4.8 Article

Targeting Kruppel-like Factor 9 in Excitatory Neurons Protects against Chronic Stress-Induced Impairments in Dendritic Spines and Fear Responses

Journal

CELL REPORTS
Volume 23, Issue 11, Pages 3183-3196

Publisher

CELL PRESS
DOI: 10.1016/j.celrep.2018.05.040

Keywords

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Categories

Funding

  1. NARSAD Young Investigator Award
  2. Bettencourt Schueller Foundation
  3. Philippe Foundation
  4. Massachusetts General Hospital (MGH) ECOR Fund for Medical Discovery (FMD) Postdoctoral Fellowship Awards
  5. NIH Biobehavioral Research Awards for Innovative New Scientists (BRAINS) [1-R01MH104175]
  6. NIH-National Institute on Aging (NIA) grant [1R01AG048908-01A1]
  7. NIH [1R01MH111729-01, MH83862, MH64168, MH40210, NS090415, MH94888, MH090964, MH098786]
  8. Ellison Medical Foundation New Scholar in Aging
  9. Whitehall Foundation
  10. Inscopix Decode award
  11. NARSAD Independent Investigator Award
  12. Ellison Family Philanthropic support
  13. Blue Guitar Fund
  14. Harvard NeuroDiscovery Center/MADRC Center Pilot Grant Award
  15. Harvard Stem Cell Institute (HSCI) Development grant
  16. HSCI seed grant
  17. American Foundation for Suicide Prevention Standard Research Grant [SRG-0-129-12]
  18. Brain and Behavior Research Foundation Independent Investigator Grant [56388]
  19. New York Stem Cell Initiative (NYSTEM) [C029157, C023054]
  20. Stroud Center for Aging Studies at Columbia University
  21. Diane Goldberg Foundation

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Stress exposure is associated with the pathogenesis of psychiatric disorders, including post-traumatic stress disorder (PTSD) and major depressive disorder (MDD). Here, we show in rodents that chronic stress exposure rapidly and transiently elevates hippocampal expression of Kruppel-like factor 9 (Klf9). Inducible genetic silencing of Klf9 expression in excitatory forebrain neurons in adulthood prior to, but not after, onset of stressor prevented chronic restraint stress (CRS)-induced potentiation of contextual fear acquisition in female mice and chronic corticosterone (CORT) exposure-induced fear generalization in male mice. Klf9 silencing prevented chronic CORT and CRS induced enlargement of dendritic spines in the ventral hippocampus of male and female mice, respectively. KLF9 mRNA density was increased in the anterior dentate gyrus of women, but not men, with more severe recent stressful life events and increased mortality. Thus, Klf9 functions as a stress-responsive transcription factor that mediates circuit and behavioral resilience in a sex-specific manner.

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