Chronic social instability stress differentially affects the behavior and the transcriptome of the anterodorsal bed nucleus of the stria terminalis between male and female mice

Abstract

Abstract Stress is comprised of systemic/physiological and processive/social factors, with social stressors requiring higher limbic processing. Sex is an important aspect of stress research as men and women show differing responses to stress and mood disorder development. We investigated how social stress affects the bed nucleus of the stria terminalis (BNST) and how sex may contribute. We used a chronic social instability stress (CSIS) paradigm to stress male and female mice for approximately 7 weeks. Afterwards, one cohort was used for avoidance behavior testing using the open field test, the elevated plus maze, the light/dark box emergence test, and the novelty suppressed feeding test. A second cohort was used for bulk RNA-sequencing of the anterodorsal (ad)BNST. A third cohort of CRH Cre+/Ai14 reporter mice were used for patch clamp electrophysiology in the adBNST. CSIS caused the females to be less avoidant, while the males became more avoidant. Low estrogen state in the females caused them to be less avoidant than in a high estrogen state. In the adBNST, we found major transcriptomic differences between the males and females. Males increased expression in more genes related to the RNA and protein processing whereas the females upregulated genes related to synaptic transmission. The transcriptome in the males is more sensitive to the stress than the females. Finally, CSIS caused adBNST CRH neurons to be hyperpolarized and have lower input resistance in males. In summary, social stress is differentially regulated between males and females, which may relate to the development of stress-related behavioral changes.