Stress-testing the brain

Microglia, the brain’s immune cells, are meant to protect and help develop the connections in our brains. Occasionally, they go rogue and harm us instead.

Marie-Ève Tremblay, associate professor in the University of Victoria’s Division of Medical Sciences, is on the leading edge of understanding exactly what causes our brain's immune cells to change so drastically and how this affects our cognitive function.

“We think that environmental and lifestyle risk factors like stress and poor diet can cause them to malfunction,” says Tremblay, Canada Research Chair of Neurobiology of Aging and Cognition. “This is really problematic. It can lead to loss of memory and other major outcomes on cognition.”

In a recent article published in Nature Communications, Tremblay worked with international collaborators to show that omega-3 deficiency in pregnant people can cause microglia to destroy neurological connections important for memory development in offspring. Her previous work has shown that psychological stress can similarly influence microglia throughout a person’s life, leading to the learning, memory and other cognitive deficits we see in schizophrenia, autism, depression and neurodegenerative diseases like Alzheimer’s, Parkinson’s and other forms of dementia.

When we are stressed psychologically, our cells are also stressed, so it’s possible to see a lot of alterations within them.
—Marie-Ève Tremblay, associate professor in UVic's Division of Medical Sciences

Tremblay adds it's these alterations that could cause microglia to change their function and cause us harm.

“Stressed microglia also emerge with exposure to other risk factors shared among diseases, like lack of physical activity,” Tremblay adds. Her research team is currently studying the effects of sleep disturbances, cigarette smoke and viral infection.

Fortunately, their research has found evidence that changes in lifestyle could help prevent, and possibly even revert, the immune cells’ alterations and fix the damage already caused. “We think that if we can normalize the cells, it will be beneficial overall,” she says. “We don’t want to kill microglia or prevent them from doing their normal functions at synapses, which are the connections between neurons in the brain. If we do, there will be other issues with learning and memory.”

These lifestyle changes include following a low carb or ketogenic diet, omega-3 supplementation and doing stress-relieving activities like exercise and socializing. The team is researching other potential therapies like cannabinoids, probiotics and exposure to nature and this list could expand as new members continue to bring their own interests and expertise to the mix.

“We want to see how we can prevent harmful microglia with something simple—not just a pharmaceutical treatment, but something everyone can implement quite easily,” she says.

Tremblay also plans to study the combined effects of ageing and lifestyle risk factors like the examples noted above. She hopes this work will result in therapies that help avoid the development of neurodegenerative diseases like Alzheimer’s, Parkinson’s and other forms of dementia—essentially making everyone “SuperAgers.”

EdgeWise

Microglia are the central nervous system’s first and foremost line of defence. These highly active cells patrol our brains, clearing away waste, injured cells, microbes and other threats by “eating” them.

Microglia also help with the normal rewiring of our brain by eating away unnecessary or weak connections between neurons in a process known as pruning. Issues arise when stressed microglia prune away the wrong connections (or simply too many of them).

Researchers must use electron microscopes to study stressed microglia as they haven’t identified the specific protein markers needed to use conventional cellular and molecular biology techniques.

The Tremblay lab will soon receive a unique-to-Canada electron microscope funded by the Canada Foundation for Innovation (CFI) and the BC government. The microscope can produce 3D images, in addition to the usual 2D, at nanometre resolution. This will allow the team to see whole stressed microglia and study exactly how they function and change their interactions with synapses with different therapies.

The lab also uses two-photon in-vivo microscopy, a non-invasive technique that allows researchers to see into a living brain through the skull. This gives them a view of microglial behaviour in a normal, undisturbed environment.

Tremblay’s research is supported by CFI, Natural Sciences and Engineering Research Council of Canada and the Canadian Institutes of Health Research.