Sex-specific modulation of neurobehavioral outcomes - The intersection of sex steroids, gut peptides, and behavior

Abstract

Despite ample evidence indicating that psychiatric disorders and their symptoms exhibit significant differences based on sex, research on their underlying mechanisms in females has historically been limited. This thesis examines how sex steroids and gut peptides like ghrelin regulate anxiety and aggression, with an emphasis on sex-specific mechanisms. In Paper I, we found that standard tests of anxiety-like behavior lack predictive validity for human sex differences. While female rats appeared less anxious in standard tests of anxiety-like behavior, they exhibited heightened startle responses, better aligning with human data and suggesting limitations in existing models. In Paper II, we found that the ghrelin system is sexually dimorphic. Female rats had higher circulating ghrelin levels, lower Leap-2 expression, and increased ghrelin receptor expression in key brain regions involved in anxiety and feeding. Increased ghrelin signaling via fasting and exogenous application also reduced anxiety more effectively in females. In Paper III we demonstrated that both male and female rats developed conditioned place preference for winning aggressive encounters, with aggression-induced dopamine release in the nucleus accumbens more pronounced in females. Blocking dopamine D1 receptors abolished this effect in both sexes, overall suggesting that male and female rats experience winning aggressive interactions as rewarding. Finally, we explored the role of central estrogen synthesis in aggression in Paper IV. Aromatase knockdown in the central amygdala increased aggression in females but not males, specifically after loss of circulating ovarian hormones via gonadectomy. It also increased anxiety-like behavior, suggesting a dampening effect of estrogen on both behaviors. Overall, the findings of this thesis highlight critical sex differences in neurobehavioral regulation and underscore the need for sex-specific considerations in preclinical research and therapeutic development.