental effects of light at night. Understanding what 'good' light exposure constitutes therefore is a key priority for mitigating circadian disruption by light.

This innovative collaborative research project will combine state-of-the-art laboratory and field assessments of circadian phase, melatonin production, visual and non-visual sensitivity, activity cycles, and other physiological and behavioural measurements. Broad training in a wide variety of techniques spanning circadian and visual neuroscience will be provided.

Our lab seeks to explore the neural mechanisms underlying cognitive function by exploiting the unique investigative opportunities provided by intracranial electrical recordings during neurosurgical procedures. Using recordings captured from epilepsy patients implanted with subdural and depth electrodes, we investigate the activation of cortical networks during memory encoding and recall. And using recordings captured during implantation of deep brain stimulators, we investigate the role of the basal ganglia in learning and decision-making.

Retroviral sequences remain dormant in the human genome and occupy nearly 7-8% of the genomic sequence. We have shown that one of these viruses termed HERV-K (HML-2) is activated in patients with amyotrophic lateral sclerosis (ALS), and transgenic animals that express the envelope protein of HERV-K develop ALS like symptoms. Hence, we are now using a wide variety of structural biology and virology tools to determine the mechanism by which its expression is regulated and causes neurotoxicity to motor neurons. 

Understand the disease mechanisms and potential treatments for hereditary motor neuron diseases such as spinal muscular atrophy and polyglutamine expansion diseases such as Huntington's disease.

Humans display robust age-dependent sex differences in diverse domains of motor, language and social development, as well as in risk for developmentally-emergent disorders. There is a robust male-bias in risk for early-emerging impairments of attention, motor control, language and social functioning, vs. a female-bias for adolescent-emergent disorders of mood and eating behaviors.  The stereotyped pattern of these sex biases suggests a role for sex differences in brain development, and further implies that these differences unfold in a spatiotemporally-specific manner. In support of this notion - in vivo structural neuroimaging studies find focal sex differences in brain anatomy that vary over development. However, the mechanisms driving these neurodevelopmental differences remain poorly understood in humans. In particular, we do not know how specific spatial and temporal instances of sex-biased brain development in humans relate to the two foundational biological differences between males and females: gonadal sex-steroid profile (henceforth “gonadal”) and X/Y-chromosome count [henceforth “sex chromosome dosage” (SCD)]. In our prior cross-sectional neuroimaging studies, we have however provided extensive evidence that gonads and SCD can both shape regional anatomy of the human brain, and that similar effects can be observed in mice. However, to date there are no available data on the temporal unfolding of gonadal and SCD effects on regional brain anatomy, and no quantitative frameworks for comparing these effects between observational humans studies and experimental work in mice.

This project will build on a longstanding productive collaboration between Drs. Lerch and Raznahan, with rich existing datasets, to better-specify sex as a neurobiological variable in health and disease. Key questions for the project relate to (i) fine-grained spatiotemporal mapping of sex, SCD and gonadal effects using neuroimaging in transgenic mice and rare patient groups, (ii) computational solutions for comparison of these maps between species, and (iii) “decoding” of imaging data using measures of gene expression in brain tissue and integrative functional genomics. The resulting anatomical, and genomic signatures for sex-biased development will be probed for association with biological bases of sex-biased brain disorders.

*This project is available for the 2021 Oxford-NIH Pilot Programme*

Use experimental medicine and neuroimaging approaches to uncover the mechanisms mood disorders in adolescents and adults. Depression is a leading cause of burden of disease worldwide yet we know little about its pathogenesis. The student is going to work across the NIMH and Oxford laboratories and use neuroimaging (fMRI, EEG and MEG) in patients and controls who undergo experimental treatments.

