Collectively, our findings demonstrate that sensitization to cocaine in early life-stressed individuals involves brain and peripheral immune responses and that this mechanism is shared between mice and humans.

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.

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Early life stress (ELS) is known to modify trajectories of brain dopaminergic development, but the mechanisms underlying have not been determined. ELS perturbs immune system and microglia reactivity, and inflammation and microglia influence dopaminergic transmission and development. Whether microglia mediate the effects of ELS on dopamine (DA) system development is still unknown. We explored the effects of repeated early social stress on development of the dopaminergic system in male and female mice through histological, electrophysiological, and transcriptomic analyses. Furthermore, we tested whether these effects could be mediated by ELS-induced altered microglia/immune activity through a pharmacological approach. We found that social stress in early life altered DA neurons morphology, reduced dopamine transporter (DAT) and tyrosine hydroxylase expression, and lowered DAT-mediated currents in the ventral tegmental area but not substantia nigra of male mice only. Notably, stress-induced DA alterations were prevented by minocycline, an inhibitor of microglia activation. Transcriptome analysis in the developing male ventral tegmental area revealed that ELS caused downregulation of dopaminergic transmission and alteration in hormonal and peptide signaling pathways. Results from this study offer new insight into the mechanisms of stress response and altered brain dopaminergic maturation after ELS, providing evidence of neuroimmune interaction, sex differences, and regional specificity.

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Child maltreatment disrupts trajectories of brain development, but the underlying pathways are unclear. Stressful stimuli in early life interfere with maturation of local inhibitory circuitry and deposition of perineuronal nets (PNNs), specialized extracellular matrix structures involved in the closure of critical periods of development. Alterations in cortical PNN and parvalbumin (PV) following early‐life stress (ELS) have been detected in human and animal studies. Aberrations in the anterior cingulate cortex (ACC) are the most consistent neuroimaging findings in maltreated people, but the molecular mechanisms linking ELS with ACC dysfunctions are unknown. Here, we employed a mouse model of early social threat to test whether ELS experienced in a sensitive period for ACC maturation could induce long‐term aberrations of PNN and PV development in the ACC, with consequences on plasticity and ACC‐dependent behavior. We found that ELS increased PNN but not PV expression in the ACC of young adult mice. This was associated with reduced frequency of inhibitory postsynaptic currents and long‐term potentiation impairments and expression of intense object phobia. Our findings provide information on the long‐term effects of ELS on ACC functionality and PNN formation and present evidence for a novel neurobiological pathway underlying the impact of early adversity on the brain.