Sex differences in molecular and cellular substrates of stress - PubMed (original) (raw)

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Sex differences in molecular and cellular substrates of stress

Debra A Bangasser et al. Cell Mol Neurobiol. 2012 Jul.

Abstract

Women are twice as likely as men to suffer from stress-related psychiatric disorders, like unipolar depression and post-traumatic stress disorder. Although the underlying neural mechanisms are not well characterized, the pivotal role of stress in the onset and severity of these diseases has led to the idea that sex differences in stress responses account for this sex bias. Corticotropin-releasing factor (CRF) orchestrates stress responses by acting both as a neurohormone to initiate the hypothalamic-pituitary-adrenal (HPA) axis and as a neuromodulator in the brain. One target of CRF modulation is the locus coeruleus (LC)-norepinephrine system, which coordinates arousal components of the stress response. Hypersecretion of CRF and dysregulation of targets downstream from CRF, such as the HPA axis and LC-norepinephrine system, are characteristic features of many stress-related psychiatric diseases, suggesting a causal role for CRF and its targets in the development of these disorders. This review will describe sex differences in CRF and the LC-norepinephrine system that can increase stress sensitivity in females, making them vulnerable to stress-related disorders. Evidence for gonadal hormone regulation of hypothalamic CRF is discussed as an effect that can lead to increased HPA axis activity in females. Sex differences in the structure of LC neurons that create the potential for hyperarousal in response to emotional stimuli are described. Finally, sex differences at the molecular level of the CRF(1) receptor that make the LC-norepinephrine system more reactive in females are reviewed. The implications of these sex differences for the treatment of stress-related psychiatric disorders also will be discussed.

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Figures

Figure 1

Figure 1

This schematic depicts the predicted model of sex biased signaling. In males the CRF1 receptor associates with β-arrestin2, which sterically hinders Gs association and biases signaling towards β-arrestin2-related pathways such as NFκB, AKT, ERK, and Src. In females, the CRF1 receptor does not associate with β-arrestin2 as well and is more highly coupled to Gs, which signals through cAMP and sometimes ERK. Note that in both males and females CRF activates the receptor, but the signaling events are unique because of sex specific interactions of CRF1 receptors with binding partners. The differential cellular responses can translate to different physiological and behavioral responses to the same stressor and different pathology.

Figure 2

Figure 2

This schematic illustrates sex differences in the LC-arousal system. The images on the left depict LC neurons with dendrites (blue) receiving afferent inputs (in green). Because the LC dendritic tree is longer and more complex in females, they are more likely to receive projections from afferent structures that terminate in the peri-LC. The images on the right depict magnified views of LC dendrites in order to illustrate sex differences in the CRF1 receptor coupling and trafficking. In males, CRF1 receptors (red) associate with β-arrestin2 following ligand binding and become localized in the cytoplasm. CRF1 receptors of females are highly coupled to Gs and following ligand binding they are predominantly found on the plasma membrane.

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