BDNF and glucocorticoids regulate corticotrophin-releasing hormone (CRH) homeostasis in the hypothalamus.
Regulation of the hypothalamic-pituitary-adrenal (HPA) axis is critical for adaptation to environmental changes. The principle regulator of the HPA axis is corticotrophin-releasing hormone (CRH), which is made in the parventricular nucleus and is an important target of negative feedback by glucocorticoids. However, the molecular mechanisms that regulate CRH are not fully understood. Disruption of normal HPA axis activity is a major risk factor of neuropsychiatric disorders in which decreased expression of the glucocorticoid receptor (GR) has been documented. To investigate the role of the GR in CRH neurons, we have targeted the deletion of the GR, specifically in the parventricular nucleus. Impairment of GR function in the parventricular nucleus resulted in an enhancement of CRH expression and an up-regulation of hypothalamic levels of BDNF and disinhibition of the HPA axis. BDNF is a stress and activity-dependent factor involved in many activities modulated by the HPA axis. Significantly, ectopic expression of BDNF in vivo increased CRH, whereas reduced expression of BDNF, or its receptor TrkB, decreased CRH expression and normal HPA functions. We find the differential regulation of CRH relies upon the cAMP response-element binding protein coactivator CRTC2, which serves as a switch for BDNF and glucocorticoids to direct the expression of CRH.
Department of Cell Biology, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, USA. freddy.jeanneteau@med.nyu
Freddy D
FD
Jeanneteau
W Marcus
WM
Lambert
Naima
N
Ismaili
Kevin G
KG
Bath
Francis S
FS
Lee
Michael J
MJ
Garabedian
Moses V
MV
Chao
D000704:Analysis of Variance; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism*; D005938:Glucocorticoids / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology*; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology; D007031:Hypothalamus / Q000502:physiology*; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D016297:Mutagenesis, Site-Directed; D009474:Neurons / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors
D019208:Brain-Derived Neurotrophic Factor; C504923:Crtc2 protein, mouse; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D015534:Trans-Activators; D014157:Transcription Factors; D003346:Corticotropin-Releasing Hormone