Resilience to Early Life Adversity Effects on Stress Reactivity by Postnatal Knockdown of 5-HT_1AAutoreceptors

Abstract

Early Life Adversity (ELA) predisposes to stress hypersensitivity in adulthood, but neurobiological mechanisms that can protect from long-lasting effects of ELA are poorly understood. Serotonin 1A (5HT1A) autoreceptors in the raphé nuclei regulate adult stress vulnerability, but if 5HT1Acould be targeted to prevent ELA effects on susceptibility to future stressors is unknown. Here, we exposed mice with postnatal knockdown of 5HT1Aautoreceptors to the limited bedding and nesting model of ELA from postnatal day (P)3-10. We then tested behavioral, neuroendocrine, neurogenic, and neuroinflammatory responses to an acute swim stress in male and female mice in adolescence (P35) and in adulthood (P56). In ELA-exposed females, adult swim stress exposure increased passive coping and despair-like behavior, corticosterone levels at baseline and after stress, and neuronal activity and corticotropin releasing hormone levels in the paraventricular nucleus of the hypothalamus. ELA also reduced neurogenesis and increased microglia activation in the ventral dentate gyrus (DG) of the hippocampus – an important mediator of individual differences in stress susceptibility. These effects of ELA were specific to females, but not males, and manifested predominantly in adulthood, but not earlier on in adolescence. Postnatal 5HT1Aautoreceptor knockdown prevented ELA effects on stress reactivity and on neurogenesis and neuroinflammation in the DG, indicating that reducing 5HT1Aautoreceptors confers resilience to ELA. Our findings demonstrate that ELA induces long-lasting and sex-specific impairments in stress reactivity and ventral DG function across development, and identify 5HT1Aautoreceptors as potential targets to prevent these persistent effects of ELA.