title: Neurotrophic factor-α1 prevents stress-induced depression through enhancement of neurogenesis and is activated by rosiglitazone.
abstract: Major depressive disorder is often linked to stress. Although short-term stress is without effect in mice, prolonged stress leads to depressive-like behavior, indicating that an allostatic mechanism exists in this difference. Here we demonstrate that mice after short-term (1 h per day for 7 days) chronic restraint stress (CRS), do not display depressive-like behavior. Analysis of the hippocampus of these mice showed increased levels of neurotrophic factor-α1 (NF-α1; also known as carboxypeptidase E, CPE), concomitant with enhanced fibroblast growth factor 2 (FGF2) expression, and an increase in neurogenesis in the dentate gyrus. In contrast, after prolonged (6 h per day for 21 days) CRS, mice show decreased hippocampal NF-α1 and FGF2 levels and depressive-like responses. In NF-α1-knockout mice, hippocampal FGF2 levels and neurogenesis are reduced. These mice exhibit depressive-like behavior that is reversed by FGF2 administration. Indeed, studies in cultured hippocampal neurons reveal that NF-α1 treatment directly upregulates FGF2 expression through extracellular signal-regulated kinase-Sp1 signaling. Thus, during short-term CRS, hippocampal NF-α1 expression is upregulated and has a key role in preventing the onset of depressive-like behavior through enhanced FGF2-mediated neurogenesis. To evaluate the therapeutic potential of this pathway, we examined, rosiglitazone (Rosi), a PPARγ agonist, which has been shown to have antidepressant activity in rodents and humans. Rosi upregulates FGF2 expression in a NF-α1-dependent manner in hippocampal neurons. Mice fed Rosi show increased hippocampal NF-α1 levels and neurogenesis compared with controls, thereby indicating the antidepressant action of this drug. Development of drugs that activate the NF-α1/FGF2/neurogenesis pathway can offer a new approach to depression therapy.
authors.affiliation: Section on Cellular Neurobiology, Program on Developmental Neuroscience, Bethesda, MD, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Durham, NC, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Rodriguiz
authors.affiliation: Section on Cellular Neurobiology, Program on Developmental Neuroscience, Bethesda, MD, USA.
authors.forename: S R K
authors.initials: SR
authors.lastname: Murthy
authors.affiliation: Section on Cellular Neurobiology, Program on Developmental Neuroscience, Bethesda, MD, USA.
authors.forename: V
authors.initials: V
authors.lastname: Senatorov
authors.affiliation: Section on Cellular Neurobiology, Program on Developmental Neuroscience, Bethesda, MD, USA.
authors.forename: E
authors.initials: E
authors.lastname: Thouennon
authors.affiliation: Section on Cellular Neurobiology, Program on Developmental Neuroscience, Bethesda, MD, USA.
authors.forename: N X
authors.initials: NX
authors.lastname: Cawley
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Durham, NC, USA.
authors.forename: D K
authors.initials: DK
authors.lastname: Aryal
authors.affiliation: Program in Genomics Differentiation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
authors.forename: S
authors.initials: S
authors.lastname: Ahn
authors.affiliation: Departments of Orthopaedic Surgery and Physiology and Pharmacology, Center for Diabetes and Endocrine Research, University of Toledo Health Sciences Campus, Toledo, OH, USA.
authors.forename: B
authors.initials: B
authors.lastname: Lecka-Czernik
authors.affiliation: 1] Department of Psychiatry and Behavioral Sciences, Durham, NC, USA [2] Departments of Neurobiology and Cell Biology, Duke University Medical Center, Durham, NC, USA.
authors.forename: W C
authors.initials: WC
authors.lastname: Wetsel
authors.affiliation: Section on Cellular Neurobiology, Program on Developmental Neuroscience, Bethesda, MD, USA.
authors.forename: Y P
authors.initials: YP
authors.lastname: Loh
mesh_terms: D000818:Animals; D043423:Carboxypeptidase H / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003863:Depression / Q000209:etiology / Q000235:genetics / Q000517:prevention & control*; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D005518:Food Preferences / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology*; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects*; D009479:Neuropeptides / Q000378:metabolism; D000077154:Rosiglitazone; D013315:Stress, Psychological / Q000150:complications; D013395:Sucrose / Q000008:administration & dosage; D013549:Sweetening Agents; D013550:Swimming / Q000523:psychology; D045162:Thiazolidinediones / Q000627:therapeutic use*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D000089622:Doublecortin Domain Proteins; D007004:Hypoglycemic Agents; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D013549:Sweetening Agents; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D013395:Sucrose; D043423:Carboxypeptidase H