Exercise Attenuates Hindpaw Hypersensitivity, Depression-like Behaviors, and Morphological Changes in the Hippocampus of Mice Exposed to Early Life Stress

Abstract

Early life stress (ELS) is associated with the development of chronic pain and mood disorders. Exposure to ELS has been correlated with suppressed hippocampal neurogenesis across the lifespan. Conversely, exercise promotes hippocampal neurogenesis, as well as prevents pain-like behaviors in ELS mice. Here, we are using an established mouse model of ELS, neonatal maternal separation (NMS), to test the hypothesis that increasing physical activity can attenuate ELS-induced pain- and depression-like behaviors and increase hippocampal neurogenesis. NMS was performed by separating whole litters from the dam for 3h/day from postnatal day 1 (P1) to P21. Mice were weaned and pair-housed with same-sex littermates on P22 and remained in sedentary caging (-Sed) or were given running wheels (-Ex) at 4 weeks of age. Mice underwent monthly hindpaw von Frey and Hargreaves testing for 4 months and were subsequently tested for sucrose preference and nest building. Ethynyldeoxyuridine (EdU) was used to quantify hippocampal neurogenesis at 5 months of age. A significant impact of NMS and exercise was observed on mechanical sensitivity in female mice, such that NMS-Ex mice had higher thresholds compared to NMS-Sed and naive-Ex mice. Male NMS-Sed mice had significantly lower withdrawal thresholds compared to naive-Sed mice, only at the end of the study. A significant impact of exercise and an NMS/Ex interaction was observed on female thermal latency with naive-Ex mice having lower withdrawal latencies. Male NMS-Ex mice had significantly lower sucrose preference compared to NMS-Sed and naive-Ex mice. Exercise significantly increased nest construction quality in female mice, with NMS-Sed mice having lower scores than naive-Sed or NMS-Ex mice. Finally, exercise increased the number of EdU-immuno-positive cells in the hippocampus of NMS mice. Taken together, our results suggest that increased voluntary physical activity can prevent the development of ELS-associated outcomes, including hypersensitivity, depression-like behaviors, and decreased hippocampal neurogenesis. This work was supported by RO1DK099611 (JAC), RO1DK103872 (JAC), T32HD057850 (BML), COBRE grant P20GM104936, IDeA grant P20GM103418, core support from IDDRC grant P30HD002528.