Abstract
Women are more susceptible to numerous stress-linked psychological disorders (e.g., depression) characterized by dysfunction of corticolimbic brain regions critical for emotion regulation and cognitive function. Although sparsely investigated, a number of studies indicate sex differences in stress effects on neuronal structure, function, and behaviors associated with these regions. We recently demonstrated a basal sex difference in- and differential effects of stress on- microglial activation in medial prefrontal cortex (mPFC). The resident immune cells of the brain, microglia are implicated in synaptic and dendritic plasticity, and cognitive-behavioral function. Here, we examined the effects of acute (3h/day, 1 day) and chronic (3h/day, 10 days) restraint stress on microglial density and morphology, as well as immune factor expression in orbitofrontal cortex (OFC), basolateral amygdala (BLA), and dorsal hippocampus (DHC) in male and female rats. Microglia were visualized, classified based on their morphology, and stereologically counted. Microglia-associated transcripts (CD40, iNOS, Arg1, CX3CL1, CX3CR1, CD200, and CD200R) were assessed in brain punches from each region. Expression of genes linked with cellular stress, neuroimmune state, and neuron-microglia communication varied between unstressed male and female rats in a region-specific manner. In OFC, chronic stress upregulated a wider variety of immune factors in females than in males. Acute stress increased microglia-associated transcripts in BLA in males, whereas chronic stress altered immune factor expression in BLA more broadly in females. In DHC, chronic stress increased immune factor expression in males but not females. Moreover, acute and chronic stress differentially affected microglial morphological activation state in male and female rats across all brain regions investigated. In males, chronic stress altered microglial activation in a pattern consistent with microglial involvement in stress-induced dendritic remodeling across OFC, BLA, and DHC. Together, these data suggest the potential for microglia-mediated sex differences in stress effects on neural structure, function, and behavior.
Highlights
Women are more vulnerable to various stress-linked psychopathologies, including depression, most anxiety disorders, and post-traumatic stress disorder [1,2,3,4,5]
We have demonstrated sex differences in- and sex-dependent stress effects on corticolimbic microglial morphology and immune factor expression
Stress altered microglial morphology and immune factor expression in a duration- and brain region-specific manner, indicating that stress effects on corticolimbic microglia are not uniform across stress sensitive brain regions in either male or female rats. These findings agree with previous studies addressing brain region-dependent stress effects on neuronal architecture and behavior, and suggest important region-specific distinctions in pathways underlying microglial activation within- and across-sex
Summary
Women are more vulnerable to various stress-linked psychopathologies, including depression, most anxiety disorders, and post-traumatic stress disorder [1,2,3,4,5]. Chronic restraint stress induces apical dendritic retraction in pyramidal neurons in mPFC and DHC in male rats, but little to no change or even dendritic growth in females [11,12,13,14]. These differences in neuronal remodeling correspond to differences in behavior: males typically show chronic stress-induced deficits in memory-associated tasks whereas females do not [8, 15,16,17]. Activated microglia can reorient their processes toward neuronal and astroglial signals (e.g. glutamate, extracellular purines) [21], and regulate neuronal function through release of neuroactive factors (e.g., inflammatory cytokines and reactive oxygen species), direct pruning of dendritic spines [22], and reorganization of dendritic architecture [23]
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