title: Forebrain CRHR1 deficiency attenuates chronic stress-induced cognitive deficits and dendritic remodeling.
abstract: Chronic stress evokes profound structural and molecular changes in the hippocampus, which may underlie spatial memory deficits. Corticotropin-releasing hormone (CRH) and CRH receptor 1 (CRHR1) mediate some of the rapid effects of stress on dendritic spine morphology and modulate learning and memory, thus providing a potential molecular basis for impaired synaptic plasticity and spatial memory by repeated stress exposure. Using adult male mice with CRHR1 conditionally inactivated in the forebrain regions, we investigated the role of CRH-CRHR1 signaling in the effects of chronic social defeat stress on spatial memory, the dendritic morphology of hippocampal CA3 pyramidal neurons, and the hippocampal expression of nectin-3, a synaptic cell adhesion molecule important in synaptic remodeling. In chronically stressed wild-type mice, spatial memory was disrupted, and the complexity of apical dendrites of CA3 neurons reduced. In contrast, stressed mice with forebrain CRHR1 deficiency exhibited normal dendritic morphology of CA3 neurons and mild impairments in spatial memory. Additionally, we showed that the expression of nectin-3 in the CA3 area was regulated by chronic stress in a CRHR1-dependent fashion and associated with spatial memory and dendritic complexity. Moreover, forebrain CRHR1 deficiency prevented the down-regulation of hippocampal glucocorticoid receptor expression by chronic stress but induced increased body weight gain during persistent stress exposure. These findings underscore the important role of forebrain CRH-CRHR1 signaling in modulating chronic stress-induced cognitive, structural and molecular adaptations, with implications for stress-related psychiatric disorders.
authors.affiliation: Max Planck Institute of Psychiatry, Kraepelinstr 2-10, 80804 Munich, Germany. wangxd@mpipsykl.mpg.de
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Wang
authors.forename: Yuncai
authors.initials: Y
authors.lastname: Chen
authors.forename: Miriam
authors.initials: M
authors.lastname: Wolf
authors.forename: Klaus V
authors.initials: KV
authors.lastname: Wagner
authors.forename: Claudia
authors.initials: C
authors.lastname: Liebl
authors.forename: Sebastian H
authors.initials: SH
authors.lastname: Scharf
authors.forename: Daniela
authors.initials: D
authors.lastname: Harbich
authors.forename: Bianca
authors.initials: B
authors.lastname: Mayer
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wurst
authors.forename: Florian
authors.initials: F
authors.lastname: Holsboer
authors.forename: Jan M
authors.initials: JM
authors.lastname: Deussing
authors.forename: Tallie Z
authors.initials: TZ
authors.lastname: Baram
authors.forename: Marianne B
authors.initials: MB
authors.lastname: Müller
authors.forename: Mathias V
authors.initials: MV
authors.lastname: Schmidt
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D001835:Body Weight / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000378:metabolism; D003712:Dendrites / Q000378:metabolism*; D004291:Dominance-Subordination; D017403:In Situ Hybridization; D008297:Male; D018782:Maze Learning / Q000502:physiology*; D008568:Memory / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D000075983:Nectins; D009474:Neurons / Q000378:metabolism; D016548:Prosencephalon / Q000378:metabolism*; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics*; D013315:Stress, Psychological / Q000235:genetics / Q000378:metabolism*; D000099052:CRF Receptor, Type 1
chemical_list: D015815:Cell Adhesion Molecules; C000619017:Nectin3 protein, mouse; D000075983:Nectins; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1