ESPE Yearbook of Paediatric Endocrinology

Brief Summary: This study demonstrates that stress during puberty in mice leads to a permanent disruption in female sexual behavior, specifically affecting sexual performance and disrupted estrous cycles.

Puberty is critical for the development of the female brain and sexual behavior^1,2. The neural circuits involved in the establishment of the control of sexual behavior are still poorly understood.

The authors found that female mice exposed to pubertal stress displayed decreased sexual receptivity and disrupted estrous cycles, spending less time in proestrus and estrus phases. These pubertal effects were associated with reduced activation of neuronal nitric oxide synthase (nNOS) neurons in the ventrolateral part of the ventromedial hypothalamus (VMHvl). These neurons have been recently described as necessary for the expression and the modulation of female sexual behavior, with nNOS neurons being a downstream target of kisspeptin^3,4. Using fiber photometry, theyshowed that these VMHvl nNOS neurons responded typically to male olfactory cues, but this response was significantly blunted in pubertally stressed females.

Additionally, the study explored the hormonal mechanisms underlying these changes, finding that pubertal stress did not affect circulating levels of estradiol or progesterone. This suggested that the observed sexual dysfunction was not hormone-driven. The researchers attempted to rescue sexual behavior in stressed females by administering a nitric oxide (NO) donor. This treatment partially restored sexual performance, further highlighting the role of nNOS neurons in the VMHvl in regulating female sexual behavior.

This study provides valuable insights into the neural mechanisms underlying the effects of pubertal stress on female sexual behavior and emphasizes the critical role of the VMHvl nNOS neurons and the importance of proper neural circuit development during puberty.

References: 1. Bakker, J., Honda, S. I., Harada, N. & Balthazart, J. The aromatase knock-out mouse provides new evidence that estradiol is required during development in the female for the expression of sociosexual behaviors in adulthood. J. Neurosci. 2002; 22, 9104–9112.2. Brock, O., Baum, M. J. & Bakker, J. The development of female sexual behavior requires prepubertal estradiol. J. Neurosci. 2011; 31, 5574–5578.3. Bentefour, Y. & Bakker, J. Kisspeptin signaling and nNOS neurons in the VMHvl modulate lordosis behavior but not mate preference in female mice. Neuropharmacology 2021; 198, 108762.4. Silva MSB, Decoster L, Trova S, Mimouni NEH, Delli V, Chachlaki K, Yu Q, Boehm U, Prevot V, Giacobini P. Female sexual behavior is disrupted in a preclinical mouse model of PCOS via an attenuated hypothalamic nitric oxide pathway. Proc Natl Acad Sci U S A. 2022;119(30):e2203503119.5. Female sexual behavior is disrupted in a preclinical mouse model of PCOS via an attenuated hypothalamic nitric oxide pathway. Proc. Natl Acad. Sci. USA 2022; 119, e2203503119.