Sex differences in stress reactivity in arousal and attention systems

Abstract

Women are more likely than men to suffer from psychiatric disorders with hyperarousal symptoms, including posttraumatic stress disorder (PTSD) and major depression. In contrast, women are less likely than men to be diagnosed with schizophrenia and attention deficit hyperactivity disorder (ADHD), which share attentional impairments as a feature. Stressful events exacerbate symptoms of the aforementioned disorders. Thus, researchers are examining whether sex differences in stress responses bias women and men towards different psychopathology. Here we review the preclinical literature suggesting that, compared to males, females are more vulnerable to stress-induced hyperarousal, while they are more resilient to stress-induced attention deficits. Specifically described are sex differences in receptors for the stress neuropeptide, corticotropin-releasing factor (CRF), that render the locus coeruleus arousal system of females more vulnerable to stress and less adaptable to CRF hypersecretion, a condition found in patients with PTSD and depression. Studies on the protective effects of ovarian hormones against CRF-induced deficits in sustained attention are also detailed. Importantly, we highlight how comparing males and females in preclinical studies can lead to the development of novel therapeutics to improve treatments for psychiatric disorders in both women and men.

Fig. 1

This schematic shows how estradiol and testosterone regulate the LC-NE system. Estradiol enhances NE activity by increasing NE production in LC neurons (blue), decreasing COMT-dependent NE degradation, and reducing presynaptic adrenergic receptors that inhibit NE release. As a possible compensatory action, estradiol also reduces adrenergic receptors on postsynaptic neurons (green). In contrast, testosterone reduces TH, the NE synthetic enzyme, while increasing presynaptic adrenergic receptors that inhibit NE release. DA dopamine, DBH dopamine β-hydroxylase, DOPA l-dihydroxyphenylalanine, COMT catechol-O-methyltransferase, NE norepinephrine

Fig. 2

Sex differences in CRF₁ receptor signaling and trafficking in LC neurons (blue). In males, CRF₁ receptors bind βarrestin2 and signal through small GTPases signaling pathways, such as Rho. This βarrestin2 binding is associated with CRF₁ receptor internalization in males. In females, CRF₁ receptors couple to the Gs protein to initiate cAMP-PKA signaling and their receptors do not internalize following stress or CRF hypersecretion.

Fig. 3

This image illustrates sex differences in ACh activity and its regulation by estradiol. Females have enhanced ACh production in cholinergic neurons (blue) and greater ACh release. At the postsynaptic level, females have greater levels of nAChRs and mAChRs. ACh acetylcholine, AChE acetylcholinesterase, ChAT choline acetyl transferase, mAChR muscarinic acetylcholine receptor, nAChR nicotinic acetylcholine receptor