title: Sprouty2 in the dorsal hippocampus regulates neurogenesis and stress responsiveness in rats.
abstract: Both the development and relief of stress-related psychiatric conditions such as major depression (MD) and post-traumatic stress disorder (PTSD) have been linked to neuroplastic changes in the brain. One such change involves the birth of new neurons (neurogenesis), which occurs throughout adulthood within discrete areas of the mammalian brain, including the dorsal hippocampus (HIP). Stress can trigger MD and PTSD in humans, and there is considerable evidence that it can decrease HIP neurogenesis in laboratory animals. In contrast, antidepressant treatments increase HIP neurogenesis, and their efficacy is eliminated by ablation of this process. These findings have led to the working hypothesis that HIP neurogenesis serves as a biomarker of neuroplasticity and stress resistance. Here we report that local alterations in the expression of Sprouty2 (SPRY2), an intracellular inhibitor of growth factor function, produces profound effects on both HIP neurogenesis and behaviors that reflect sensitivity to stressors. Viral vector-mediated disruption of endogenous Sprouty2 function (via a dominant negative construct) within the dorsal HIP of adult rats stimulates neurogenesis and produces signs of stress resilience including enhanced extinction of conditioned fear. Conversely, viral vector-mediated elevation of SPRY2 expression intensifies the behavioral consequences of stress. Studies of these manipulations in HIP primary cultures indicate that SPRY2 negatively regulates fibroblast growth factor-2 (FGF2), which has been previously shown to produce antidepressant- and anxiolytic-like effects via actions in the HIP. Our findings strengthen the relationship between HIP plasticity and stress responsiveness, and identify a specific intracellular pathway that could be targeted to study and treat stress-related disorders.
authors.affiliation: Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts, United States of America.
authors.forename: Antonia L
authors.initials: AL
authors.lastname: Dow
authors.affiliation: Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts, United States of America.
authors.forename: Tiffany V
authors.initials: TV
authors.lastname: Lin
authors.affiliation: Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts, United States of America.
authors.forename: Elena H
authors.initials: EH
authors.lastname: Chartoff
authors.affiliation: Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Potter
authors.affiliation: Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts, United States of America.
authors.forename: Donna L
authors.initials: DL
authors.lastname: McPhie
authors.affiliation: Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts, United States of America.
authors.forename: Ashlee V
authors.initials: AV
authors.lastname: Van't Veer
authors.affiliation: Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts, United States of America.
authors.forename: Allison T
authors.initials: AT
authors.lastname: Knoll
authors.affiliation: Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts, United States of America.
authors.forename: Kristen N
authors.initials: KN
authors.lastname: Lee
authors.affiliation: Viral Gene Transfer Core Facility, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
authors.forename: Rachael L
authors.initials: RL
authors.lastname: Neve
authors.affiliation: Department of Pharmacology, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois, United States of America.
authors.forename: Tarun B
authors.initials: TB
authors.lastname: Patel
authors.affiliation: Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts, United States of America.
authors.forename: Dost
authors.initials: D
authors.lastname: Ongur
authors.affiliation: Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts, United States of America.
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Cohen
authors.affiliation: Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts, United States of America.
authors.forename: William A
authors.initials: WA
authors.lastname: Carlezon
mesh_terms: D000818:Animals; D003863:Depression / Q000378:metabolism / Q000503:physiopathology; D003865:Major Depressive Disorder / Q000378:metabolism / Q000503:physiopathology; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D055495:Neurogenesis / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013313:Stress Disorders, Post-Traumatic / Q000378:metabolism / Q000503:physiopathology; D013315:Stress, Psychological / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D009419:Nerve Tissue Proteins; C404992:Spry2 protein, rat; D016222:Fibroblast Growth Factor 2
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