Cannabinoid receptor 1 signalling modulates stress susceptibility and microglial responses to chronic social defeat stress

• Published in: Translational psychiatry Vol. 11; no. 1; p. 164
• Main Authors: Beins, Eva C., Beiert, Thomas, Jenniches, Imke, Hansen, Jan N., Leidmaa, Este, Schrickel, Jan W., Zimmer, Andreas
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15-03-2021; Nature Publishing Group
• Subjects: 13; 13/21; 13/31; 13/51; 14; 14/63; 38; 631/378/340; 631/443; 64/60; Animals; Behavioral Sciences; Biological Psychology; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; Microglia; Neurosciences; Pharmacotherapy; Pituitary-Adrenal System; Psychiatry; Receptor, Cannabinoid, CB1 - genetics; Receptors, Cannabinoid; Social Defeat; Stress, Psychological
• ISSN: 2158-3188; 2158-3188
• DOI: 10.1038/s41398-021-01283-0

Psychosocial stress is one of the main environmental factors contributing to the development of psychiatric disorders. In humans and rodents, chronic stress is associated with elevated inflammatory responses, indicated by increased numbers of circulating myeloid cells and activation of microglia, the brain-resident immune cells. The endocannabinoid system (ECS) regulates neuronal and endocrine stress responses via the cannabinoid receptor 1 (CB1). CB1-deficient mice (
Cnr1
−/−
) are highly sensitive to stress, but if this involves altered inflammatory responses is not known. To test this, we exposed
Cnr1
+/+
and
Cnr1
−/−
mice to chronic social defeat stress (CSDS).
Cnr1
−/−
mice were extremely sensitive to a standard protocol of CSDS, indicated by an increased mortality rate. Therefore, a mild CSDS protocol was established, which still induced a behavioural phenotype in susceptible
Cnr1
−/−
mice. These mice also showed altered glucocorticoid levels after mild CSDS, suggesting dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis. Mild CSDS induced weak myelopoiesis in the periphery, but no recruitment of myeloid cells to the brain. In contrast, mild CSDS altered microglial activation marker expression and morphology in
Cnr1
−/−
mice. These microglial changes correlated with the severity of the behavioural phenotype. Furthermore, microglia of
Cnr1
−/−
mice showed increased expression of
Fkbp5
, an important regulator of glucocorticoid signalling. Overall, the results confirm that CB1 signalling protects the organism from the physical and emotional harm of social stress and implicate endocannabinoid-mediated modulation of microglia in the development of stress-related pathologies.