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. 2019 Aug 14;197(3):319–328. doi: 10.1111/cei.13351

Figure 1.

Figure 1

A schematic representation of how early life adversities may contribute to peripheral and central immune activation through activation of the sympathetic nervous system (SNS). Orange arrows indicate neural pathways, blue indicate central microglial effects and green the influence of peripheral monocytes. (1) Exposure to early life adversity (ELA) such as childhood trauma results in (2) activation of the brain stress circuitry and (3) increased outflow of the sympathetic nervous system to the bone marrow with increased noradrenaline (NA) release. (4) This decreases the expression of the chemokine CXCL12 in the bone marrow haematopoietic stem cell niche, which accelerates proliferation of haematopoietic stem cells resulting in enhanced production of proinflammatory CD14+/CD16– monocytes, which are released into circulation and (5) traffic to the blood–brain barrier through the vasculature. (6) At the same time, central microglial cells are also activated in response to neural cues as a result of stress circuit activation. These cells facilitate the infiltration of the peripheral monocytes through secretion of specific cytokines and chemokines, which modulate endothelial cell permeability and allow ingress of the monocytes from the vasculature to the perivascular space and the brain parenchyma. (7) The infiltrating proinflammatory monocytes lead to further sustained activation of neural stress circuits, resulting in the emergence of abnormal behaviour. (8) In parallel, ELA exposure may also influence the development and function of central microglia. Converging lines of evidence suggest that microglia play key roles in shaping the development of the brain including the formation and pruning of dendritic spines and synapses. Hence, any disruption of this process following stress exposure in early life may result in the abnormal neural circuit development which, by itself, may predispose an individual to psychopathology in later life. PFC = prefrontal cortex; AMYG = amygdala; HPC = hippocampus; SNS = sympathetic nervous system.