Could dark microglia remodel the extracellular matrix?

Microglia, the brain’s resident immune cells, play an important role in regulating a person’s brain function and behaviour throughout their lifetime. More specifically, these cells are essential regulators of synaptic plasticity – the ability for brain connections to change, which is fundamental to learning and memory – and behaviour. This ability may become compromised with chronic stress, thus leading to behavioural alterations and cognitive impairment. Among the underlying mechanisms, in addition to directly removing synaptic connections through their phagocytosis, microglia were shown to remodel the extracellular matrix (ECM), a structure that binds together the brain cells and their compartments. This remodelling of the ECM could underlie microglia’s role in learning, memory, and behaviour. It’s possible that chronic stress could compromise this process.

Using a new NSERC Discovery Grant, Dr. Marie-Ève Tremblay (pictured) and her research team, including students Jared VanderZwaag (PhD student) and Antonia Landwehr (MSc student), plan to find out whether dark microglia – a specific form of the immune cell – remodel the ECM in the context of chronic stress. This work is conducted in collaboration with Dr. Laura Maggi at the Sapienza University of Rome and Dr. Sandra Siegert at the Institute of Science and Technology Austria.

Previous studies from the Tremblay lab suggest dark microglia are abundant and active in youth during brain development, which is when brain connections form and remodel. This activity is normal, and the cells seem to disappear when they’re no longer needed. However, dark microglia are not as common in adults. The cells tend to increase in number after exposure to environmental triggers, such as chronic stress, and this increase seems to correlate with disease, neuropsychiatric and neurodegenerative disorders, and other pathology associated with synaptic loss and cognitive impairment.

Tremblay and her team hypothesize that like normal microglia, dark microglia will regulate the state of lattice-like structures in the ECM called perineuronal nets (PNNs) through their dynamic remodelling. When controlled by normal microglia, this remodelling would ensure a tight balance between plasticity and scaffold maintenance in the adult brain. However, it’s possible that exacerbated or misguided remodelling by dark microglia (which could happen after someone was exposed to chronic stress) will alter the delicate PNNs balance and lead to changes in behaviour and synaptic plasticity across sexes and brain regions.

The lab will use multiple technologies—including multi-modal microscopy, in situ and in vivo electrophysiology, and microglial multi-omics—to test their theory in multiple regions of the brain. In the short term, this work will determine how different states of microglia remodel the brain while under normal and stressful physiological conditions. In the long term, this research program will provide an in-depth understanding of the roles of microglia (including dark microglia) in mediating synaptic plasticity and behaviour, and it will accelerate the development of tools to selectively study the roles and functions of different microglial states.