Brain region-specific immune responses driving concussion-related injury

Concussion - just a bang on the head?

The term concussion is part of everyday vocabulary. People know that it refers to a pretty severe bang on the head, that may leave the person unconscious for a short period, with a headache and possibly even some memory loss. Many people may have seen a concussion occur, if they watch sports such as rugby and football, but they may not know that most concussions occur due to car accidents and domestic violence. The other thing people may not know is that, in the long-term, concussion may cause mood swings and anxiety, or even problems like dementia in later life. We are beginning to understand that concussion is more dangerous than we thought, though we still don't know why. One issue for scientists is that normal brain scans are not sensitive enough to show any major problems in the brains of people concussion. However, using models of brain injury in mice, our research suggests that we may have been looking in the wrong places. We have seen that a protective membrane around the brain, called the meninges, becomes inflamed after a concussion, as does another area called the cerebellum (latin for 'little
brain'). We do not usually look at these brain areas when someone has a head injury.

Therefore, our work has two major aims:

1) Test in animal models if the inflammation in these two understudied places (the meninges and cerebellum) are responsible for increases in anxiety and reduced brain function after concussion

2) Develop new types of brain scans in people, so we can see these processes in those who have suffered a concussion

We will do this work at the University of Manchester within the world leading Lydia Becker Institute of Immunology and Inflammation in collaboration with neurosurgeons and neuroimaging experts at Salford Royal NHS Foundation Trust.

If successful we hope to find new ways to image the brains of patients and new target areas for therapies against the effects of concussion. This is extremely important as, at the moment, we have little understanding of these processes no treatment options for those affected.

Concussion, or mild traumatic brain injury, affects millions world-wide each year. It is now appreciated that concussion increases the risk of developing long-term emotional and cognitive disorders such as anxiety and depression and neurodegenerative disease. Inflammation is a key regulator of brain injury and preliminary data show that two understudied brain regions, the meninges and cerebellum, may be more sensitive to inflammation and drive concussion-related symptoms.

Aims and objectives
1) Define immune cell-mediated inflammation in the meninges and cerebellum in a mouse model of concussion
2) Investigate if communication between the meninges and cerebellum underlie emotional and neurological disorders in this model
3) Examine meningeal and cerebellar abnormalities in human concussion to provide biomarkers for treatment options

Methodology
We will use a well characterised a clinically relevant model of single and repeated closed-head injury in mice, to investigate the mechanisms of concussive injury. Flow Cytometry, immunofluorescence, Hyperion Imaging Mass Cytometry and RNA-sequencing will define the immune response in the meninges and distinct brain regions, including the cerebellum. Through various pharmacological and genetic cell-specific targeting techniques, we will remove defined immune cell populations from the brain and assess emotional and cognitive behaviours after concussion. Finally, we recruit patients with acute head injury or history of concussion and perform the latest MRI and PET-MRI protocols to assess meningeal and cerebellar abnormalities.

Scientific/Medical opportunities
New imaging protocols will establish diagnostic biomarkers for human concussion. The neuroimmunological mechanisms will be relevant across a broad range of injury and disease, where meningeal inflammation is present. This work will be the foundation of a research program that will include the investigation of concussion as risk for neurodegenerative disease.