Activation of the brain's stress response in the 'mood center' of the brain produces sex-dependent changes

or, technically, 
Sex Differences in Corticotropin-Releasing Factor Receptor-1 Action Within the Dorsal Raphe Nucleus in Stress Responsivity [See the original abstract on PubMed]

Authors: Alexis R. Howerton, Alison V. Roland, Jessica M. Fluharty, Anikò Marshall, Alon Chen, Derek Daniels, Sheryl G. Beck, Tracy L. Bale

Brief prepared by: Felicia Davatolhagh
Brief approved by: Elaine Liu & Carolyn Keating
Section Chief: David Reiner
Date posted: August 10, 2017 

Brief in Brief (TL;DR)

What do we know: Women are twice as likely as men to suffer from stress-related disorders, such as depression and anxiety. A hormone called CRF is involved in the stress response and can act in in the 'mood center' of the brain, a region called the dorsal raphe. 

What don’t we know: Does CRF act differently within the dorsal raphe in males and females? 

What this study shows: CRF in the dorsal raphe does work differently in males and females. Females have a decreased response to CRF, compared to males. 

What we can do in the future because of this study:We can better understand sex differences that exist in stress-related disorders and improve how we treat men and women that have these disorders. 

Why you should care: CRF-targeting drugs, which are used to treat disorders such as depression, anxiety, and addiction, are sometimes unsuccessful in patients. Identifying and addressing sex differences in the brain's stress response might help fix this.

Brief for Non-Neuroscientists

In the United States, women are twice as likely as men to be afflicted by a stress-related affective disorder. Corticotropin-releasing factor (CRF) is a peptide hormone and neurotransmitter that mediates stress response through signaling in an area of the brain called the dorsal raphe (DR). CRF receptor-1 (CRFr1) inactivators have been extensively studied in the hope that they can alleviate symptoms of stress-related affective disorders; however, none has been successful in clinical trials. Differences in stress response circuitry between males and females might account for these unsatisfactory results. This study found that in males, infusions of a CRFr1 antagonist into the DR reduced production of the stress hormone corticosterone and alleviated anxiety-like behavior. On the other hand, the CRFr1 antagonist did not affect corticosterone levels or behavior in females. These results suggest sex-dependent differences in CRFr1 activity in the DR. Overall, these findings warrant further investigation into pharmacological therapies tailored toward sex-dependent differences in the brain's stress response system.

Brief for Neuroscientists

The prevalence of affective disorders is twice as high in women as it is in men. Corticotropin-releasing factor (CRF) has been shown to contribute to the development of affective disorders through excessive activation of its receptor CRFr1. The dorsal raphe (DR) is implicated in the central stress pathway response, through activation of CRFr1. This study aimed to elucidate the sex differences within the DR in response to stress, specifically examining CRF modulation in the DR circuits. Infusion of the CRFr1 antagonist NBI35965 (NBI) or CRF into the DR, resulted in robust bidirectional modulation of corticosterone production and behavioral stress response in males, while females were minimally responsive. Furthermore, male mice showed enhanced membrane excitability following CRF application, but the response in female mice was blunted. Therefore, these sex differences in stress circuitry might explain why CRFr1 antagonists have been unsuccessful in clinical trials. These studies warrant further investigation into pharmacological treatments directed at addressing sex differences in the CRF system.