Glucocorticoid mechanisms of neonatal separation effects on adult learning
Principal Investigator: Aaron A Wilber
Abstract: DESCRIPTION (provided by applicant): Many studies have documented the relationship between adverse early experience and the development of psychiatric disorders such as depression, post-traumatic stress disorder, and schizophrenia. Neonatal maternal separation in the rat is a good model system for assessing the effects of adverse early experience, and eyeblink conditioning learning and memory is a good model system for studying the relationship between neonatal stress and adult behavior. This research will support the scientific integration of brain and behavior, to provide a foundation for understanding mental disorders, and will also define environmental risk for mental disorders. Previously, I showed that neonatal maternal separation increases adult glucocorticoid receptor expression in the interpositus nucleus of the cerebellum and impairs eyeblink conditioning. I have subsequently found that maternal separation during the first two postnatal weeks prevents a decrease in glucocorticoid receptor expression in the interpositus nucleus that occurs with normal development during the third postnatal week. The objective of the proposed research is to characterize the role of glucocorticoids in the impairment of learning I observed, and to explore alterations in neuronal morphology as a potential consequence of glucocorticoid alterations and mechanism of impaired eyeblink conditioning. In addition, perinatal corticosterone exposure influences development of several brain structures, including the cerebellum, and the effects we observed may be mediated by neonatal increases in corticosterone. Therefore, in two different experiments, I will assess a) the effect of glucocorticoid receptor blockade during maternal separation on adult eyeblink conditioning, neuronal morphology, and glucocorticoid receptor expression;and b) the effect of neonatal corticosterone administration on adult eyeblink conditioning and glucocorticoid receptor expression. If the increased glucocorticoid receptor expression in the interpositus nucleus is responsible for the adult eyeblink conditioning deficits we observed, then blocking these receptors during conditioning in adult rats that were separated neonatally should improve eyeblink conditioning. To test this hypothesis, I will assess the effects of infusion of a glucocorticoid receptor antagonist into the interpositus nucleus during eyeblink conditioning in neonatally separated rats. The findings of this research are relevant for public health. One in four U. S. citizens are affected by mental disorders every year. Understanding the mental health consequences of intentional (e.g., abuse and neglect) and unintentional (e.g., NICU) perinatal stressors is crucial to preventative treatment.
Funding Period: ----------------2010 - ---------------2011-
more information: NIH RePORT
- Glucocorticoid receptor blockade in the posterior interpositus nucleus reverses maternal separation-induced deficits in adult eyeblink conditioningAaron A Wilber
Department of Psychological and Brain Sciences and Program in Neuroscience, Indiana University, Bloomington, IN 47405, United States
Neurobiol Learn Mem 94:263-8. 2010..Mifepristone infusions improved conditioning in separated rats, but impaired control rats' performance. Thus, separation-induced increases in GRs may mediate the learning deficit seen in adult neonatally separated rats...
- Chronic stress alters neural activity in medial prefrontal cortex during retrieval of extinctionA A Wilber
Department of Psychological and Brain Sciences and Program in Neuroscience, 1101 East 10th Street, Indiana University, Bloomington, IN 47405, USA
Neuroscience 174:115-31. 2011..Thus, the stress-induced alteration of neuronal activity in infralimbic cortex may be responsible for the stress-induced deficit in retrieval of extinction...
- Neonatal corticosterone administration impairs adult eyeblink conditioning and decreases glucocorticoid receptor expression in the cerebellar interpositus nucleusA A Wilber
Canadian Centre for Behavioural Neuroscience, University of Lethbridge, 4401 University Drive West, Lethbridge, AB, Canada T1K 3M4
Neuroscience 177:56-65. 2011..This suggests an inverted U-shaped relationship may exist between both neonatal corticosterone levels and adult GR expression in the interpositus nucleus, and adult GR expression in the interpositus and eyeblink conditioning...