Abstract
Stress is one of major factors that cause sleep problems. Hypocretin represents a stress-related neuropeptide and is well known in maintaining physiological wakefulness. The hypocretinergic neurons originate in the lateral hypothalamic area (LHA) and transmit to several brain regions, including the median raphe nuclei (MRNs). The MRNs modulate both fear responses and sleep-wake activity; however, it remains unclear whether stress alters the levels of hypocretin to regulate MRNs and consequently disrupt sleep. In this paper, we employed the inescapable footshock stimuli (IFS) as a stressor and hypothesized that the IFS-induced sleep disruption is mediated by increased hypocretins in the MRNs. Our results demonstrate that the concentrations of hypocretin in the hypothalamus increased after IFS. Rapid eye movement (REM) sleep was reduced after footshock, and microinjection of non-selective hypocretin receptor antagonist TCS-1102 into the MRNs blocked the IFS-induced decrease of REM sleep. Furthermore, administration of hypocretins into the MRNs mimicked the IFS-induced REM sleep reduction. These results conclude that the increased levels of hypocretins in the MRNs mediate the IFS-induced REM sleep reduction.
Highlights
Both brain functions and mental processes are influenced by stress[1,2]
The time spent in NREM sleep and waking showed no significant change after the inescapable footshock stimuli (IFS) when compared to the data obtained after pyrogen-free saline (PFS) (Fig. 1A,B,D,E)
The time spent in NREM sleep was significantly decreased during the first 6 hours after the IFS (Fig. 2B,E)
Summary
Both brain functions and mental processes are influenced by stress[1,2]. Stress experiences in the daytime may cause sleep disturbances during the night[3]. Based on the rationales that hcrts mediate stress response[12], the MRN receives hypocretinergic afferents from LHA17, and the MRN regulates REM sleep activity[30], we hypothesized that hcrts in the MRNs play an important role in the IFS-induced REM sleep disruption. Especially for the IFS stressor, increases the releases of hcrts in the MRNs and subsequently mediates the IFS-induced sleep alterations To test this hypothesis, the expressions of hcrts and prepro-hcrt in the LHA after IFS were determined, the concentrations of hcrts in the hypothalamus after IFS were quantified by enzyme-linked immunosorbent assay (ELISA), hcrt receptor agonists or antagonist were administered into the bilateral MRNs with the IFS, and the sleep-wake activities were measured. We demonstrated the neuronal mechanism of sleep disturbance underlying the IFS stress
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