Brain Star Award winner Katarzyna Anna Dudek

Identification of a cannabinoid receptor as target to promote resilience in major depressive disorders

One out of every five people will suffer from major depressive disorder (MDD) in their lifetime, and about 30-50% of individuals with depression are unresponsive to commonly prescribed antidepressant treatments, suggesting that biological mechanisms remain untreated. Recent evidence suggests that the blood-brain barrier, which is responsible for regulating molecular exchange between the periphery and the brain, is altered in MDD and by chronic stress, which is the main environmental risk factor for depression. A new study by Katarzyna Anna Dudek, working in the laboratory of Caroline Ménard at Université Laval, identified a brain receptor for cannabinoids that promotes resilience by dampening stress induced blood-brain barrier alterations.

The blood-brain barrier (BBB) is the ultimate frontier between the brain and inflammatory signals circulating in the blood. Depression pathology and vulnerability to chronic stress are associated with loss of BBB integrity in brain regions key for mood regulation, such as the nucleus accumbens (NAc) and prefrontal cortex (PFC). The proper function of the endocannabinoid system   is crucial for stress response adaptation, while its disruption has been implicated in depressive symptoms in both clinical and preclinical settings. This study identified a protein called astrocytic cannabinoid receptor 1 (Cnr1) as being perfectly positioned to modulate BBB properties during stress exposure and mood disorders, yet it remained understudied. Katarzyna Anna Dudek’s innovative approach used a well-established mouse chronic social defeat (CSDS) paradigm, enabling her to study BBB-related mechanism leading to pathology or positive stress adaptation. Her work revealed that stress resilience in mice is linked to sex-specific regional increase of Cnr1 expression near blood vessels (in the Nucleus Accumbens in males, and in the prefrontal cortex in females). Accordingly, rescue interventions with physical exercise and antidepressant treatment were associated with increased regional Cnr1 expression in mice. Change in CNR1 expression was validated in postmortem human brain samples from individuals with MDD, adding translational value. These findings support an active role of the BBB, via astrocyte endocannabinoids, in stress resilience.

Challenging existing paradigms, this study focused on identifying biological determinants of resilience to provide new insights into disease mechanisms and identify novel therapeutic targets.  This research has contributed to a revised understanding of the importance of neurovascular health and stress resilience in the context of stress-related mood disorders, impacting subsequent research and the trajectory of the field. Neurovascular health and endocannabinoid system are at the nexus of depression pathology and represent a promising drug target. By understanding how chronic stress regulates endocannabinoids and blood-brain barrier function to ultimately promote stress susceptibility or resilience, we may be able to augment current antidepressant treatments and identify new avenues for biological interventions. Importantly, these results complement evidence suggesting that chronic stress affects the neurovasculature in a sex-specific manner, which may contribute to better understanding of sex differences reported in MDD prevalence, symptoms, and treatment response.

The estimated cost for depression is $30 billion/year in Canada. By developing preventive treatment strategies, based on resilience research, we can improve health of Canadian women and men.

This research has been covered by major national and international news outlets, including The Washington Post, Forbes and ICI Radio-Canada, and work has been named one of the discoveries of the year by Radio-Canada Quebec. This work raises awareness toward the need to understand not only depression pathology but also positive adaptations resulting in stress resilience and their potential in the development of preventive therapies.

About Katarzyna Anna Dudek

I am a postdoctoral researcher affiliated with the Hotchkiss Brain Institute at the University of Calgary.  In my work I aim to elucidate the role of the endocannabinoid system in regulation of neurovascular health, crucial for proper brain function , and its potential in promoting stress resilience. The subject is vastly understudied which makes the project both exciting and challenging. The strength of my approach is a reverse translational strategy in which studying stress responses in animal models enables me to unravel novel biological mechanisms underlying stress-related disorders. By understanding how stress-induced changes in endocannabinoid tone affect brain vasculature, neuroinflammation and subsequently central nervous system homeostasis we may augment current therapies or reveal novel biomarkers of mood disorders.

Sources of funding

This research was supported by the Brain Canada Foundation (2019 Future Leaders in Canadian Brain Research), Canadian Institutes for Health Research (CIHR, project grant 427011 to C. Menard), Fonds de recherche du Quebec—Sante (FRQS, Junior 1 Salary Award to Caroline Menard) and Caroline Menard Sentinel North Research Chair funded by Canada First Research Excellence Fund. Caroline Menard is also supported by grants from the European Research Council (Retina-Rhythm), the Irish Research Council and an SFI Centres grant supported in part by a research grant from SFI under grant 16/RC/3948 and cofunded under the European Regional Development Fund by FutureNeuro industry partners. The Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis awarded to Vincenzo Di Marzo is funded by the Canadian Federal Tri-Agency. Katarzyna A. Dudek, Sam E. J. Paton, Luisa Bandeira Binder, Adeline Collignon, Laurence Dion-Albert, Alice Cadoret, Manon Lebel, Olivier Lavoie, Jonathan Bouchard and Fernanda Neutzling Kaufmann are supported by scholarships or fellowships from CIHR, FRQS, the Natural Sciences and Engineering Research Council of Canada and NeuroQuebec. The Douglas-Bell Canada Brain Bank is funded by the RQSHA (FRQS) and platform support grants from Brain Canada and Healthy Brain Healthy Lives (Canada First Research Excellence Fund).