Forebrain-specific CRF overproduction during development is sufficient to induce enduring anxiety and startle abnormalities in adult mice

M. Tóth, Jodi E. Gresack, Debra A. Bangasser, Zach Plona, Rita J. Valentino, Elizabeth I. Flandreau, Isabelle M. Mansuy, Emilio Merlo-Pich, Mark A. Geyer, Victoria B. Risbrough

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Corticotropin releasing factor (CRF) regulates physiological and behavioral responses to stress. Trauma in early life or adulthood is associated with increased CRF in the cerebrospinal fluid and heightened anxiety. Genetic variance in CRF receptors is linked to altered risk for stress disorders. Thus, both heritable differences and environmentally induced changes in CRF neurotransmission across the lifespan may modulate anxiety traits. To test the hypothesis that CRF hypersignaling is sufficient to modify anxiety-related phenotypes (avoidance, startle, and conditioned fear), we induced transient forebrain-specific overexpression of CRF (CRFOE) in mice (1) during development to model early-life stress, (2) in adulthood to model adult-onset stress, or (3) across the entire postnatal lifespan to model heritable increases in CRF signaling. The consequences of these manipulations on CRF peptide levels and behavioral responses were examined in adulthood. We found that transient CRFOE during development decreased startle habituation and prepulse inhibition, and increased avoidance (particularly in females) recapitulating the behavioral effects of lifetime CRFOE despite lower CRF peptide levels at testing. In contrast, CRFOE limited to adulthood reduced contextual fear learning in females and increased startle reactivity in males but did not change avoidance or startle plasticity. These findings suggest that forebrain CRFOE limited to development is sufficient to induce enduring alterations in startle plasticity and anxiety, while forebrain CRFOE during adulthood results in a different phenotype profile. These findings suggest that startle circuits are particularly sensitive to forebrain CRFOE, and that the impact of CRFOE may be dependent on the time of exposure.

Original languageEnglish
Pages (from-to)1409-1419
Number of pages11
JournalNeuropsychopharmacology
Volume39
Issue number6
DOIs
Publication statusPublished - 2014

Fingerprint

Corticotropin-Releasing Hormone
Prosencephalon
Anxiety
Fear
Corticotropin-Releasing Hormone Receptors
Phenotype
Peptides
Psychological Stress
Synaptic Transmission
Cerebrospinal Fluid
Learning
Wounds and Injuries

Keywords

  • anxiety
  • CRF overexpression
  • development
  • sex differences
  • startle

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health
  • Medicine(all)

Cite this

Forebrain-specific CRF overproduction during development is sufficient to induce enduring anxiety and startle abnormalities in adult mice. / Tóth, M.; Gresack, Jodi E.; Bangasser, Debra A.; Plona, Zach; Valentino, Rita J.; Flandreau, Elizabeth I.; Mansuy, Isabelle M.; Merlo-Pich, Emilio; Geyer, Mark A.; Risbrough, Victoria B.

In: Neuropsychopharmacology, Vol. 39, No. 6, 2014, p. 1409-1419.

Research output: Contribution to journalArticle

Tóth, M, Gresack, JE, Bangasser, DA, Plona, Z, Valentino, RJ, Flandreau, EI, Mansuy, IM, Merlo-Pich, E, Geyer, MA & Risbrough, VB 2014, 'Forebrain-specific CRF overproduction during development is sufficient to induce enduring anxiety and startle abnormalities in adult mice', Neuropsychopharmacology, vol. 39, no. 6, pp. 1409-1419. https://doi.org/10.1038/npp.2013.336
Tóth, M. ; Gresack, Jodi E. ; Bangasser, Debra A. ; Plona, Zach ; Valentino, Rita J. ; Flandreau, Elizabeth I. ; Mansuy, Isabelle M. ; Merlo-Pich, Emilio ; Geyer, Mark A. ; Risbrough, Victoria B. / Forebrain-specific CRF overproduction during development is sufficient to induce enduring anxiety and startle abnormalities in adult mice. In: Neuropsychopharmacology. 2014 ; Vol. 39, No. 6. pp. 1409-1419.
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