Sex Differences in Risk and Resilience: Stress Effects on the Neural Substrates of Emotion and Motivation

Abstract

Risk for stress-sensitive psychopathologies differs in men and women, yet little is known about sex-dependent effects of stress on cellular structure and function in corticolimbic regions implicated in these disorders. Determining how stress influences these regions in males and females will deepen our understanding of the mechanisms underlying sex-biased psychopathology. Here, we discuss sex differences in CRF regulation of arousal and cognition, glucocorticoid modulation of amygdalar physiology and alcohol consumption, the age-dependent impact of social stress on prefrontal pyramidal cell excitability, stress effects on the prefrontal parvalbumin system in relation to emotional behaviors, contributions of stress and gonadal hormones to stress effects on prefrontal glia, and alterations in corticolimbic structure and function after cessation of chronic stress. These studies demonstrate that, while sex differences in stress effects may be nuanced, nonuniform, and nonlinear, investigations of these differences are nonetheless critical for developing effective, sex-specific treatments for psychological disorders.

Keywords: corticolimbic regions; corticosterone; corticotropin releasing factor; microglia; parvalbumin.

Figure 1.

Sex differences in CRF₁ receptors in LC. A, In females, CRF₁ receptors bind to Gs and signal more through the cAMP-PKA pathway, but they do not internalize following stress and CRF overexpression, leading to a large LC response to CRF. B, In males, CRF₁ receptors in LC internalize following stress and CRF overexpression, resulting in a smaller response to CRF. Adapted with permission from Bangasser et al. (2018).

Figure 2.

Model of alterations in basolateral-central amygdala circuit activity by alcohol and stress. Neurons of the CeL and CeM in males and females display similar basal glutamatergic postsynaptic responses to stimulation of BLA inputs (top). Given similar baseline single-neuron responses, male and female CeM projection neurons may similarly release GABA in downstream targets. However, after acute exposure to alcohol or the stress hormone corticosterone (CORT), the magnitude of the CeA response to BLA stimulation is dampened in a sexually divergent fashion (bottom). Specifically, alcohol, but not CORT, reduces postsynaptic response magnitude in both CeL and CeM neurons in males, whereas CORT, but not alcohol, reduces response magnitude in only CeL neurons in females. At the circuit level, these reductions in BLA excitation of CeA, measured ex vivo at the single-neuron level, are predicted to combine to produce similar alterations in GABA release by CeM projection neurons, resulting in altered alcohol intake and anxiety-like behavior in both sexes.

Figure 3.

Hormonal contributions to sex-dependent stress effects on neuronal and glial morphology, and glia-neuron interaction in mPFC. Males (blue) exhibit increased apical dendritic complexity in pyramidal cells (red), increased astroglial ramification (purple), and reduced microglial activation (tan) compared with females. In males, chronic stress increases microglial activation, microglia-neuron interaction, and microglia-mediated synaptic pruning, decreases astroglial coverage, and reduces dendritic arborization. In females, chronic stress reduces microglial density and activation and increases astroglial coverage and dendritic complexity in mPFC. Estradiol (E) is necessary for stress-induced microglial deactivation in females and the stress-linked dendritic remodeling reported by Garrett and Wellman (2009).

Figure 4.

Sex differences in dendritic remodeling following CRS. Following CRS, males show initial retraction, overgrowth, and then retraction; immediately after cessation of CRS, females show either minimal remodeling (A) or growth (B), which may be dependent on mPFC subregion or duration of chronic stress, and no dynamic post-stress remodeling.