Stress in utero alters neonatal stress-induced regulation of the synaptic plasticity proteins Arc and Egr1 in a sex-specific manner.

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The present study in juvenile rats investigated a "two-hit model" to test the impact of prenatal stress exposure ("first hit") on the regulation of the synaptic plasticity immediate early genes Arc and Egr1 in response to a second neonatal stressor ("second hit") in a sex-specific manner. Three stress-exposed animal groups were compared at the age of 21days in relation to unstressed controls (CON): preS animals were exposed to various unpredictable stressors during the last gestational trimester; postS animals were exposed to 45min restraint stress at postnatal day 21, pre/postS animals were exposed to a combination of pre- and postnatal stress as described for the two previous groups. The postS and pre/postS groups were killed 2h after exposure to the postnatal stressor, males and females were separately analyzed. In line with our hypothesis we detected sex-specific stress sensitivity for both analyzed proteins. Males did not show any significant changes in Arc expression irrespective of the stress condition. In contrast, females, which had been pre-exposed to prenatal stress, displayed an "amplified" Arc upregulation in response to postnatal stress (pre/postS group) compared to unstressed controls, which may reflect a "sensitization" effect of prenatal stress. For Egr1, the females did not show any stress-induced regulation irrespective of the stress condition, whereas in males, which were pre-exposed to prenatal stress, we observed a "protective" effect of prenatal stress on postnatal stress-induced downregulation of Egr1 expression (pre/postS group), which may indicate that prenatal stress exposure may induce "resilience".