The putative effects of early-life stress (ELS) on later behavior and neurobiology have been widely investigated. Recently, microglia have been implicated in mediating some of the effects of ELS on behavior. In this review, findings from preclinical and clinical literature with a specific focus on microglial alterations induced by the exposure to ELS (i.e., exposure to behavioral stressors or environmental agents and infection) are summarized. These studies were utilized to interpret changes in developmental trajectories based on the time at which the stress occurred, as well as the paradigm used. ELS and microglial alterations were found to be associated with a wide array of deficits including cognitive performance, memory, reward processing, and processing of social stimuli. Four general conclusions emerged: (1) ELS interferes with microglial developmental programs, including their proliferation and death and their phagocytic activity; (2) this can affect neuronal and non-neuronal developmental processes, which are dynamic during development and for which microglial activity is instrumental; (3) the effects are extremely dependent on the time point at which the investigation is carried out; and (4) both pre- and postnatal ELS can prime microglial reactivity, indicating a long-lasting alteration, which has been implicated in behavioral abnormalities later in life.

The brain employs distinct circuitries to encode positive and negative valence stimuli, and dysfunctions of these neuronal circuits have a key role in the etiopathogenesis of many psychiatric disorders. The Dorsal Raphè Nucleus (DRN) is involved in various behaviors and drives the emotional response to rewarding and aversive experiences. Whether specific subpopulations of neurons within the DRN encode these behaviors with different valence is still unknown. Notably, microRNA expression in the mammalian brain is characterized by tissue and neuronal specificity, suggesting that it might play a role in cell and circuit functionality. However, this specificity has not been fully exploited. Here, we demonstrate that microRNA-34a (miR-34a) is selectively expressed in a subpopulation of GABAergic neurons of the ventrolateral DRN. Moreover, we report that acute exposure to both aversive (restraint stress) and rewarding (chocolate) stimuli reduces GABA release in the DRN, an effect prevented by the inactivation of DRN miR-34a or its genetic deletion in GABAergic neurons in aversive but not rewarding conditions. Finally, miR-34a inhibition selectively reduced passive coping with severe stressors. These data support a role of miR-34a in regulating GABAergic neurotransmitter activity and behavior in a context-dependent manner and suggest that microRNAs could represent a functional signature of specific neuronal subpopulations with valence-specific activity in the brain.

Objective: Sex disparities in the association between psychosocial stress and cardiovascular risk have been reported, yet the extent to which social stress impacts cardiovascular function in a sex-specific manner remains unclear. The objectives of this study were to investigate sex differences in the electromechanical remodeling of the heart of socially stressed rats, and to explore potential epigenetic mechanisms (cardiac microRNAs). Methods: Adult wild-type Groningen rats of both sexes vicariously experienced the social defeat bout between 2 males for 9 consecutive days [“witness stress” (WS) paradigm] or were exposed to a control condition ( n =8/sex/group). After repeated WS exposure, arrhythmic vulnerability was evaluated via beta-adrenergic stimulation with isoproterenol in conscious rats, while cardiac contractile properties were assessed via hemodynamic analyses under anesthesia. Cardiac tissue was collected to measure expression levels of several miRNAs (including miR-22 and miR-34a) and their molecular targets (eg, SIRT1) involved in the regulation of cardiac electromechanical function. Results: An increased vulnerability to isoproterenol-induced arrhythmias was found in male, but not female, rats with a history of WS. Signs of contractile dysfunction were found in both sexes after WS, but to a greater extent in males. In addition, only male WS rats exhibited a significantly higher cardiac expression of miR-34a and miR-22, which were associated with a reduced expression of their common molecular target (SIRT-1). Conclusion: These findings suggest an epigenetic mechanism underlying the larger vulnerability to adverse cardiac electromechanical remodeling in socially stressed male rats, informing our understanding of the sex-specific impact of social stress on cardiac function.