Interactions between early adversity and the serotonin system determine lifespan immune responses in the hippocampus

Abstract

Early Life Adversity (ELA) is a major risk factor for psychiatric disorders, but the neurobiological mechanisms that mediate the long-lasting effects of ELA are largely unknown. One candidate process implicated in stress-induced psychiatric disorders that is also increased by ELA, is neuroinflammation. Reducing neuroinflammation may thus be a promising new strategy to rescue the impact of ELA on brain function and mental health. To test this hypothesis, we exposed mice to ELA (limited bedding and nesting material from postnatal day (PND)3 to PND10). We then tested their behavior in a fear discrimination task and collected brains at PND35 (adolescence), PND56 (adulthood), and at 18 months of age (old age). While ELA did not alter adolescent behavior, we find that ELA causes fear discrimination deficits in female mice from adulthood (PND56; n=12, p=0.009) that last into old age (18 months; n=5, p=0.02). At the neurobiological level, we used immunohistochemistry for CD68+/Iba1+ to determine the number of activated microglia. We found a strong and long-lasting increase in the number of activated microglia in the hippocampus of ELA-exposed mice in adulthood and in old age (n=6; p<0.001). We then used a transgenic mouse line to increase hippocampal serotonin (5-HT) by knockdown of the 5-HT1A autoreceptor, and found that adolescent 5-HT1A knockdown can rescue ELA effects on fear discrimination and neuroinflammation later on. Our findings provide new insight into the potential of targeting the 5-HT system to prevent the neuroinflammatory and behavioral deficits resulting from ELA.