Early estradiol exposure masculinizes disease‐relevant behaviors in female mice

Abstract

Most psychiatric disorders show a sex bias in incidence, symptomatology, and/or response to treatment. Males are more susceptible to neurodevelopmental disorders including autism spectrum disorder and attention‐deficit activity disorder, while women are more prone to major depressive disorder and anxiety disorders after puberty. A striking difference between males and females in humans and other mammals is that males undergo a process of brain masculinization due to the early exposure to gonadal hormones. In rodents, this developmental organization of the brain is essential for adult males to express the appropriate sexual behaviors in the presence of a receptive female. Our goal was to determine whether this process of brain masculinization influences behaviors relevant to psychiatric disorders. To this aim, we studied sex differences and the effect of neonatal 17β‐estradiol benzoate treatment of female mice on different disease‐relevant behaviors. Our analysis includes postnatal behavior, juvenile play, and adult tests for sociability, repetitive behaviors, anxiety, and depression. Our results show that the sex differences observed in exploration, repetitive behaviors, and depression‐related behaviors are largely reduced when females are neonatally treated with 17β‐estradiol benzoate. These results suggest a role of neonatal sex steroids in the development of disease‐relevant behaviors and provide evidence supporting a role for perinatal exposure to estrogens and androgens on the development and manifestation of psychiatric disorders.

Juvenile handling rescues autism-related effects of prenatal exposure to valproic acid

“…Sample size was decided from previous works on the VPA model in this mouse strain and behavioral analyses 10 , 66 . To control for the litter effect 67 , only one or two animals from each litter were assigned to each juvenile treatment group and the mother was treated as a random factor in the linear fixed-effects models.…”

“…We followed the protocol previously reported 66 . Animals were suspended by their tails (about 4/5 from the base) to a wire suspended 25 cm above the floor, during 5 min under an illumination of 50 lx.…”

“…This test was performed as previously described 66 . Each animal was gently placed into a glass beaker (27 cm high × 18 cm diameter) filled with 15 cm of warm water (24 °C) under an illumination of 50 lx during 6 min.…”

Sex Differences in Anxiety and Depression: What Can (and Cannot) Preclinical Studies Tell Us?

“…These results suggest that anxiety-and depressive-like tasks are differentially susceptible to testosterone's organizational or activational effects [54]. Intriguingly, it has been recently reported that neonatal estradiol treatment of females increased immobility time in the FST to the same level as untreated male CF1 mice tested when adults, indicating that a sex difference in the expression of this depressive-like behavior may be attributed to the organizational effects of sex steroids [93]. Lu et al (2016) have shown that stress induced by chronic light deprivation produced a more severe phenotype of depression in prepubertal female than in prepubertal male ICR mice, associated with a decreased intrinsic excitability of cortical neurons, indicating that the female perinatal organized brain may predispose to depressive vulnerability [61].…”

“…Perinatal exposition to gonadal hormones in males has been inversely associated with later development of anxiety and depressive-like phenotype [61,69,94,125,126]. However, some evidence seems to indicate the contrary [68,93]. HPA axis responsiveness and limbic areas of the brain are particularly sensitive to environmental and hormonal influences during this period and later conditions exert differential responses in males and females.…”