Gonadal hormones differentially regulate sex‐specific stress effects on glia in the medial prefrontal cortex

Abstract

Women are more susceptible to various stress‐linked psychopathologies, including depression. Dysfunction of the medial prefrontal cortex (mPFC) has been implicated in depression, and studies indicate sex differences in stress effects on mPFC structure and function. For example, chronic stress induces dendritic atrophy in the mPFC in male rats, yet dendritic growth in females. Recent findings suggest glial pathways toward depression. Glia are highly responsive to neuronal activity and function as critical regulators of synaptic plasticity. Preclinical models demonstrate stress‐induced microglial activation in mPFC in males, yet deactivation in females. By contrast, stress reduces astrocyte complexity in mPFC in male rats, whereas the effects in females are unknown. Glia possess receptors for most gonadal hormones and gonadal hormones are known to modulate neuronal activity. Thus, gonadal hormones represent a potential mechanism underlying sex differences in glia, as well as divergent stress effects. Therefore, we examined the role of gonadal hormones in sex‐specific stress effects on neuronal activity (ie FosB/ ΔFosB induction) and glia in the mPFC. The findings obtained indicate greater microglial activation in mPFC in females and a greater astrocyte area in males. Basal astrocyte morphology is modulated by androgens, whereas androgens or oestrogens dampen the microglial state in males. Astrocyte morphology is associated with neuronal activity in both sexes, regardless of hormonal condition. Chronic stress induced astrocytic atrophy in males, yet hypertrophy in females, with gonadal hormones partly regulating this difference. Stress effects on microglia are oestradiol‐dependent in females. Taken together, these data suggest sex‐specific, gonadal hormone‐dependent stress effects on astrocytes and microglia in the mPFC.

Schizophrenia and Sex Hormones: What Is the Link?

“…Higher brain functions, such as cognition, mood, and memory, are modulated by gonadal hormones ( 7 ). Their action is accompanied by alterations in neuron and synapse numbers, as well as in dendritic and synaptic morphology ( 8 , 9 ). Although the determined sex difference in schizophrenia is relatively small, (male: female ratio 58:42 (the age of onset is earlier in males and is accompanied by more severe negative symptoms ( 10 , 11 ).…”

Sex-specific calibration of memory recall by glucocorticoid receptors on cortical astrocytes

“…Then there are data to suggest that exposure to stress can alter astrocyte biology. In the PFC, chronic stress decreases expression of astrocyte-markers (GFAP) and induces atrophy of astrocyte processes in males, while increasing GFAP expression and complexity of astrocyte anatomy in females [71,72]. Such data demonstrate that characteristics of astrocytes at baseline, expression of astrocytic markers, and stress-induced changes in astrocytes are different in males and females.…”

Infralimbic cortical glutamate output is necessary for the neural and behavioral consequences of chronic stress

“…The quantitative mapping of ∆ FosB+ cells provided an activity-based atlas of chronic stress in the frontal cortex. CVS increased ∆ FosB in the IL, an effect that is specific to non-habituating heterotypic stress regimens (Bollinger et al, 2019;Flak et al, 2012;Lehmann & Herkenham, 2011). This was extended to show that ∆ FosB expression is specific to pyramidal cells and not observed in interneurons.…”

“…Similar to previous rodent studies of mPFC and stress processing, these experiments were limited to males. Although, recent studies have demonstrated that chronic stress-induced morphological changes in mPFC pyramidal neurons are similar in male and female rats (Anderson et al, 2019) and that homotypic chronic stress does not affect mPFC ∆ FosB expression differentially by sex (Bollinger et al, 2019). However, more widespread frontal lobe changes are sexually-divergent (Carvalho-Netto et al, 2011;Moench et al, 2019) and the behavioral consequences of chronic stress vary by sex (Borrow et al, 2018;Smith et al, 2018).…”