Gut-based reelin could play a role in stress-related disorders like depression

Depression is the leading cause of disability worldwide, affecting approximately 16 per cent of the population at some point in their lives. While many people use antidepressants to ease their symptoms, these treatments don’t work for everyone. In fact, about one third of patients who take them do not show adequate symptom remission.

There is a need for alternative solutions, and master’s student Ciara Halvorson (pictured; Caruncho Lab) is helping search for them using her new Canada Graduate Scholarship – Master’s (CGS-M) from the Natural Sciences and Engineering Research Council of Canada (NSERC). She isn’t focusing her research on the brain, however; she’s looking at the gut.

Chronic stress is a major risk factor for depression, and researchers are increasingly linking stress-related disorders with gut disfunction. However, “there remains much to be discovered in terms of the mechanisms underlying this relationship and the implications for treatment development,” Ciara explains. 

Her project is exploring these mechanisms through a protein called reelin, which helps regulate and renew the gut lining every few days. Ciara will simulate chronic stress conditions in preclinical models to see how it affects the protein’s expression and function in the small intestine. If she finds anything, this study will provide the first evidence of reelin-related disturbances in the gut under chronic stress conditions.

Ciara says that if stress causes intestinal reelin levels to decrease, this decrease could lead to a disruption in the gut lining renewal process. When the gut lining is not regenerated properly, the gut become more permeable and “leaks.” As previous research suggests a leaky gut could contribute to immune system activation and other issues, possibly including stress-related disorders.

Ciara is focusing on reelin as it is also found in the brain, where decreased levels of the protein are already connected to psychiatric disorders. In the brain, reelin ensures proper brain organization during development and continues to modulate neuron structure and circuitry in the brain during adulthood. Previous studies have shown that increased levels of the stress hormone corticosterone decrease brain reelin levels, leading to alterations in brain neurochemistry that render preclinical models more vulnerable to developing depressive-like symptoms.

In her study, Ciara will also look at how intestinal reelin affects other proteins connected with gut health and/or depression. One of these is caspase-3, an enzymes that helps initiate programmed cell death, which is a process that can offer insight into issues potentially causing improper regeneration of the gut lining. She will also look at serotonin transporter as serotonin, which is mainly produced in the gut, is heavily implicated in the development of depression. Finally, she will look at the glucocorticoid receptor, which binds to cortisol, influencing digestive processes and gut barrier integrity.

CGS-M awards are administered jointly by Canada’s three granting agencies: NSERC, the Canadian Institutes of Health Research, and the Social Sciences and Humanities Research Council. These awards are highly competitive and are designed to support research excellence, innovation, and impact in the health field.