Adult glucocorticoid receptor mRNA expression volatility in response to an acute stressor and juvenile CSF corticotropin-releasing factor: A pilot neurodevelopmental study.
Early life stress (ELS) has been shown to play a role in establishing persistent maladaptive HPA axis modifications that may contribute to the pathogenesis of mood and anxiety disorders. Central glucocorticoid receptor (GR) messenger RNA (mRNA) expression may facilitate (mal)adaptive responsivity to ELS. The role of adult monocytic GR mRNA expression, a putative CNS proxy, during acute stress exposure was explored as well as the ELS marker, juvenile cerebrospinal fluid (CSF) corticotropin-releasing factor.



Six adult macaques (three of which were exposed to variable foraging demand, a form of ELS) underwent acute restraint. Baseline GR expression and plasma cortisol concentrations were separately measured followed by subsequent measurements following stress completion (t=0min, 4h, 5 days and 7 days). Juvenile CSF CRF concentrations were available in five subjects to determine their developmental association with GR expression in response to stress.



As expected acute restraint stress produced a significant increase in plasma cortisol concentrations most robustly observed at 4h post-stress time point. There was a significant juvenile CSF CRF concentration x time interaction in predicting adult GR mRNA expression in response to stress (partial η2=0.80). During acute stress juvenile CRF concentrations negatively predicted GR expression and during recovery, "flipped" to positively predict expression. Juvenile CSF CRF concentrations positively correlated with the volatility of adult GR mRNA expression.



During acute stress, relatively high CSF CRF concentrations are associated with relatively rapid reductions in GR expression. Return to an ambient post-stress state was characterized by a direct relationship, consistent with increased HPA axis restraint in high CRF subjects. An ELS-associated allostatic adaptation suggests relative elevations of juvenile CSF CRF concentration set the stage for a relative hyper-volatility of adult GR mRNA expression in response to acute stress with potential long-term implications for HPA axis regulation.
Department of Psychiatry & Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, USA; Department of Psychiatry & Behavioral Sciences, State University of New York, Downstate Medical Center, Brooklyn, NY, USA.
Shariful A
SA
Syed
Division of Hematology/Oncology, Department of Internal Medicine, SUNY DMC, Brooklyn, NY, USA.
Eric L P
EL
Smith
Division of Hematology/Oncology, Department of Internal Medicine, SUNY DMC, Brooklyn, NY, USA.
Olcay
O
Batuman
Department of Psychiatry & Behavioral Sciences, State University of New York, Downstate Medical Center, Brooklyn, NY, USA.
Leonard A
LA
Rosenblum
Department of Psychiatry & Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.
Michael J
MJ
Owens
Department of Psychiatry & Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, USA.
Charles B
CB
Nemeroff
Department of Psychiatry & Behavioral Sciences, State University of New York, Downstate Medical Center, Brooklyn, NY, USA. Electronic address: jeremy.coplan@downstate.edu.
Jeremy D
JD
Coplan
D000818:Animals; D001070:Appetitive Behavior; D003346:Corticotropin-Releasing Hormone / Q000134:cerebrospinal fluid*; D005247:Feeding Behavior; D006854:Hydrocortisone / Q000097:blood; D008251:Macaca; D008297:Male; D008425:Maternal Behavior; D009000:Monocytes / Q000378:metabolism; D010865:Pilot Projects; D012333:RNA, Messenger / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D012149:Restraint, Physical; D013315:Stress, Psychological / Q000134:cerebrospinal fluid / Q000378:metabolism*
D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D003346:Corticotropin-Releasing Hormone; D006854:Hydrocortisone