Early-life stress alters sleep structure and the excitatory-inhibitory balance in the nucleus accumbens in aged mice

Background: Exposure to adverse experiences in early life may profoundly reshape the neurodevelopmental trajectories of the brain and lead to long-lasting behavioral and neural alterations. One deleterious effect of early-life stress that manifests in later life is sleep disturbance, but this has not been examined in aged mice and the underlying neural mechanisms remain unknown. Considering the important role of the nucleus accumbens (NAc) in the sleep-wake regulation, this study aimed to assess the effects of early-life stress on the sleep behaviors in aged mice and the potential involvement of the NAc in stress-induced sleep abnormalities. Methods: Twenty aged male C57BL/6 mice (>16 months, n = 10 per group) were used in this study. During post-natal days 2 to 9, dams were provided with either sufficient (control) or a limited nesting and bedding materials (stressed). When the mice were 16 to 17 months old, their sleep-wake behaviors were recorded over 24 h using electroencephalogram and electromyelogram. The amount of each sleep-wake stage, mean duration, and stage transition was analyzed. Then, five animals were randomly chosen from each group and were used to measure the expression levels of vesicular glutamate transporter-1 (VGluT1) and vesicular transporters of gamma-aminobutyric acid (VGAT) in the NAc using immunohistochemistry. Group comparisons were carried out using Student t rest or analysis of variances when appropriate. Results: Compared with the control mice, the early-life stressed aged mice spent less time awake over 24 h (697.97 +/- 77.47 min vs. 631.33 +/- 34.73 min, t(17) = 2.376, A = 0.030), accordingly, non-rapid eye movement sleep time was increased (667.37 +/- 62.07 min vs. 723.54 +/- 39.21 min, t(17) = 2.326, P = 0.033) and mean duration of rapid eye movement sleep was prolonged (73.00 +/- 8.98 min vs. 89.39 +/- 12.69 min, t(17) = 3.277, P = 0.004). Meanwhile, we observed decreased VGluT1/VGAT ratios in the NAc in the stressed group (F-(1,F-16) = 81.04, P < 0.001). Conclusion: Early adverse experiences disrupt sleep behaviors in aged mice, which might be associated with the excitatory-inhibitory imbalance in the NAc.