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Microglial control of neuronal activity in the healthy and the injured brain

Periodic Reporting for period 4 - MicroCONtACT (Microglial control of neuronal activity in the healthy and the injured brain)

Okres sprawozdawczy: 2021-10-01 do 2023-03-31

Neurological disorders represent a growing burden on society, while therapeutic opportunities are limited. Recent research has highlighted the important role of inflammatory mechanisms in the development and progression of common brain disorders. Our project focuses on the mechanisms through which microglia, the main inflammatory cells of the central nervous system contribute to normal brain function and neuronal injury. We have identified a novel form of interaction between microglia and neurons, which appears particularly important for microglial monitoring of neuronal activity and for microglia-mediated actions shaping neuronal fate in health and disease. We have revealed some of the main molecular pathways that contribute to the formation and maintenance of these structures named somatic microglial junctions, which are very common in both the mouse and the human brain. Blockade of microglial junction formation leads to increased neuronal loss after acute brain injury induced by stroke. We reveal that these compartment-specific microglia-neuron interactions are already essential for developing neurons and show major changes in different forms of brain disorders and in old age. In line with this, we show that microglia also interact with different cell types around cerebral blood vessels and regulate cerebral blood flow in both the healthy and the injured brain. The contribution of microglial inflammatory responses to limiting the spread of viral infections in the brain and to the maintenance of chronic pain have also been revealed. Collectively, our data suggest that via targeted modulation of microglial responses it may be possible to shape the outcome of diverse neurological disorders. Further research is required to understand the complex interactions between microglia, neurons and blood vessels that are influenced by diverse inflammatory processes. These efforts may facilitate the development of novel therapeutic strategies to treat neurological disorders.
We have established and developed several novel approaches to modulate microglial actions and inflammatory processes in the brain. These include advanced animal models allowing the elimination of key proinflammatory molecules from different cell types in the brain (microglia, neurons, endothelial cells) and selective pharmacological or genetic manipulation of microglia. In line with this, we use the latest imaging technologies combined with high resolution microscopy and a broad range of cellular / molecular biology approaches to uncover the molecular mechanisms through which microglia shape neuronal and vascular responses in health and disease. Advanced histological methodologies have also been developed, to study inflammatory processes and microglial actions in human brain tissues from patients with different neurological diseases. Collectively, we have revealed novel mechanisms through which microglia shape neuronal injury, inflammation and cerebral blood blow in both the healthy brain and in different forms of neuropathologies. These efforts may help us to understand the clinical relevance of our experimental findings and to identify novel therapeutic targets.
TThe research project successfully explored some of the main molecular pathways whereby microglia shape neuronal fate at different types of compartment-specific interaction sites, including the molecular anatomy and functioning of the newly identified somatic purinergic junctions. We have also explored how microglia regulate cerebral blood flow, neurovascular coupling and adaptation to hypoperfusion in the brain. We reveal how microglia-neuron and microglia-vascular interactions change under pathological conditions. The research program also involved the development and characterisation of novel research tools to shape microglial activity in real time by using chemogenetic and optogenetic approaches. The effect of modulation of microglial actions have been tested on several experimental models of neuroinflammation and brain injury, allowing the identification of novel therapeutic targets. Collectively, this research program provides better understanding of how inflammatory processes impact on the brain and revealed disease mechanisms that can be therapeutically targeted.
Molecular anatomy of somatic purinergic microglia-neuron junctions