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

Abstract

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 21 days in relation to unstressed controls (CON): preS animals were exposed to various unpredictable stressors during the last gestational trimester; postS animals were exposed to 45 min 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 2 h 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".

Exposure to extrinsic stressors, social defeat or bisphenol A, eliminates sex differences in DNA methyltransferase expression in the amygdala

“…An environmental stressor experienced during development might render an individual more susceptible to a second extrinsic stressor experienced later in life, as predicted by the two-hit hypothesis. 15,[54][55][56] Our results indicate that future research investigating epigenetic changes in the amygdala following stress will need to consider the possibility of sex differences in DNMT expression leading to sex-specific transcriptional responses to extrinsic stressors.…”

Vulnerability and resilience to Alzheimer’s disease: early life conditions modulate neuropathology and determine cognitive reserve

“…Over a period of about 2 weeks (for the hippocampus), expression levels slowly increase to reach adult levels [ 169 ]. Interestingly, neonatal handling increased EGR1 mRNA and protein levels [ 176 ], while postnatal restraint stress downregulated EGR1 [ 177 ]. Furthermore, early life stress induces rapid alterations in the acetylation of histones H3 and H4, which correlate with the expression of EGR1, and stress-induced activation of the GR itself also regulates EGR1 expression [ 178 ].…”

Prenatal and postnatal stress and wheeze in Mexican children

“…26 Exposure to prenatal stress may lead to altered programming of the stress response and individuals exposed to stress prenatally may be more vulnerable to subsequent stressful events due to these alterations (ie “two-hit model”). 48 Moreover, studies show that a poor postnatal environment can modulate the consequences of in utero exposure to stress in a sex-specific manner, with females generally being more adversely affected. 49 This should be further explored in future research.…”