Synaptic and behavioral effects of chronic stress are linked to dynamic and sex-specific changes in microglia function and astrocyte dystrophy

Abstract

Emerging evidence indicates that males and females display different neurobiological responses to chronic stress which contribute to varied behavioral adaptations. In particular, pyramidal neurons undergo dendritic atrophy and synapse loss in the prefrontal cortex (PFC) of male, but not female, mice. Our recent work shows that chronic stress also provokes microglia-mediated neuronal remodeling, which contributes to synaptic deficits in the PFC and associated behavioral consequences in males. Separate studies indicate that chronic stress promotes astrocyte dystrophy in the PFC which is associated with behavioral despair. Notably, these prior reports focused primarily on stress effects in males. In the present studies, male and female mice were exposed to 14 or 28 days of chronic unpredictable stress (CUS) to assess molecular and cellular adaptations of microglia, astrocytes, and neurons in the medial PFC. Consistent with our recent work, male, but not female, mice displayed behavioral and cognitive deficits with corresponding perturbations of neuroimmune factors in the PFC after 14 days of CUS. Fluorescence-activated cell sorting and gene expression analyses revealed that CUS increased expression of select markers of phagocytosis in male PFC microglia. Confocal imaging in Thy1-GFP(M) mice showed that CUS reduced dendritic spine density, decreased GFAP immunolabeling, and increased microglia-mediated neuronal remodeling only in male mice. After 28 days of CUS, both male and female mice displayed behavioral and cognitive impairments. Interestingly, there were limited stress effects on neuroimmune factors and measures of microglial phagocytosis in the PFC of both sexes. Despite limited changes in neuroimmune function, reduced GFAP immunolabeling and dendritic spine deficits persisted in male mice. Further, GFAP immunolabeling and dendritic spine density remained unaltered in the PFC of females. These findings indicate that chronic stress causes sex-specific and temporally dynamic changes in microglial function which are associated with different neurobiological and behavioral adaptations. In all, these results suggest that microglia-mediated neuronal remodeling, astrocyte dystrophy, and synapse loss contribute to stress-induced PFC dysfunction and associated behavioral consequences in male mice.

The semantics of microglia activation: neuroinflammation, homeostasis, and stress

“…For example, microglia in the developing subventricular zone and cortex display amoeboid morphology, yet the cytokines and growth factors they produce are essential for neuronal growth and differentiation [150,151]. Even within the context of chronic stress, changes in microglial morphology vary between brain region, sex, species, stress paradigm, and stress duration, without specific biological or behavioral implications [136,[152][153][154][155][156]. In this context, it is not accurate to suggest that morphological changes in microglia alone can provide insight into their functional state.…”

“…Ultimately, this neuronal remodeling by microglia contributes to synapse loss in the medial PFC and associated stress-induced behavioral changes [ 169 , 182 ]. Interestingly, our recent work suggests that while synapse loss persists over the course of chronic stress, microglia-mediated neuronal remodeling diminishes over time, indicating that this is a coordinated process and that spine loss is maintained by other mechanisms [ 152 ].…”

LGI1 governs neuritin-mediated resilience to chronic stress

“…The localization of LGI1 is of particular importance because of previous findings that the MML, which is located 50 μm from the granule cell body in the DG, shows dynamic behavior following stress and antidepressant treatment ( Kitahara et al, 2016 ). Lastly, the present study was confined to male mice since it appears that only males suffer behavioral impairments accompanied by morphological deficits in neurons after 28 days of CUS ( Woodburn et al, 2021 ). Based on the higher incidence of depression in women, further investigations of gender differences in the regulatory functions of neuritin, including IR activation in the MDD, are warranted.…”

Uncovering microglial pathways driving sex-specific neurobiological effects in stress and depression

“…Findings indicate an increased ratio of microglia with broadened morphology (large cell body with thick processes)-to-surveillant microglia (small cell body with thin, highly ramified processes) in the mPFC in female as compared to male rats, suggesting microglial process engagement ( Bollinger et al., 2016 ). Females also show increased levels of prefrontal Cx3cl1 and Cx3cr1 transcript alongside greater Csf1r , Cd11b , and Tgfbr1 expression in frontal cortex microglia ( Bollinger et al., 2016 ; Woodburn et al., 2021 ). These gene pathways are particularly relevant to microglia-neuron interaction and are important regulators of microglial survival, migration, and synaptic pruning ( Paolicelli et al., 2011 ; Schafer et al., 2012 ; Elmore et al., 2014 ).…”

“…Recently, a study by Woodburn et al. (2021) revealed a sex-specific and temporally-dynamic role for microglia in guiding stress effects on neuroplasticity in the mPFC.…”