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Review
.2013 May;465(5):601-26.
doi: 10.1007/s00424-013-1271-7. Epub 2013 Apr 16.

Sex differences in anxiety and emotional behavior

Affiliations
Review

Sex differences in anxiety and emotional behavior

Nina C Donner et al. Pflugers Arch.2013 May.

Abstract

Research has elucidated causal links between stress exposure and the development of anxiety disorders, but due to the limited use of female or sex-comparative animal models, little is known about the mechanisms underlying sex differences in those disorders. This is despite an overwhelming wealth of evidence from the clinical literature that the prevalence of anxiety disorders is about twice as high in women compared to men, in addition to gender differences in severity and treatment efficacy. We here review human gender differences in generalized anxiety disorder, panic disorder, posttraumatic stress disorder and anxiety-relevant biological functions, discuss the limitations of classic conflict anxiety tests to measure naturally occurring sex differences in anxiety-like behaviors, describe sex-dependent manifestation of anxiety states after gestational, neonatal, or adolescent stressors, and present animal models of chronic anxiety states induced by acute or chronic stressors during adulthood. Potential mechanisms underlying sex differences in stress-related anxiety states include emerging evidence supporting the existence of two anatomically and functionally distinct serotonergic circuits that are related to the modulation of conflict anxiety and panic-like anxiety, respectively. We discuss how these serotonergic circuits may be controlled by reproductive steroid hormone-dependent modulation of crfr1 and crfr2 expression in the midbrain dorsal raphe nucleus and by estrous stage-dependent alterations of γ-aminobutyric acid (GABAergic) neurotransmission in the periaqueductal gray, ultimately leading to sex differences in emotional behavior.

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Figures

Fig. 1
Fig. 1
Schematic comparison of the 4-day rodent reproductive cycle and the 28-day human menstrual cycle. Depicted are average fluctuations of the circulating hormones 17-beta-estradiol, progesterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) in a female rat (left panel) vs. a female human (right panel).Gray bars in theleft panel depict the dark phases. Data for individual hormones were adapted from [120, 339, 353]
Fig. 2
Fig. 2
Schematic overview of commonly used tests of unconditioned conflict anxiety in adult rodents and of neonatal ultrasonic vocalization.Shades of gray represent darker (or, in case of theOF andSI test, more protected) zones of the respective test paradigm.Thick black lines designate walls of the test apparatus or cage (in the case of novelty-suppressed feeding/neophagia). In theOF, light–dark (white/black) box,EPM, andETM, an increased latency to enter into and less time spent in the brighter (or more exposed) zones designates anxiety-like behavior. Similarly, decreased SI behavior with an age-matched, weight-matched, and sex-matched conspecific, decreased numbers of shock-punished licks (1 shock every 20 licks) at the drinking bottle after 16–24 h of water deprivation in the Vogel punished drinking test, and suppressed consumption of food in a brightly lit, novel cage or arena also indicate an anxiety-like behavioral state. Frequency and duration of neonatal ultrasonic vocalizations at 40–50 kHz are used to screen for anxiolytic drugs and are strongly correlated with adult trait anxiety
Fig. 3
Fig. 3
Hypothetical model of how stress-induced increases in corticotropin-releasing factor (CRF) expression and signaling from the bed nucleus of the stria terminalis (BNST) may interact with decreased GABAergic inhibition from the ventrolateral periaqueductal gray (VLPAG) during late diestrus to enhance serotonergic output in the conflict anxiety-related dorsal and caudal DR (DRD/DRC). During late diestrus in rodents, declining circulating concentrations of progesterone and its neuroactive metabolite allopregnanolone cause increased expression of α4, β1, and δ subunits of the γ-aminobutyric acid (GABA) receptor type A within the PAG [143, 144], including the VLPAG, ultimately resulting in attenuated ongoing GABAergic inhibitory signaling [221]. Attenuated activity of GABAergic neurons from the VLPAG render serotonergic neurons in the DRD/DRC more active [183], and stress induces CRF expression in the conflict anxiety-related BNST [232, 331, 375]. Enhanced CRF release from BNST projections further activates serotonergic neurons through CRF receptor type 2 (CRFR2) [204] within the DRD/DRC [335]. Together with stress-induced desensitization of autoinhibitory 5-HT1A receptors on DRD/ DRC serotonin neurons [313], late diestrus-enhanced hyperactivity of the DRD/DRC causes increased serotonergic output to distal target sites controlling conflict anxiety-like behavior, in particular through actions on excitatory 5-HT2C receptors [76] in the BL [12, 150]. Neuronal projections are drawn unilaterally solely for simplicity and do not imply functional laterality
Fig. 4
Fig. 4
Hypothetical model of how stress-induced increases in corticotropin-releasing factor (CRF) expression and signaling from the basolateral (BL) and central (CE) amygdaloid complex likely function to activate serotonergic output from the “lateral wings” of the dorsal raphe nucleus (DR) and may interact with decreased GABAergic inhibition from the periaqueductal gray (PAG) during late diestrus to increase panic-like responses. During late diestrus in rodents, declining circulating concentrations of progesterone and its neuroactive metabolite allopregnanolone cause increased expression of α4, β1, and δ subunits of the γ-aminobutyric acid (GABA) receptor type A within the PAG [143, 144], ultimately resulting in attenuated ongoing GABAergic inhibitory signaling [221] within the panic-related dorsal PAG (DPAG). Stress-induced elevation of CRF within the BL leads to increased CRF release from CE projections that target the “lateral wings” of the DR, namely, the ventrolateral portions of the DR and PAG (DRVL/VLPAG), either acting on CRF receptor type 2 (CRFR2) directly on serotonergic neurons [204] or indirectly via CRFR2-mediated inhibition of nonserotonergic neurons [289]. This normally leads to increased activation of the DRVL/VLPAG, increased serotonergic output to distal target sites, and postsynaptic 5-HT1A-mediated and/or 5-HT2A-mediated inhibition of panic-like responses. During late diestrus, however, decreased GABAergic signaling disinhibits the DPAG, facilitating fight-or-flight and panic/escape-like responses [134]. Neuronal projections are drawn unilaterally solely for simplicity and do not imply functional laterality
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