Investigating inflammatory and neuronal mechanisms driving cognitive dysfunction in mild traumatic brain injury (concussion)

Concussion, or mild traumatic brain injury (mTBI) 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 mTBI on brain health.

Over the last decade there is a growing literature emerging on how glial cells (microglia and astrocytes) and neuronal populations interact to control normal function and to understand how neuroinflammatory changes may be involved in the progression of a range of neuropsy chiatric and neurodegenerative disorders, a number of which are characterised by cognitive deficits.

In normal brain cognition is highly dependent on a balance between excitation (firing of pyramidal glutamatergic neurons) and inhibition (synchronisation of firing by parvalbumin containing GABAergic interneurons (PVI)). Gamma band oscillations, generated by these PVIs are crucial for maintenance of normal cognition. These interneurons are fast spiking, fast firing, have a high energy demand and as such are particularly susceptible to changes in neuroinflammation and oxidative stress. These interactions in different brains regions of relevance to cognition (e.g. prefrontal cortex & dorsal hippocampus) are now under intense scrutiny as changes in inflammation appear to be key drivers of brain injury, mood disorders and neurodegenerative disease. Understanding these interactions and their relationship over time in validated preclinical models related to TBI will aid in the identification and testing of novel therapeutic (both pharmacological and non-pharmacological (e.g. exercise)) interventions.

In the current project, we will investigate the immune cell response to mTBI in a clinically relevant mouse model. Our overall aims are to:

• Assess the influence mTBI on brain resident immune cells (microglia/astrocyte density and activation), brain tissue inflammation (multiplex cytokine array analysis) and neuronal populations (parvalbumin GABAergic interneurons and associated perineuronal nets)
• Utilise transgenic models and cell-depletion strategies in the mild TBI model. (Complimentary studies will be conducted in the moderate TBI model in Melbourne).
• Target immune and neuronal cell subtypes and functions in the brain to prevent / reverse neuronal and behavioural deficits in mice after mTBI.