Blunted behavioral and molecular responses to chronic mild stress in adult rats with experience of infancy maternal separation.

Childhood adversity has profound and persistent effects on brain functions and has been implicated in the etiology of depression. Brain-derived neurotrophic factor (BDNF) and cAMP response element-binding protein (CREB) play critical roles during brain development to maintain neuronal function and structural integrity in adulthood. We therefore investigated the long-term effects of early life adversity on the depression-related behavior and the expression of BDNF and CREB in the hippocampus. Male Sprague-Dawley newborn rats were subjected to maternal separation for 3 h/day on postnatal days 2-14. After the postnatal day 90, rats with or without the experience of infancy maternal separation received a series of unpredictable chronic mild stress (CMS) for 21 days. Sucrose preference and spontaneous activity in the open field test were recorded, and the expression of BDNF and CREB in the hippocampus was measured by real-time RT-PCR and Western blot analyses. Before exposure to CMS, the rats with maternal separation showed the significant decreases in sucrose preference, spontaneous activity, and hippocampal expression of BDNF and CREB, compared to the animals without maternal separation. In contrast, the rats without maternal separation showed greater decreases of the above indictors after CMS, the levels of which were lower than those observed in the rats with maternal separation. Thus, early life adversity leads to long-term decreases in the capacity of enjoying sweetness, spontaneous activity, and hippocampal expression of BDNF and CREB. Moreover, childhood neglect may decrease the neurobehavioral plasticity, thereby blunting the responses to adulthood stress and increasing the susceptibility to depression.