Males and females use distinct brain circuits to cope with similar challenges. Using RNA sequencing of ribosome-bound mRNA from hippocampal CA3 neurons, we found remarkable sex differences and discovered that female mice displayed greater gene expression activation after acute stress than males. Stress-sensitive BDNF Val66Met mice of both sexes show a pre-stressed translational phenotype in which the same genes that are activated without applied stress are also induced in wild-type mice by an acute stressor. Behaviourally, only heterozygous BDNF Val66Met females exhibit spatial memory impairment, regardless of acute stress. Interestingly, this effect is not observed in ovariectomized heterozygous BDNF Val66Met females, suggesting that circulating ovarian hormones induce cognitive impairment in Met carriers. Cognitive deficits are not observed in males of either genotype. Thus, in a brain region not normally associated with sex differences, this work sheds light on ways that genes, environment and sex interact to affect the transcriptome’s response to a stressor.

Anorexia nervosa (AN) is a psychiatric illness characterized by restricted eating and irrational fears of gaining weight. There is no accepted pharmacological treatment for AN, and AN has the highest mortality rate among psychiatric illnesses. Anorexia nervosa most commonly affects females during adolescence, suggesting an effect of sex and hormones on vulnerability to the disease. Activity-based anorexia (ABA) is a rodent model of AN that shares symptoms with AN, including over-exercise, elevation of stress hormones, and genetic links to anxiety traits. We previously reported that ABA in adolescent female rats results in increased apical dendritic branching in CA1 pyramidal cells of the ventral hippocampus at postnatal day 44 (P44). To examine the long-term effects of adolescent ABA (P44) in female rats, we compared the apical branching in the ventral hippocampal CA1 after recovery from ABA (P51) and after a relapse of ABA (P55) with age-matched controls. To examine the age-dependence of the hippocampal plasticity, we examined the effect of ABA during adulthood (P67). We found that while ABA at P44 resulted in increased branching of ventral hippocampal pyramidal cells, relapse of ABA at P55 resulted in decreased branching. Activity-based anorexia induced during adulthood did not have an effect on dendritic branching, suggesting an age-dependence of the vulnerability to structural plasticity. Cells from control animals were found to exhibit a dramatic increase in branching, more than doubling from P44 to P51, followed by pruning from P51 to P55. The proportion of mature spines on dendrites from the P44-ABA animals is similar to that on dendrites from P55-CON animals. These results suggest that the experience of ABA may cause precocious anatomical development of the ventral hippocampus. Importantly, we found that adolescence is a period of continued development of the hippocampus, and increased vulnerability to mental disorders during adolescence may be due to insults during this developmentally critical period.

We aimed to determine the short-term effects of early-life stress in the form of maternal separation (MS) on anxiety-like behavior in male rat pups. In order to assess anxiety, we measured 40 kHz separation-induced ultrasonic vocalizations (USV) on postnatal day (PND) 11. We further aimed to evaluate the potential involvement of two neurochemical systems known to regulate social and anxiety-like behaviors throughout life: oxytocin (OT) and fibroblast growth factor 2 (FGF2). For these purposes, we tested the effects of neonatal administration (on PND1) of an acute dose of FGF2 on USV and its potential interaction with MS. In addition, we validated the anxiolytic effects of OT and measured oxytocin receptor (OTR) gene expression, binding and epigenetic regulation via histone acetylation. Our results show that MS potentiated USV while acute administration of OT and FGF2 attenuated them. Further, we found that both FGF2 and MS increased OTR gene expression and the association of acH3K14 with the OTR promoter in the bed nucleus of the stria terminalis (BNST). Comparable changes, though not as pronounced, were also found for the central amygdala (CeA). Our findings suggest that FGF2 may exert its anxiolytic effects in male MS rats by a compensatory increase in the acetylation of the OTR promoter to overcome reduced OT levels in the BNST.