Abstract
Exposure to early life stress (ELS) causes abnormal hippocampal development and functional deficits in rodents and humans, but no meta-analysis has been used yet to quantify the effects of different rodent models of ELS on hippocampal-dependent memory. We searched PubMed and Web of Science for publications that assessed the effects of handling, maternal separation (MS), and limited bedding and nesting (LBN) on performance in the Morris water maze (MWM), novel object recognition (NOR), and contextual fear conditioning (CFC). Forty-five studies met inclusion criteria (n = 451–763 rodents per test) and were used to calculate standardized mean differences (Hedge’s g) and to assess heterogeneity, publication bias, and the moderating effects of sex and species (rats vs. mice). We found significantly lower heterogeneity in LBN compared to handling and MS with no consistent effects of sex or species across the three paradigms. LBN and MS caused similar cognitive deficits in tasks that rely heavily on the dorsal hippocampus, such as MWM and NOR, and were significantly different compared to the improved performance seen in rodents exposed to handling. In the CFC task, which relies more on the ventral hippocampus, all three paradigms showed reduced freezing with moderate effect sizes that were not statistically different. These findings demonstrate the utility of using meta-analysis to quantify outcomes in a large number of inconsistent preclinical studies and highlight the need to further investigate the possibility that handling causes different alterations in the dorsal hippocampus but similar outcomes in the ventral hippocampus when compared to MS and LBN.
Highlights
Life stress (ELS) impairs the development of several interconnected brain regions including the hippocampus, prefrontal cortex, striatum, and amygdala[1,2]
A forest plot summary of the effects of handling (7 studies, n = 162 rodents), maternal separation (MS) (15 studies, n = 338 rodents), and limited bedding and nesting (LBN) (11 studies, n = 243 rodents) on spatial learning in the Morris water maze (MWM) is shown in Fig. 1 and Fig. S2
Exposure to handing showed improved performance in the latency to find platform and probe trial of the MWM, with no clear difference compared to control condition in the novel object recognition (NOR) (Fig. S2). These results demonstrate both quantitative and qualitative differences between handling and MS and LBN in the MWM and NOR and are consistent with previous work showing that handling causes different outcomes in stress reactivity[33,37] and sensitivity to pain compared to MS30
Summary
Life stress (ELS) impairs the development of several interconnected brain regions including the hippocampus, prefrontal cortex, striatum, and amygdala[1,2]. Of these, reduced hippocampal volume and abnormal hippocampal function are some of the most reproducible findings in individuals exposed to ELS1,3,4 This is not surprising given that the hippocampus undergoes substantial developmental changes during childhood that are highly sensitive to stress[5,6,7]. The hippocampus forms extensive connections with other brain regions involved in declarative memory, spatial learning, threat detection, stress reactivity, and mood regulation[8,9]. These features make the hippocampus a potentially important hub in mediating several of the cognitive, emotional, and physiological abnormalities seen in individuals exposed to ELS1,3,4.
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