Isolation rearing-induced deficits in contextual fear learning do not require CRF(2) receptors

Abstract

Post-weaning social isolation of rodents is used to model developmental stressors linked to neuropsychiatric disorders including schizophrenia as well as anxiety and mood disorders. Isolation rearing produces alterations in emotional memory and hippocampal neuropathology. Corticotropin releasing factor (CRF) signaling has recently been shown to be involved in behavioral effects of isolation rearing. Activation of the CRF(2) receptor is linked to stress-induced alterations in fear learning and may also be involved in long-term adaptation to stress. Here we tested the hypothesis that CRF(2) contributes to isolation rearing effects on emotional memory. At weaning, mice were housed either in groups of three or individually in standard mouse cages. In adulthood, isolation-reared mice exhibited significant reductions in context-specific, but not cue-specific, freezing. Isolation-reared mice exhibited no significant changes in locomotor exploration during brief exposure to a novel environment, suggesting that the reduced freezing in response to context cues was not due to activity confounds. Isolation rearing also disrupted context fear memory in mice with a CRF(2) gene null mutation, indicating that the CRF(2) receptor is not required for isolation effects on fear memory. Thus, isolation rearing disrupts hippocampal-dependent fear learning as indicated by consistent reductions in context-conditioned freezing in two separate cohorts of mice, and these effects are via a CRF(2)-independent mechanism. These findings may be clinically relevant because they suggest that isolation rearing in mice may be a useful model of developmental perturbations linked to disruptions in emotional memory in a variety of neuropsychiatric disorders.

Figure 1

Isolation rearing disrupts contextual (A) but not cued (B) fear learning. Mice reared in social groups (Social) or under isolation (Isolate) were trained for fear conditioning to a tone CS. Twenty four hours after training mice were re-exposed to the conditioning context (Panel A). Twenty four hours later mice were placed back into the chambers which had altered visual, tactile and odor cues and tested for freezing during the tone CS (Panel B). Note freezing to the tone CS is reported as total freezing to tone minus freezing before tone was presented. Data are expressed as mean+/−SEM of percent freezing. *p<0.05 vs. Socially housed group (Panel A) or Isolate group (Panel B), Tukey’s post hoc test.

Figure 2

Isolation induced disruption of context fear learning is independent of CRF₂ genotype. CRF₂ wildtype (WT) and gene knockout (KO) mice reared in social groups (Social) or under isolation (Isolate) were trained for fear conditioning to a tone CS. Twenty four hours after training mice were re-exposed to the conditioning context, with isolation reared mice exhibiting a significant reduction in freezing across genotype (Panel A). Twenty four hours later mice were placed back into the chambers which had altered visual, tactile and odor cues and tested for freezing during the tone CS (Panel B). Note freezing to the tone CS is reported as total freezing to tone minus freezing before tone was presented. Data are expressed as mean+/−SEM of percent freezing, see results section for detailed statistics. *p<0.05 vs. Socially-housed groups (i.e. significant main effect of Rearing Condition).