Sexual differentiation of neural mechanisms of stress sensitivity during puberty.

Anxiety disorders are a major public health concern and current treatments are inadequate for many individuals. Anxiety is more common in women than men and this difference arises during puberty. Sex differences in physiological stress responses may contribute to this variability. During puberty, gonadal hormones shape brain structure and function, but the extent to which these changes affect stress sensitivity is unknown. We examined how pubertal androgens shape behavioral and neural responses to social stress in California mice (Peromyscus californicus), a model species for studying sex differences in stress responses. In adults, social defeat reduces social approach and increases social vigilance in females but not males. We show this sex difference is absent in juveniles, and that prepubertal castration sensitizes adult males to social defeat. Adult gonadectomy does not alter behavioral responses to defeat, indicating that gonadal hormones act during puberty to program behavioral responses to stress in adulthood. Calcium imaging in the medioventral bed nucleus of the stria terminalis (BNST) showed that social threats increased neural activity and that prepubertal castration generalized these responses to less threatening social contexts. These results support recent hypotheses that the BNST responds to immediate threats. Prepubertal treatment with the nonaromatizable androgen dihydrotestosterone acts in males and females to reduce the effects of defeat on social approach and vigilance in adults. These data indicate that activation of androgen receptors during puberty is critical for programming behavioral responses to stress in adulthood.

Cognitive development from infancy to young adulthood in common marmosets (Callithrix jacchus): Effect of age, sex, and hormones on learning and affective state.

Studies looking at individual variability in cognition have increased in recent years. We followed 43 marmosets (21 males, 22 females) from infancy to young adulthood. At 3-months old, marmosets were trained to touch a rewarded stimulus. At 9-, 15-, and 21-months old, they were given visual discrimination and cognitive bias tests, and urine samples were collected to examine hormone levels. Marmosets were significantly more successful learners at 15 months than 9 months. Individuals who were more successful learners at 9 months were also more successful at 15 months, with more male learners than expected at 15 months. At 9 months, learning success was associated with higher cortisol levels. At 15 months, males with higher estradiol levels were more successful learners, whereas at 21 months, females with higher estradiol and cortisol levels tended to be less successful learners and more pessimistic. Nine months, therefore, appears to be an important developmental timepoint for acquiring cognitive control, which has developed by 15 months. Steroids may have differential effects on each sex, with complex interactions between gonadal and adrenal hormones having an influence on cognitive function over the lifespan. This longitudinal study offers new insight into cognition, including its development and biological underpinnings.

Key Considerations for Studying the Effects of High-Fat Diet on the Nulligravid Mouse Endometrium.

The obesity epidemic continues to increase, with half of US women predicted to be obese by 2030. Women with obesity are at increased risk for not only cardiovascular and liver disease, but also reproductive disorders. Although mouse models are useful in studying the effects of obesity, there is inconsistency in obesity-induction methods, diet composition, and mouse strains, and studies using female mice are limited. In this study, we sought to compare the effects of a 45% high-fat diet (HFD) versus a 60% HFD on the uterine estrous cycle of nulligravid C57BL/6J mice. For 22 weeks, we placed a total of 20 mice on either a 60% HFD, 45% HFD, or each HFD-matched control diet (CD). Both HFDs produced significant weight gain, with 60% HFD and 45% HFD gaining significant weight after 2 weeks and 15 weeks, respectively. Additionally, both HFDs led to glucose intolerance, fatty liver, and adipocyte hypertrophy. Mice fed 60% HFD displayed hyperphagia in the first 12 weeks of HFD treatment. Moreover, 60% HFD-treated mice had a longer estrous cycle length and an increased percentage of estrus stage samplings compared to CD-treated mice. Estrous cycle stage-controlled 60% HFD-treated mice displayed an increased estrogen-to-progesterone ratio and decreased ovarian corpora lutea compared to CD-treated mice, which may underlie the observed estrous cycle differences. There was no significant difference between diets regarding endometrial morphology or the percent of endometrial CD45+ immune cells. Our results indicate that consideration is needed when selecting a HFD-induced obesity mouse model for research involving female reproductive health.