Chronic variable mild stress alters the transcriptome and signaling properties of the anterodorsal bed nuceleus of the stria terminalis in a sex-dependent manner
Chronic stress is a physiological state marked by dysregulation of the hypo-pituitary-adrenal axis and high circulating levels of stress hormones, such as corticosterone in mice or cortisol in humans. This dysregulated state may result in the development of mood disorders but the process by which this occurs is still unknown. The bed nucleus of the stria terminalis (BNST) serves as an integration center for stress signaling and is therefore likely an important area for the development of mood disorders. This project utilized a chronic variable mild stress (CVMS) paradigm to persistently stress mice for 6 weeks followed by RNA-Sequencing of the anterodorsal (ad) BNST and electrophysiology of corticotropin releasing hormone-expressing cells in the adBNST. Our results show significant sex-biases in the transcriptome of the adBNST as well as effects of CVMS on the transcriptome of the adBNST specifically in males. Female biased genes are related to synaptic transmission while male biased genes are related to RNA processing. Stress sensitive genes in males are related to synaptic transmission and synapse formation. Additionally, electrophysiology data showed that CVMS suppressed the M-current in males but not females. However, CVMS increased the strength of excitatory post-synaptic currents in females but not males. This suggests significant differences in how males and females process chronic stress. It also suggests that the BNST is more sensitive to chronic stress in males than in females. Overall design: At 7-9 weeks of age, male and female mice were selected for either control conditions or chronic variable mild stress (CVMS). This resulted in 4 experimental groups with 15 mice each. After CVMS or control conditions, mice were anesthetized with ketamine, then the brain was dissections, sliced, and microdissected to isolate the anterodorsal bed nucleus of the stria terminalis. This occured 1 hour after the last stressor in CVMS mice, which was wet bedding. Tissue samples from 3 biological replicates were then pooled prior to RNA extraction. RNA-Sequencing had a sample size of n=5 for each group with no outliers.