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

Abstract

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 γ-aminobutyric acid (VGAT) in the NAc using immunohistochemistry. Group comparisons were carried out using Student t test 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, P = 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, 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.

The arousal-motor hypothesis of dopamine function: evidence that dopamine facilitates reward seeking in part by maintaining arousal

“…Conversely, activation and inhibition of VTA GABA neurons was found to promote sleep and wakefulness, respectively (Chowdhury et al, 2019; Yu et al, 2019), in part due to the impact of these manipulations on the activity of VTA dopamine neurons. Because the VTA is the major source of dopaminergic innervation of the NAc, these findings are consistent with multiple additional lines of evidence implicating the NAc in the regulation of arousal and sleep (Barik and de Beaurepaire, 2005; Lazarus et al, 2011; Lena et al, 2005; Luo et al, 2018; Oishi et al, 2017b; Qiu et al, 2012; Wang et al, 2019; Zhou et al, 2019). For example, the wake-promoting actions of caffeine (Lazarus et al, 2011) and modafinil (Qiu et al, 2012) crucially depend on their effects in the NAc.…”

The Arousal-motor Hypothesis of Dopamine Function: Evidence that Dopamine Facilitates Reward Seeking in Part by Maintaining Arousal

“…Conversely, activation and inhibition of VTA GABA neurons was found to promote sleep and wakefulness, respectively (Chowdhury et al, 2019;Yu et al, 2019), in part due to the impact of these manipulations on the activity of VTA dopamine neurons. Because the VTA is the major source of dopaminergic innervation of the NAc, these findings are consistent with multiple additional lines of evidence implicating the NAc in the regulation of (Barik and de Beaurepaire, 2005;Lazarus et al, 2011;Lena et al, 2005;Luo et al, 2018;Oishi et al, 2017b;Qiu et al, 2012;Wang et al, 2019;Zhou et al, 2019). For example, the wake-promoting actions of caffeine (Lazarus et al, 2011) and modafinil (Qiu et al, 2012) crucially depend on their effects in the NAc.…”

Exposure to Prenatal Stress Is Associated With an Excitatory/Inhibitory Imbalance in Rat Prefrontal Cortex and Amygdala and an Increased Risk for Emotional Dysregulation

“…Sex-related discrepancies were consistent for the vesicular transporters Vglut1 and Vgat and their ratio (Wang et al, 2019) in the PFC, where PNS males showed increased levels of Vglut1 expression and, consequently, higher Vglut1:Vgat, than did controls, which may foster dysregulation of the prefrontal glutamatergic system. On the other hand, females did not exhibit any effect of PNS on these genes in this region.…”