title: Forebrain-specific CRF overproduction during development is sufficient to induce enduring anxiety and startle abnormalities in adult mice.
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.
authors: 1] Department of Psychiatry, University of California San Diego, La Jolla, CA, USA [2] Center of Excellence for Stress and Mental Health, Veterans Affairs Hospital, La Jolla, CA, USA.
authors: Mate
authors: M
authors: Toth
authors: 1] Department of Psychiatry, University of California San Diego, La Jolla, CA, USA [2] Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY, USA.
authors: Jodi E
authors: JE
authors: Gresack
authors: 1] Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA [2] Department of Psychology and Neuroscience Program, Temple University, Philadelphia, PA, USA.
authors: Debra A
authors: DA
authors: Bangasser
authors: Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors: Zach
authors: Z
authors: Plona
authors: Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors: Rita J
authors: RJ
authors: Valentino
authors: Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
authors: Elizabeth I
authors: EI
authors: Flandreau
authors: Brain Research Institute, University and ETH Zürich, Zürich, Switzerland.
authors: Isabelle M
authors: IM
authors: Mansuy
authors: Neuroscience Disease Therapeutic Area, Pharmaceutical Division, F. Hoffman-La Roche, Basel, Switzerland.
authors: Emilio
authors: E
authors: Merlo-Pich
authors: 1] Department of Psychiatry, University of California San Diego, La Jolla, CA, USA [2] Center of Excellence for Stress and Mental Health, Veterans Affairs Hospital, La Jolla, CA, USA.
authors: Mark A
authors: MA
authors: Geyer
authors: 1] Department of Psychiatry, University of California San Diego, La Jolla, CA, USA [2] Center of Excellence for Stress and Mental Health, Veterans Affairs Hospital, La Jolla, CA, USA.
authors: Victoria B
authors: VB
authors: Risbrough
mesh_terms: D000818:Animals; D001007:Anxiety / Q000503:physiopathology*; D001362:Avoidance Learning / Q000502:physiology; D003213:Conditioning, Psychological / Q000502:physiology; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000502:physiology; D005239:Fear / Q000502:physiology; D005260:Female; D006185:Habituation, Psychophysiologic / Q000502:physiology; D007266:Inhibition, Psychological; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016548:Prosencephalon / Q000254:growth & development* / Q000503:physiopathology*; D013216:Reflex, Startle / Q000502:physiology*; D055139:Sensory Gating / Q000502:physiology; D012737:Sex Factors; D013315:Stress, Psychological / Q000503:physiopathology
chemical_list: D003346:Corticotropin-Releasing Hormone