Brain Health
The Kavli INsD’s Brain Health research theme brings together scientists across disciplines to address major research challenges related to the brain. A large portion of our research in this area relates to dementia and neurodegeneration, sleep and circadian rhythms, and mental health. The genetic and mechanistic basis for migraine headaches is another area of focus, led by Zameel Cader.
Our research aims to improve understanding of the mechanisms underlying conditions such as Alzheimer’s and depression and the role of the body clock in health and disease. Ultimately, we aim to translate that understanding into better strategies for disease prevention, diagnosis and treatment.
Dementia and neurodegenerative diseases, including Alzheimer’s, Parkinson’s and motor neuron disease, represent an increasing healthcare burden for an ageing global population. Largely untreatable, these diseases are already a leading cause of disability and their prevalence is rising.
Our research aims to understand the fundamental biological processes that underlie normal brain development and are responsible for neurodegeneration, and to inform the development of treatments. Our work relies on diverse models, ranging from in vitro systems to cellular models, such as induced pluripotent stem cells (iPSCs), as well as on human tissue samples. The ability to generate, engineer, differentiate and phenotype iPSC-derived neurons and glia from healthy people and those with neurodegenerative disorders makes it possible to study relevant human models of disease.
For this research, we develop and make use of a rich array of experimental tools, which include mass spectrometry, NMR spectroscopy, cryogenic electron microscopy, genome editing, X-ray crystallography, and super-resolution microscopy. These techniques, combined with computation tools, enable detailed characterisation of relevant biomolecular interactions, structure and dynamics.
We also benefit from links with the Oxford Parkinson's Disease Centre, the Oxford Motor Neuron Disease Centre, the Translational Neuroscience and Dementia Research Group, and the ARUK Oxford Drug Development Institute.
Our work in this area focuses on:
- Identifying the genetic regulatory pathways involved in normal and aberrant neurodevelopment as well as susceptibility to neurodegeneration (Noel Buckley, Richard Wade-Martins)
- Understanding the molecular mechanisms of protection against protein mis-folding and aggregation, and the role of molecular chaperones in particular (Justin Benesch, Andrew Baldwin)
- Exploring the formation of complex tissues, including neural networks (Elena Seiradake)
- Identifying therapeutic targets for treatment of motor neuron diseases (Kevin Talbot)
- Elucidating the molecular and cellular mechanisms of cerebellar ataxia, and identifying potential therapeutics (Esther Becker)
- Investigating protein trafficking and degradation pathways in Parkinson’s disease and their translation into potential targets for therapies or biomarkers (George Tofaris)
- Studying regulation of the lysosome, a metabolic signalling hub that plays a role in the degradation of protein aggregates and neurodegeneration (Simon Newstead)
- Identifying and validating new drug targets and signalling pathways involved in blood-brain barrier dysfunction in neurodegenerative diseases and brain injuries (Mootaz Salman)
A growing awareness of the importance of mental health in recent years has been accompanied by a significant increase in the prevalence of mental health conditions worldwide. One of the most common is depression, which is a leading cause of disability and can have a major impact on all aspects of a person’s life.
While treatments are available for depression, their effectiveness is variable and they may cause negative side effects. Meanwhile, there is a persistent lack of direct evidence linking biological mechanisms to depression symptoms, such as a reduced ability to feel pleasure.
Researchers in Kavli INsD are charting differences at the molecular level of the receptors and transporters at the blood-brain barrier. By comparing targeted brain regions of patients suffering from anhedonia, as opposed to those who are unaffected by depression, they aim to understand how small molecules cross this barrier. A further goal is to develop effective biomarkers for anhedonic depression to better inform therapeutic interventions.
Our work in this area focuses on:
- Investigating how proteins in the brain are modified during anhedonic depression (Carol Robinson)
- Studying the relationship between sleep and mental health (Colin Espie, Simon Kyle)
- Anhedonic depression (Corinne Lutomski, Tarick El-Baba and Carol Robinson)
Every day, how we feel and what we do is shaped by day and night, and our patterns of sleep vs wakefulness. Our 24-hour body clock or ‘circadian’ clock is centrally controlled within the brain. The clock helps regulate not just our sleep, but also our metabolisms, immune systems and other important aspects of health. Disruption to sleep patterns can lead to a range of health problems, highlighting the interconnectedness of the pathways that govern circadian rhythms and other fundamental physiological systems.
Housed within the Kavli INsD is the University of Oxford’s Sleep and Circadian Neuroscience Institute (SCNi), which brings together scientists and clinicians to investigate circadian rhythms and disease. Their research explores the links between daylight, sleep, and health and behaviour – at the levels of molecules, cells, whole organisms and even populations.
More specifically, our research in this area focuses on:
- Researching the molecular mechanisms underlying sleep and circadian rhythm regulation (Aarti Jagannath, Stuart Peirson, Vladyslav Vyazovskiy)
- Understanding the mechanisms by which light regulates vertebrate circadian rhythms, physiology and behaviour (Russell Foster, Stuart Peirson)
- Studying the relationship between sleep and mental health (Colin Espie, Simon Kyle)
- Studying the relationship between sleep and metabolic health (Colin Espie)
- Understanding neurophysiological mechanisms of brain oscillations during waking and sleep (Vladyslav Vyazovskiy)
- Investigating neurobiology and regulation of torpor (Vladyslav Vyazovskiy)
- Investigating circadian rhythms and nuclear receptors in inflammation and energy metabolism (David Ray)
- Developing regenerative therapies for those with vision loss (Mark Hankins)
- Investigating light-dependent signalling in the retina and brain, and the role of photopigments (Mark Hankins)
