Due to the increasing pressure of modern social life and work, anxiety and other emotional disorders are becoming more prevalent. Epidemiological studies indicate that the incidence of anxiety disorders in women is twice that of men, but the underlying neural mechanisms remain unclear. Recently, a team led by Dr. Xia Zhang and Dr. Ying Wang from the Institute of Neuropsychiatric Disorders at the School of Medicine, Qingdao University, published an article inScience Advances(aSciencefamily journal) titled "Hyperexcitation of ovBNST CRF neurons during stress contributes to female-biased expression of anxiety-like avoidance behaviors." This study found that sexual differences in the expression and function of CRF receptors (CRFR1) in the ovBNST can mediate sexually different excitation patterns of ovBNST CRF neurons under acute stress, leading to female-biased susceptibility to anxiety. This research was supported by the Ministry of Science and Technology's 2030 Major Project and the National Natural Science Foundation's Major Project. PhD students Na Zhang and Sha Zhao, and research assistant Yanqiao Ma from School of Basic Medicine are the co-first authors; Professor Xia Zhang and Assistant Professor Ying Wang from the Institute of Neuropsychiatric Disorders are the co-corresponding authors of this paper.

The oval nucleus of the bed nuclei of the stria terminalis (ovBNST) is a critical site regulating anxiety and stress, and rich in stress hormone corticotropin-releasing factor (CRF) and CRF neurons. Previous studies have found that during acute stress, CRF levels in the ovBNST increase, and CRF neurons are activated, while optogenetic inhibition of ovBNST neurons can alleviate anxiety. Interestingly, the ovBNST is also a sexually dimorphic nucleus; anatomical studies have found that the volume of ovBNST in male is twice of that in female, and the female ovBNST contains more CRF neurons than male. Therefore, the ovBNST may play an important role in gender differences in anxiety susceptibility, but the related mechanisms are unknown.

The research team first established afemale-biased stress paradigm in mice using forced swimming acute stress. Based on this paradigm, we found that CRF release in the ovBNST during acute stress showed female-biased pattern, and bothin vivoandin vitrostudies found that ovBNST CRF neuronsinfemale mice were persistently activated by stress stimuli, whereas only transiently activated in male mice. Subsequently, to verify whether the gender differences in the excitation patterns of ovBNST CRF neurons during stress mediate the sexual differences in anxiety susceptibility, the research team used optogenetic regulation to exchange the excitation patterns of ovBNST CRF neurons between male and female mice during stress. That is, during stress, the ovBNST CRF neurons in male mice were persistently activated, while those in female mice were transiently activated. This pattern exchange was found to reverse the sexual differences in anxiety susceptibility. Since CRF release during stress can activate neurons through action on CRFR1 receptors, the research team further verified whether ovBNST CRFR1 mediates the sexually different excitation patterns of ovBNST CRF neurons during stress. The results showed that in physiological condition, CRFR1 expression in the ovBNST of female mice is higher than that in males. Specific knockdown of the CRFR1 level ovBNST CRF neurons in female or overexpression that in male could reverse their susceptibility to anxiety. In summary, this study confirms that CRFR1 mediates the hyperexcitation of ovBNST CRF neurons in female mice during stress, further encoding the female-biased susceptibility to anxiety.

Fromo：https://www.science.org/doi/10.1126/sciadv.adk7636