Midbrain dopamine neurons have fundamental roles in reward learning and movement control, and their dysfunction is associated with various disorders in particular Parkinson’s disease. Recent studies have shown substantial diversity in the activity of these neurons depending on where in the striatum their axons project. In our recent experiments we recorded the activity of dopamine axonal terminals while systematically manipulating stimuli, actions and rewards in a precise behavioural task. While the activity of dopamine projections to ventral regions of striatum mainly reflected rewards, dopamine axonal projections to dorsal striatum encoded contralateral stimuli and actions with negligible representation of reward value. These findings raise the questions of whether dopamine signals across striatum encode specific aspects of associations between stimuli, actions and rewards during learning, and whether these anatomically-specific dopamine signals are impaired during Parkinson’s disease. This project will address these questions using a combination of imaging, computational and behavioural experiments in healthy mice as well as mouse models of Parkinson’s disease. In Oxford University (Lak lab), we will use recent genetically–encoded dopamine sensors in combination with fiber photometry to monitor the dynamics of dopamine signals across the striatum while healthy mice perform a learning task guided by sensory stimuli and rewards. These results will provide a foundation for examining these dopamine signals during Parkinson’s disease, which will be performed at NIH (Cui lab). Using MitoPark mouse line (with progressive and robust phynotype of Parkinson’s disease), we will examine the dynamics of striatal dopamine signals using photometry during learning tasks established in healthy mice in Oxford. In analysing the data, we will use learning models to relate dopamine signals with normative computational models of decision making and learning. The project is primarily experimental in nature but will provide an opportunity to develop computational skills. The project will provide fundamental insights into behaviourally-relevant computations that dopamine signals across the striatum encode, and will uncover how these neuronal computations change during Parkinson’s disease. For further information visit: https://www.niehs.nih.gov/research/atniehs/labs/ln/pi/iv/index.cfm and www.laklab.org

*This project is available for the 2021 Oxford-NIH Pilot Programme*

Humans and animals adjust their feeding behaviour according to many environmental factors, including the spatial context where food is found and consumed. Such contextual control of food seeking and eating is notably central to the ability to meet future needs and maximise chances of survival to changes in feeding routines but their underpinning brain network mechanisms and pathways remain unclear. The Dupret laboratory (MRC Brain Network Dynamics Unit at the University of Oxford) investigates how the concerted spiking activity of neurons supports memory and the Krashes laboratory NIH/NIDDK) investigates homeostatic and non-homeostatic feeding behaviour. An integrated project between the two labs, in collaboration with an NIH OxCam Scholar would be designed to enable the pursuit of an Ph.D. revealing circuit mechanisms of contextual control of feeding behaviour using in vivo large-scale network recordings in behaving rodents, combined with optogenetic and closed-loop optogenetic manipulations.

Alzheimer’s disease is the most common neurodegenerative disease. It affects millions of individuals worldwide. Because of large scale genomic studies, we know a number of genetic risk factors that increase the risk for disease. We also know a few factors that promote resilience to disease onset. The Narayan lab seeks to identify, understand, and modulate the cellular pathways that underlie risk and resilience to Alzheimer’s disease.  We do this with the goal of developing new therapeutic or preventative strategies for neurodegenerative diseases. To accomplish our research goals, we use a combination of genetics, biochemistry, molecular biology, and human induced pluripotent stem cell (iPSC)-derived neuronal and glial cell types. We’re excited to welcome new team members interested in studying the cell biology behind neurodegenerative disease risk.

Neuronal plasticity is fundamental to nervous system development and function. We have recently discovered that reactive oxygen species (ROS), known for their destructive capacity in the ageing or diseased brain, function as second messengers for implementing structural plasticity at synaptic terminals. Moreover, different sources of ROS (cytoplasmic vs mitochondrially generated) regulate genetically distinct aspects of synapse development (growth vs release site number). Do ROS sculpt synapse plasticity in response to the metabolic state of neurons? How does ROS signaling intersect with other signaling pathways regulating synaptic plasticity, such as BMP and Wnt? This project will combine biochemical and genetic approaches with electrophysiology and methods for live and super-resolution imaging to investigate the contribution of various signaling pathways to synapse plasticity. We expect this project to redefine our understanding of how multiple signaling pathways integrate at the synapse to regulate distinct elements of plasticity.