title: Increased vulnerability of the brain norepinephrine system of females to corticotropin-releasing factor overexpression.
abstract: Stress-related psychiatric disorders are more prevalent in women than men. As hypersecretion of the stress neuromediator, corticotropin-releasing factor (CRF) has been implicated in these disorders, sex differences in CRF sensitivity could underlie this disparity. Hyperarousal is a core symptom that is shared by stress-related disorders and this has been attributed to CRF regulation of the locus ceruleus (LC)-norepinephrine arousal system. We recently identified sex differences in CRF(1) receptor (CRF(1)) signaling and trafficking that render LC neurons of female rats more sensitive to CRF and potentially less able to adapt to excess CRF compared with male rats. The present study used a genetic model of CRF overexpression to test the hypothesis that females would be more vulnerable to LC dysregulation by conditions of excess CRF. In both male and female CRF overexpressing (CRF-OE) mice, the LC was more densely innervated by CRF compared with wild-type controls. Despite the equally dense CRF innervation of the LC in male and female CRF-OE mice, LC discharge rates recorded in slices in vitro were selectively elevated in female CRF-OE mice. Immunoelectron microscopy revealed that this sex difference resulted from differential CRF(1) trafficking. In male CRF-OE mice, CRF(1) immunolabeling was prominent in the cytoplasm of LC neurons, indicative of internalization, a process that would protect cells from excessive CRF. However, in female CRF-OE mice, CRF(1) labeling was more prominent on the plasma membrane, suggesting that the compensatory response of internalization was compromised. Together, the findings suggest that the LC-norepinephrine system of females will be particularly affected by conditions resulting in elevated CRF because of differences in receptor trafficking. As excessive LC activation has been implicated in the arousal components of stress-related psychiatric disorders, this may be a cellular mechanism that contributes to the increased incidence of these disorders in females.
authors.affiliation: Department of Anesthesiology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. dbangasser@yahoo.com
authors.forename: D A
authors.initials: DA
authors.lastname: Bangasser
authors.forename: B A S
authors.initials: BA
authors.lastname: Reyes
authors.forename: D
authors.initials: D
authors.lastname: Piel
authors.forename: V
authors.initials: V
authors.lastname: Garachh
authors.forename: X-Y
authors.initials: XY
authors.lastname: Zhang
authors.forename: Z M
authors.initials: ZM
authors.lastname: Plona
authors.forename: E J
authors.initials: EJ
authors.lastname: Van Bockstaele
authors.forename: S G
authors.initials: SG
authors.lastname: Beck
authors.forename: R J
authors.initials: RJ
authors.lastname: Valentino
mesh_terms: D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D003712:Dendrites / Q000378:metabolism / Q000648:ultrastructure; D004558:Electric Stimulation; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D005838:Genotype; D066298:In Vitro Techniques; D008125:Locus Coeruleus / Q000166:cytology / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016253:Microscopy, Immunoelectron; D009434:Neural Pathways / Q000378:metabolism / Q000648:ultrastructure; D009474:Neurons / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D009638:Norepinephrine / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D018019:Receptors, Corticotropin-Releasing Hormone / Q000378:metabolism; D012727:Sex Characteristics; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D000099052:CRF Receptor, Type 1
chemical_list: D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone; D014446:Tyrosine 3-Monooxygenase; D009638:Norepinephrine