Axonal Guidance Dysregulation in Hippocampus underlines a three-hit model of stress susceptibility

Abstract

Under some combinations of genetic components (hit-1) and early-life conditions (hit-2), the developing phenotype gets compromised when exposed to challenges later in life (hit-3), enhancing the risk for psychiatric symptoms. We tested this “three-hit” hypothesis in a rat line that was genetically selected for high apomorphine-susceptibility (APO-SUS) as the first-hit using Wistar rats as controls. Pups that received low maternal care, as judged from low maternal licking and grooming (LG) scores, were considered to suffer from the second-hit, compared to pups receiving high maternal-LG. As a third-hit, some rats were exposed to post-weaning isolation-rearing, with social-rearing as the control condition. All adult APO-SUS rats displayed high levels of apomorphine-induced gnawing (p<.001; n=120/strain). The APO-SUS Low-LG offspring displayed enhanced hormonal response to stress (p<.001 for ACTH and corticosterone; n=15/maternal care group) and low acoustic startle (p<.050; n=30/maternal care group). The APO-SUS Low-LG offspring that were reared in isolation displayed low acoustic startle and a severe deficit in pre-pulse-inhibition (PPI), which was restored rapidly by CORT-treatment (p<.001 for both; n=10/LG by rearing group). The differential-expression signature in hippocampus (95 genes FDR5%) was enriched with neuron-specific genes (p<.001) and suggested altered axonal guidance (B-H p<.001). Human hippocampal expression signatures of childhood trauma survivors with and without genetic susceptibility for stress are concordant with the rat study. We conclude that cumulative stressful experience during development in genetically-predisposed individuals precipitates behavioral alterations associated with altered stress responsiveness and compromised hippocampus function.