Neuroscience in the 21st Century is expanding beyond the traditional focus on the nervous system to consider how it interacts with the rest of the body and the role of non-neuronal cells in neurological diseases. Research in the Beyond the Neuron (BTN) theme seeks to understand the role of glia and immune cells in health and disease, particularly: (a) astrocyte, oligodendrocyte and microglia biology; (b) glia-neuronal interactions; (c) role of glia in neuroinflammation; and (d) characteristics of human immune cells in neuropsychiatric brain disorders. The theme also covers brain control of energy homeostasis. At Cambridge researchers take advantage of expertise in glial and stem cell biology to develop human models for studying the interactions between different cell types within the nervous system and identifying potential avenues for new interventions for disease. Ultimately, our aim is to translate fundamental discoveries to therapies for people with disease and in several areas that has already been achieved; for instance, we have shown that repurposing a cancer drug, which is an agonist of the retinoid X receptor, promotes remyelination in people with multiple sclerosis. This research community is highly collaborative across the Departments of Clinical Neurosciences, Physiology, Development and Neuroscience, Biochemistry, Medicine, Pharmacology, Engineering, Paediatrics and Wellcome-MRC Institute of Metabolic Sciences with close interactions with the Wellcome-MRC Cambridge Stem Cell Institute, MRC Laboratory of Molecular Biology, European Bioinformatics Institute and Sanger Institute.
Research on the roles of microglia and astrocytes in neuroinflammation and neurodegeneration has been rapidly expanding in Cambridge because of the roles that these non-neuronal cells play in neurodevelopment and neuropathology. For example, research has identified multiple genetic variants of microglial genes linked to Alzheimer’s disease and how these microglial protein variants may cause disease. Similarly, the importance of microglia in tau pathology has been shown through studying how microglia phagocytose neurons with tau aggregates while neurons are still alive. Indeed, there is active work on-going to identify the roles of microglia in a variety of pathological sates, from Ataxia Teleangiectasia to Parkinson’s disease and schizophrenia, as well as understanding how microglia contribute to the neuroinflammation association with depression and ageing. Similarly, research is also focused on delineating the contribution of astrocytes to neuronal network activity and the roles of astrocytes in conditions, such as epilepsy and amyotrophic lateral sclerosis. One particular condition that has a long history of research success in Cambridge is multiple sclerosis, where the myelin sheath is stripped off nerves in the brain and spinal cord. The drug alemtuzumab [Lemtrada] was developed in Cambridge from the 1990s, being licensed as a treatment in 2013 in the UK, and works by suppressing the patients’ immune systems. Such drugs do not however repair the damage already done. Yet, in adult human brains, there are stem cells [“oligodendrocyte progenitor cells”] that can differentiate into mature cells that make more myelin, but these cells are not activated in people with multiple sclerosis. The Cambridge Centre for Myelin Repair, funded by the UK MS society, is focused on developing treatments that promote myelin repair for people with multiple sclerosis.
There is also a growing centre of pain research in Cambridge across a wide range of pain conditions with strong links between pre-clinical and clinical teams. The driver of pain is activation of sensory neurones tuned to detect noxious stimuli, so called nociceptors, which do not innervate empty space, but rather interact with a variety of different cell types, such as epithelial cells and immune cells, as well as the mediators they release. Recent MRC funding for the ADVANTAGE visceral pain consortium will link up human phenotyping and genotyping with mechanistic studies in rodents to identify key neuroimmune interactions in a variety of chronic pain conditions. The ADVANTAGE consortium aims to improve how we treat people with visceral diseases and better understand the neural basis of the underlying pain. In fact, one in twenty individuals in the UK are disabled by visceral pain arising from conditions such as endometriosis, colitis and kidney disease. Using a translational and interdisciplinary approach, uniting patient experts, clinical and pre-clinical pain researchers, visceral disease experts, psychologists, engineers and industrial collaborators will maximise the development of novel study tools, drugs and treatments – specifically tailored for visceral pain.
Work at the Wellcome-MRC Institute of Metabolic Sciences is far reaching and interdisciplinary at its core. Current work aims to identify new molecules and pathways that play a role in the brain control of energy homeostasis, and thus reveal new potential therapeutic targets to tackle obesity. Genetic studies point to the brain, and in particular the hypothalamus, as having a crucial role in modulating appetitive behaviour. The inaccessibility of the human hypothalamus has, to date, meant our understanding of circuitry controlling food intake has emerged primarily from murine studies. This has resulted in the integrated reference atlas of the mouse hypothalamus called ‘HypoMap’. This represents the most comprehensive database of its kind. It can serve as an important platform to unravel the functional organisation of hypothalamic circuits, and to identify novel druggable targets for treating metabolic disorders.
Researchers are using a multi-disciplinary approach coupling calcium imaging to characterise the neurophysiology of metabolic-sensing neurons, discrete manipulations of brain neurocircuits and nutrient sensing pathways using cutting-edge molecular genetics, and refined functional assessments in behaving rodents to characterize how proteins are detected by the brain to maintain energy homeostasis in health and disease.