Early maternal separation and chronic variable stress in adulthood changes the neural activity and the expression of glucocorticoid receptor in limbic structures

There is increasing evidence that early adverse experience contributes to the development of stress susceptibility, and increases the onset of stress-related psychiatric disorders in stressful environments in adulthood. This study addressed whether or not prolonged maternal separation, a well-established model of early stress, affects adult limbic areas related to the regulation of the hypothalamic-pituitary-adrenal axis in exposure to chronic variable stress in adulthood. Rats were subjected to daily maternal separation for 4.5 h during postnatal days 1–21. As adults, the animals were exposed to a variable chronic stress paradigm of 24 days. Persistent changes were assessed in glucocorticoid receptor density and Fos activity in the anterodorsal thalamic nuclei, mammillary nuclei and retrosplenial cortex. Immunohistochemical analysis revealed that adult maternally separated animals had increased levels of c-Fos immunoreactivity in the anterodorsal thalamic nuclei as well as in the mammillary nuclei compared to normal non-maternally separated animals. Chronic variable stress in maternally separated and non-maternally separated animals diminished glucocorticoid receptor density in the anterodorsal thalamic nuclei but not in the rest of the nuclei analyzed. These results indicate that c-Fos immunoreactivity as well as glucocorticoid receptor expression in the anterodorsal thalamic nuclei and mammillary nuclei exhibit long-term alterations in adult rats following repeated maternal separation and subsequent stress exposure. Recognition of these adaptations helps to define the brain regions and neural circuitry associated with persistent alterations induced by early life environment and the development of stress-associated disorders.