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Improving the resolution of Neuroinflammation during repetitive mild Traumatic Brain Injury with dietary fatty acid Derivatives

Periodic Reporting for period 1 - INBID (Improving the resolution of Neuroinflammation during repetitive mild Traumatic Brain Injury with dietary fatty acid Derivatives)

Reporting period: 2018-11-01 to 2020-10-31

Historically, the two major ‘systems’ of the body were divided into nervous and immune. The former containing the electrical wiring governing our senses and our mind, the latter consisting of mobile defence cells ready to fight infection, disease and injury. Little did we know that our nerves and immune cells are so intertwined that their roles are dependent on one another. Microglia, the brain’s resident immune cells are now known to be involved in a host of brain functions, including development, neuronal function and protection from - or propagation of - disease. Recent evidence also shows that the higher functions of mammalian brains, those that manage emotions such as anxiety, and social behaviour and memory, can even be affected by mobile immune cells that have travelled to the edges of the brain. Here, immune cells do not enter the brain tissue itself, but reside in different structures bordering the brain and release factors that can change the way nerves work, and as a result, how animals behave. In certain circumstances, the brain may become inflamed, due to an injury or disease. This can even happen in ‘mild’ injuries such as a bang to the head, resulting in mild traumatic brain injury or concussion.

Concussion affects millions of people world-wide each year due to accidents, assaults, domestic violence, contact sports and war. These injuries increase the risk of developing mental health issues such as long-term anxiety and depression and neurodegenerative diseases such as Alzheimer's. Repeated head injury is particularly dangerous. Therefore, understanding the mechanisms that underpin these problems is critical to treating brain injury and disease.

Overall objectives of the work

1) Define the immune-mediated brain inflammation in mouse model of brain injury

2) Develop approaches to promote the resolution of brain inflammation in response to brain injury, with a special focus on dietary lipids as beneficial agents.
We have developed and characterised a clinically relevant model of single and repeated closed-head injury which produces acute neurological symptoms, meningeal inflammation, region-specific microglial activation and emotional and cognitive deficits that persist for one week and continue for 30 days after injury, in adult mice.

This model is currently being used to assess various treatments for disrupted emotional and cognitive behaviour, including the use of different types of diet.

The experiments are ongoing but, if validated, the findings may change the way brain damage is assessed in the clinic after a head injury.
We have made several novel discoveries, some of which have been unexpected and therefore all the more exciting. Our results point to brain region-specific changes after mild brain injury. These studies indicate that certain areas within the brain are underappreciated in terms of their relevance to patient wellbeing after injury. As a result, we envisage the establishment of new imaging protocols that could provide diagnostic biomarkers for human concussion.

Such translational work would sit at the crossroads of neuroscience and immunology, investigating a brain injury as a cause of mental health issues that may be driven by fundamental immune mechanisms. These neuroimmunological mechanisms will be relevant across a broad range of injury and disease. This may be the foundation of a long-term research program that could change how mild brain injuries are diagnosed and treated.