Research Opportunities

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.