Abstract
The mechanisms by which childhood maltreatment increases anxiety is unclear, but a propensity for increased defensive behavior in rodent models of early life stress (ELS) suggests that work in rodents may clarify important mechanistic details about this association. A key challenge in studying the effects of ELS on defensive behavior in rodents is the plethora of inconsistent results. This is particularly prominent with the maternal separation (MS) literature, one of the most commonly used ELS models in rodents. To address this issue we conducted a systematic review and meta-analysis, examining the effects of MS on exploratory-defensive behavior in mice and rats using the open field test (OFT) and the elevated plus maze (EPM). This search yielded a total of 49 studies, 24 assessing the effect of MS on behavior in the EPM, 11 tested behavior in the OFT, and 14 studies provided data on both tasks. MS was associated with increased defensive behavior in rats (EPM: Hedge’s g = −0.48, p = 0.02; OFT: Hedge’s g = −0.33, p = 0.05), effect sizes that are consistent with the anxiogenic effect of early adversity reported in humans. In contrast, MS did not alter exploratory behavior in mice (EPM: Hedge’s g = −0.04, p = 0.75; OFT: Hedge’s g = −0.03, p = 0.8). There was a considerable amount of heterogeneity between studies likely related to the lack of standardization of the MS protocol. Together, these findings suggest important differences in the ability of MS to alter circuits that regulate defensive behaviors in mice and rats.
Highlights
Childhood maltreatment is a heterogenous group of adversities that includes parental neglect/abuse, poverty, neighborhood violence, and bullying by peers[1,2]
The overall effect of maternal separation was significant in the elevated plus maze (EPM) [Hedges g = −0.31 ± 0.11 (95% confidence interval (CI) = −0.52–(−0.10)), z = −2.85, p = 0.004, k = 67 treatment arms] with significant heterogeneity between studies
Given the robust increase in anxiety and defensive behaviors seen in clinical setting[3,4,12,13,14], we focused on the effects of maternal separation (MS), one of the most commonly used paradigms of early life stress in rodents, on defensive-exploratory behavior in the EPM (n = 1529) and open field test (OFT) (n = 1117)
Summary
Childhood maltreatment is a heterogenous group of adversities that includes parental neglect/abuse, poverty, neighborhood violence, and bullying by peers[1,2]. Different types of adversities co-occur to increase the risk for developing multiple psychiatric and medical conditions in a dose-dependent manner[3,4,5,6]. One of the most robust clinical findings in individuals exposed to childhood maltreatment is a 2–3 fold increase in the odds-ratio for developing anxiety disorder[3,4,12,13,14], including conditions such as specific phobias, social anxiety, and panic disorders that have prominent defensive features such as increased autonomic responses and avoidance[15]. The defensive circuitry, unlike higher cortical processing of subjective experiences, is relatively conserved between humans and rodents[15]
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