CRF2 null mutation increases sensitivity to isolation rearing effects on locomotor activity in mice

Abstract

Background: Developmental stressors are consistently reported to increase risk for certain neuropsychiatric disorders including schizophrenia, depression, and post-traumatic stress disorder. Recent clinical evidence supports a "double-hit" hypothesis of genetic vulnerability interacting with developmental challenges to modulate this risk. Early life stressor effects on behavior may be modulated in part by alterations in corticotropin releasing factor (CRF) signaling via two known receptors, CRF(1) and CRF(2). One extant hypothesis is that CRF(2) activation may modulate long-term adaptive responses after homeostatic challenge. As such, loss of CRF(2) activity via genetic variance may increase sensitivity to the long-term effects of developmental stress.

Methods: We tested the hypothesis that CRF(2) function may mitigate the behavioral effects of isolation rearing, predicting that loss of CRF(2) function increases sensitivity to this developmental challenge. Using the behavioral pattern monitor (BPM), we examined exploratory behavior and locomotor patterns in adult CRF(2) wild-type (WT) and gene knockout (KO) mice reared socially or in isolation.

Results: Isolation housing produced robust increases in the amount of locomotor activity and investigatory holepoking, and altered the temporal distribution of activity in CRF(2) KO but not CRF(2) WT mice. Isolation housing significantly increased rearing behavior and altered spatial patterns of locomotor activity regardless of genotype.

Conclusions: Loss of CRF(2) function increased sensitivity to the effects of chronic social isolation on exploratory locomotor behavior. Thus, CRF(2) activation appears to mitigate isolation rearing effects on exploratory behavior. Further research assessing the interaction between CRF(2) function and developmental challenges is warranted.

Figure 1

CRF₂ KO mice exhibit greater sensitivity to isolation rearing effects on exploratory activity. Data depicted are mean+/−SEM number of transitions (top panels), holepokes (center panels), and rearings (bottom panels) across CRF₂ receptor wild-type (WT, left panels) and knockout (KO, right panels) mice. *p<0.05 Post-hoc simple comparison of housing effects in KO mice for transitions and hole poke measures. +p<0.05 Main effect of housing across both genotypes on rearing behavior, see results for details.

Figure 2

Locomotor exploration paths. Plots depict the x–y position (in black) and holepoke frequency (each red dot represents a holepoke event) during the last 30 min block of the 60 min session. Representative mice were chosen based on having the most similar transitions and holepoke frequency as their respective group average. Columns depict housing status (social or isolation) and rows depict genotype (CRF₂ WT or KO).