Chronic stress and its effects on behavior, RNA expression of the bed nucleus of the stria terminalis, and the M-current of NPY neurons.

Mood disorders, like major depressive disorder, can be precipitated by chronic stress and are more likely to be diagnosed in cisgender women than in cisgender men. This suggests that stress signaling in the brain is sexually dimorphic. We used a chronic variable mild stress paradigm to stress female and male mice for 6 weeks, followed by an assessment of avoidance behavior: the open field test, the elevated plus maze, the light/dark box emergence test, and the novelty suppressed feeding test. Additional cohorts were used for bulk RNA-Sequencing of the anterodorsal bed nucleus of the stria terminalis (adBNST) and whole-cell patch clamp electrophysiology in NPY-expressing neurons of the adBNST to record stress-sensitive M-currents. Our results indicate that females are more affected by chronic stress as indicated by an increase in avoidance behaviors, but that this is also dependent on the estrous stage of the animals such that diestrus females show more avoidant behaviors regardless of stress treatment. Results also indicate that NPY-expressing neurons of the adBNST are not major mediators of chronic stress as the M-current was not affected by treatment. RNA-Sequencing data suggests sex differences in estrogen signaling, serotonin signaling, and orexin signaling in the adBNST. Our results indicate that chronic stress influences behavior in a sex- and estrous stage-dependent manner but NPY-expressing neurons in the BNST are not the mediators of these effects.

Deletion of Growth Hormone Secretagogue Receptor in Kisspeptin Neurons in Female Mice Blocks Diet-Induced Obesity.

The gut peptide, ghrelin, mediates energy homeostasis and reproduction by acting through its receptor, growth hormone secretagogue receptor (GHSR), expressed in hypothalamic neurons in the arcuate (ARC). We have shown 17ß-estradiol (E2) increases Ghsr expression in Kisspeptin/Neurokinin B/Dynorphin (KNDy) neurons, enhancing sensitivity to ghrelin. We hypothesized that E2-induced Ghsr expression augments KNDy sensitivity in a fasting state by elevating ghrelin to disrupt energy expenditure in females. We produced a Kiss1-GHSR knockout to determine the role of GHSR in ARC KNDy neurons. We found that changes in ARC gene expression with estradiol benzoate (EB) treatment were abrogated by the deletion of GHSR and ghrelin abolished these differences. We also observed changes in metabolism and fasting glucose levels. Additionally, knockouts were resistant to body weight gain on a high fat diet (HFD). Behaviorally, we found that knockouts on HFD exhibited reduced anxiety-like behavior. Furthermore, knockouts did not refeed to the same extent as controls after a 24 h fast. Finally, in response to cold stress, knockout females had elevated metabolic parameters compared to controls. These data indicate GHSR in Kiss1 neurons modulate ARC gene expression, metabolism, glucose homeostasis, behavior, and thermoregulation, illustrating a novel mechanism for E2 and ghrelin to control Kiss1 neurons.