Transient Early-Life Forebrain Corticotropin-Releasing Hormone Elevation Causes Long-Lasting Anxiogenic and Despair-Like Changes in Mice

• Published in: The Journal of neuroscience Vol. 30; no. 7; pp. 2571 - 2581
• Main Authors: Kolber, Benedict J, Boyle, Maureen P, Wieczorek, Lindsay, Kelley, Crystal L, Onwuzurike, Chiamaka C, Nettles, Sabin A, Vogt, Sherri K, Muglia, Louis J
• Format: Journal Article
• Language: English
• Published: United States Soc Neuroscience 17-02-2010; Society for Neuroscience
• Subjects: Adaptation, Ocular - drug effects; Adaptation, Ocular - genetics; Age Factors; Analysis of Variance; Animals; Animals, Newborn; Antidepressive Agents - pharmacology; Antidepressive Agents - therapeutic use; Anxiety - drug therapy; Anxiety - etiology; Anxiety - genetics; Behavior, Animal - physiology; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - genetics; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism; Circadian Rhythm - drug effects; Circadian Rhythm - genetics; Corticotropin-Releasing Hormone - genetics; Corticotropin-Releasing Hormone - metabolism; Depression - drug therapy; Depression - etiology; Depression - genetics; Disease Models, Animal; Doxycycline - administration & dosage; Embryo, Mammalian; Exploratory Behavior - drug effects; Exploratory Behavior - physiology; Gene Expression Regulation, Developmental - drug effects; Gene Expression Regulation, Developmental - genetics; Gene Expression Regulation, Developmental - physiology; Growth Hormone - metabolism; Hindlimb Suspension - methods; Hypothalamo-Hypophyseal System - growth & development; Hypothalamo-Hypophyseal System - metabolism; Imipramine - pharmacology; Imipramine - therapeutic use; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation - genetics; Pituitary-Adrenal System - growth & development; Pituitary-Adrenal System - metabolism; Prosencephalon - embryology; Prosencephalon - growth & development; Prosencephalon - metabolism; Radioimmunoassay - methods; Reaction Time - genetics; Receptors, Corticotropin-Releasing Hormone - genetics; Receptors, Corticotropin-Releasing Hormone - metabolism
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.4470-09.2010

During development, early-life stress, such as abuse or trauma, induces long-lasting changes that are linked to adult anxiety and depressive behavior. It has been postulated that altered expression of corticotropin-releasing hormone (CRH) can at least partially account for the various effects of stress on behavior. In accord with this hypothesis, evidence from pharmacological and genetic studies has indicated the capacity of differing levels of CRH activity in different brain areas to produce behavioral changes. Furthermore, stress during early life or adulthood causes an increase in CRH release in a variety of neural sites. To evaluate the temporal and spatial specificity of the effect of early-life CRH exposure on adult behavior, the tetracycline-off system was used to produce mice with forebrain-restricted inducible expression of CRH. After transient elevation of CRH during development only, behavioral testing in adult mice revealed a persistent anxiogenic and despair-like phenotype. These behavioral changes were not associated with alterations in adult circadian or stress-induced corticosterone release but were associated with changes in CRH receptor type 1 expression. Furthermore, the despair-like changes were normalized with antidepressant treatment. Overall, these studies suggest that forebrain-restricted CRH signaling during development can permanently alter stress adaptation leading to increases in maladaptive behavior in adulthood.