Immune cells at the blood-brain interface driving concussion-related symptoms

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Concussion, or mild traumatic brain injury, affects millions world-wide each year due to motor accidents, falls, assaults, domestic violence, contact sports and war. It is now appreciated that a history of concussion increases the risk of developing long-term emotional and neurocognitive disorders. These include anxiety and depression, as well as neurodegenerative conditions such as Alzheimer's. Critically, we do not know the mechanisms behind long-term negative effects of concussion on brain health.Recent advances in the field of neuroimmunology have opened up our understanding of the connection between the central nervous system and inflammation. The following project will investigate the role of infiltrating immune cells within critical structures at the blood-brain interface and how they contribute to concussive symptoms. We hypothesise that immune responses at these interfaces are key to concussive symptoms after head injury. The interfaces between the periphery and the brain are now under intense scrutiny as hubs of inflammation and potential drivers of brain injury, mood disorders and neurodegenerative disease. Two of the key blood-brain interfaces are the meninges and the choroid plexus. The meninges are a set of protective membranes that surround the brain and the choroid plexus is a structure that produces cerebrospinal fluid and is essential for a variety of brain function. Recent data has shown that the meninges and choroid plexus contain immune cells that are proposed to play important functions in the brain. Surprisingly, little is known of the role of the choroid plexus or meninges and the immune cells within them in concussion.To address this, the project will investigate the role of innate and adaptive lymphocytes in the response to concussive injury in a clinically relevant mouse model. T cells and Innate Lymphoid Cells (ILCs) are potent regulators of the immune response, and are emerging as key players in neuroinflammation while residing in the meningeal membranes and choroid plexus. Moreover, danger signals and soluble factors known to activate lymphocytes, including ILCs, are also known to regulate brain function and recovery after injury, though it remains unknown how lymphocytes contribute to concussion-related symptoms.We predict that a concussive-symptoms are driven by lymphocyte-dependent inflammation in the meninges and choroid plexus and can be targeted to improve outcome after injury. This interdisciplinary project is at crossroads of neuroscience and immunology, reflected by the modelling of brain injury and assessment of emotional behaviour and cognition, while investigating fundamental immune mechanisms driving behavioural deficits.