Transient early-life forebrain corticotropin-releasing hormone elevation causes long-lasting anxiogenic and despair-like changes in mice.
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.
Kolber
Benedict J
BJ
Department of Pediatrics, Washington University, St. Louis, Missouri 63110, USA.
Boyle
Maureen P
MP
Wieczorek
Lindsay
L
Kelley
Crystal L
CL
Onwuzurike
Chiamaka C
CC
Nettles
Sabin A
SA
Vogt
Sherri K
SK
Muglia
Louis J
LJ
D000221:Adaptation, Ocular / Q000187:drug effects / Q000235:genetics; D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D001007:Anxiety / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics; D001522:Behavior, Animal / Q000502:physiology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism; D002940:Circadian Rhythm / Q000187:drug effects / Q000235:genetics; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D003863:Depression / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics; D004195:Disease Models, Animal; D004318:Doxycycline / Q000008:administration & dosage; D004622:Embryo, Mammalian; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013006:Growth Hormone / Q000378:metabolism; D019417:Hindlimb Suspension / Q000379:methods; D007030:Hypothalamo-Hypophyseal System / Q000254:growth & development / Q000378:metabolism; D007099:Imipramine / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D010913:Pituitary-Adrenal System / Q000254:growth & development / Q000378:metabolism; D016548:Prosencephalon / Q000196:embryology / Q000254:growth & development / Q000378:metabolism*; D011863:Radioimmunoassay / Q000379:methods; D011930:Reaction Time / Q000235:genetics; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D000099052:CRF Receptor, Type 1
D000928:Antidepressive Agents; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D013006:Growth Hormone; D003346:Corticotropin-Releasing Hormone; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D004318:Doxycycline; D007099:Imipramine