Behavioral response to fluoxetine in both female and male mice is modulated by dentate gyrus granule cell activity.

Depression is a complex psychiatric disorder that is a major burden on society, with only ~33% of depressed patients attaining remission upon initial monotherapy with a selective serotonin reuptake inhibitor (SSRI). In preclinical studies using rodents, chronic stress paradigms, such as chronic corticosterone and social instability stress, are used to induce avoidance behaviors associated with negative affective states. Chronic fluoxetine (FLX; an SSRI) treatment reverses these chronic stress-induced behavioral changes in some, but not all mice, permitting stratification of mice into behavioral responders and non-responders to FLX. We previously reported that 5-HT1A receptors, which are Gi-coupled inhibitory receptors, on mature granule cells (GCs) in the dentate gyrus (DG) are necessary and sufficient for the behavioral, neurogenic, and neuroendocrine response to chronic SSRI treatment. Since inhibition of mature DG GCs through cell autonomous Gi-coupled receptors is critical for mounting an antidepressant response, we assessed the relationship between behavioral response to FLX and DG GC activation in FLX responders, non-responders, and stress controls in both male and female mice. Intriguingly, using disparate stress paradigms, we found that male and female behavioral FLX responders show decreased DG GC activation (as measured by cFos immunostaining) relative to non-responders and stress controls. We then show in both sexes that chronic inhibition of ventral DG GCs (through usage of Gi-DREADDs) results in a decrease in maladaptive avoidance behaviors, while ventral DG GCs stimulation with Gq-DREADDs increases maladaptive behaviors. Finally, we were able to bidirectionally control the behavioral response to FLX through modulation of DG GCs. Chronic inhibition of ventral DG GCs with Gi-DREADDs converted FLX non-responders into responders, while activation of ventral DG GCs with Gq-DREADDs converted FLX responders into non-responders. This study illustrates ventral DG GC activity is a major modulator of the behavioral response to FLX in both male and female mice.

Chronic non-discriminatory social defeat is an effective chronic stress paradigm for both male and female mice.

Stress-related mood disorders are more prevalent in females than males, yet preclinical chronic stress paradigms were developed in male rodents and are less effective in female rodents. Here we characterize a novel chronic non-discriminatory social defeat stress (CNSDS) paradigm that results in comparable stress effects in both sexes. Male and female C57BL/6J mice were simultaneously introduced into the home cage of resident CD-1 aggressors for 10 daily 5-min sessions. CD-1 aggressors attacked males and females indiscriminately, resulting in stress resilient and susceptible subpopulations in both sexes. CD-1 aggressors attacked C57BL/6J male intruders faster and more frequently than female intruders. However, CNSDS similarly induced negative valence behaviors in SUS mice of both sexes relative to RES and CNTRL mice. Furthermore, SUS male and female mice displayed similar increases in plasma corticosterone levels following CNSDS exposure relative to pre-stress exposure levels. The estrous cycle did not impact CD-1 attack behavior or negative valence behaviors. Thus, CNSDS induces chronic stress behavioral and neuroendocrine effects in both male and female C57BL/6J mice and allows direct comparisons between sexes. Adoption of this modified social defeat paradigm will help advance the initiative to include female rodents in preclinical chronic stress research.