The double-edged sword effect of adverse childhood experiences forging adult stress into depression and anxiety

Adverse childhood experiences (ACEs) are a high risk factor for depression and anxiety in adulthood and are associated with the alterations in the hypothalamic‒pituitary‒adrenal (HPA) axis and monoamine neurotransmitters. This study aimed to elucidate the behavioral, neuroendocrine, and neural circuit mechanisms underlying the impact of ACEs effect on adult second-hit stress. We employed a "two-hit" mouse model that combines maternal separation (MS) with restraint stress (RS). To investigate the potential pathological effects of ACEs on depressive- and anxiety-like behaviors in second-hit model mice. The mice were assessed through the behaviors test of sucrose preference test (SPT), tail suspension test (TST), open field test (OFT) and elevated zero maze (EZM). We analyzed the neural circuits in mice by immunohistochemical (IHC) technique, and detected the neuroendocrine changes of the HPA axis and monoamine neurotransmitters by ELISA, flow cytometry (FCM), and high performance liquid chromatography-electrochemical detection (HPLC-ECD). Mice in the RS and MS + RS groups exhibited depressive- and anxiety-like behaviors in the SPT, TST, OFT and EZM. Serum levels of GR, CORT, ACTH and CRH levels were decreased in the RS and MS + RS groups. Limbic‑system‑related neural circuits were activated in short- and long-term stress, with the expression of c-Fos decreasing and that of FosB increasing. Moreover, the concentrations of 5‑HT, dopamine (DA), norepinephrine (NE), and epinephrine (E) were lowered in the prefrontal cortex, amygdala, hippocampus, and hypothalamus. Maternal separation exerts a time-dependent dual effect on adult mice's response to restraint stress: initially enhancing resilience, but later increasing susceptibility to depressive- and anxiety-like behaviors. These effects are likely mediated by neuroendocrine regulation of neural circuits involving HPA axis hormones and monoamine neurotransmitters. This study provides a novel two-hit mouse model for exploring how ACEs shape adult respond to stress.