Research Opportunities

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*