Glucocorticoid Mechanisms Of Neonatal Separation Effects On Adult Learning And Memory

Abstract

Many studies have documented the relationship between adverse early experience and the development of psychiatric disorders. Understanding the mental health consequences of perinatal stressors is crucial to preventative treatment. Neonatal maternal separation in the rat is a good model system for assessing the effects of adverse early experience, and eyeblink conditioning is a good model for studying the relationship between neonatal stress and adult learning and memory. Previously, I showed that daily neonatal maternal separation (1h/day on postnatal days 2-14) increases plasma corticosterone levels during the first and second postnatal week. Further, I showed that neonatal maternal separation impairs adult eyeblink conditioning and produces a correlated increase in glucocorticoid receptor expression in the posterior interpositus nucleus of the cerebellum. My dissertation research is focused on characterizing the role of glucocorticoids in this effect. I measured cerebellar glucocorticoid receptor expression on postnatal day 15 and 21, and found that maternal separation (1h/day on postnatal days 2-14) prevented a normal decrease in glucocorticorticoid receptor expression in the interpositus from postnatal day 15 to 21. Further, I showed that infusion of a glucocorticoid receptor blocker into the interpositus of adult rats before training normalized eyeblink conditioning in separated rats. This suggests that the increased glucocorticoid receptor expression in the interpositus mediates the adult deficit in eyeblink conditioning. Next, I showed that either neonatal corticosterone or vehicle injections on postnatal days 2-14,which both produced larger increases in plasma corticosterone than did neonatal separation and mimicked the separation-induced impairment in adult eyeblink conditioning, but did so by decreasing glucocorticoid receptor expression. This suggests an inverted-U shaped relationship between both the magnitude of neonatal stress and adult glucocorticoid receptor expression; and adult glucocorticoid receptor activation and learning. Finally, I found that blocking glucocorticoid receptors during maternal separation (1h/day on postnatal days 2-14) attenuated the separation-induced impairment in adult eyeblink conditioning and increased GR expression. Together, these experiments suggest that neonatal separation alters glucocorticoid receptor modulation of adult associative learning, and separation-induced increases in neonatal plasma corticosterone may play a role in this effect.