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. 2014 May;39(6):1409-19.
doi: 10.1038/npp.2013.336. Epub 2013 Dec 11.

Forebrain-specific CRF Overproduction During Development Is Sufficient to Induce Enduring Anxiety and Startle Abnormalities in Adult Mice

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Free PMC article

Forebrain-specific CRF Overproduction During Development Is Sufficient to Induce Enduring Anxiety and Startle Abnormalities in Adult Mice

Mate Toth et al. Neuropsychopharmacology. .
Free PMC article

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.

Figures

Figure 1
Figure 1
Histological verification of CRFOE during and following CRFOEdev, CRFOElife, and CRFOEadult. (a) Representative photomicrographs displaying CRF immunoreactivity (white) at PD90 in selected coronal sections from 1.18 mm to −5.40 mm relative to Bregma (Paxinos and Franklin, 2004). Distinct patterns of CRF immunoreactivity are shown (from left to right) in wild-type C57BL/6J mice, metallothionein promoter-driven CRFOE mice (MT-CRF), controls (double mutant, DOX off) and double mutant mice exposed to CRFOEdev, CRFOEadult, and CRFOElife. (b) Transient CRFOE during development indicated by in situ hybridization. Upper and middle panels show sagittal brain sections of CRFOEdev and control/DOX off mice, respectively, on PD7, PD14, PD23, and PD37. CRFOEdev mice exhibited a gradual increase of CRFOE from PD7 to PD23, which was reversed close to control levels by PD37. Lower panels show Nissl-stained sagittal brain sections of CRFOEdev mice. BNST, bed nucleus of stria terminalis; CA3, field CA3 of the hippocampus; CeA, central amygdala; Cer, cerebellum; CPu, caudate putamen; Ctx, neocortex; DG, dentate gyrus; DR, dorsal raphe; EP, entopeduncular nucleus; Hip, hippocampus; Hyp, hypothalamus; GP, globus pallidus; IC, inferior colliculus; peri-LC, surrounding area of the locus coeruleus; LS, lateral septum; PO, preoptic area; PVN, paraventricular nucleus of the hypothalamus; SNC, substantia nigra, compact part; SNR, substantia nigra, reticular part; VP, ventral pallidum; VTA, ventral tegmental area.
Figure 2
Figure 2
Changes of startle plasticity and sensorimotor gating. (a) Habituation of the startle response following CRFOEdev, CRFOElife, and CRFOEadult. Startle habituation was markedly diminished in both sexes following CRFOEdev. Male and female CRFOElife mice showed a similar trend, which was absent in CRFOEadult mice. (b) Prepulse inhibition of the startle response following CRFOEdev, CRFOElife, and CRFOEadult. CRFOEdev significantly reduced PPI in female mice whereas CRFOElife reduced PPI in both sexes with a more pronounced effect in males. In contrast, CRFOEadult had no effect on PPI. *p<0.05, #p<0.10 compared to same-sex control. Data are presented as mean±SEM.
Figure 3
Figure 3
Avoidance behavior in the light-dark box following CRFOEdev, CRFOElife, and CRFOEadult. CRFOEdev and CRFOElife but not CRFOEadult increased avoidance in female mice as indicated by the time spent in the dark compartment. Avoidance behavior in male subjects was not affected by CRFOE. *p<0.05 compared to same-sex control. Data are presented as mean±SEM.

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