Abstract
The goal of this study was to quantitatively assess the changes in the cerebral neurochemical profile and to identify those factors that contribute to the alteration of endogenous biomolecules when rats are subjected to stress-induced sleep disturbance. We exposed Sprague-Dawley rats (controls: n = 9; stress-induced sleep perturbation rats: n = 11) to a psychological stressor (cage exchange method) to achieve stress-induced sleep perturbation. In vivo magnetic resonance imaging assessments were carried out using a high-resolution 9.4 T system. For in vivo neurochemical analysis, a single voxel was localized in the right dorsal hippocampal region, and in vivo spectra were quantified for 17 cerebral neurochemical signals. Rats were sacrificed upon completion of the magnetic resonance spectroscopy protocol, and whole-brain tissue was harvested from twenty subjects. The dopamine and serotonin signals were obtained by performing in vitro liquid chromatography-tandem mass spectrometry on the harvested tissue. In the right dorsal hippocampal region, the gamma-aminobutyric-acid (GABA) and glutamine (Gln) concentrations were significantly higher in the sleep-perturbed rats than in the sham controls. The ratios of Gln/Glu (glutamate), Gln/tCr (total-creatine), and GABA/Glu were also significantly higher in the sleep-perturbed group, while serotonin concentrations were significantly lower in the sleep-perturbed rats. Pearson correlation results among individual rat data indicate that concentrations of dopamine (DA) and serotonin (5-HT) were significantly higher in SSP rats. A larger correlation coefficient was also observed for the SSP rats. Analysis of the correlation between the in vivo and in vitro signals indicated that the concentrations of Gln, 5-HT, and DA exhibited a significant negative correlation in the SSP rat data but not in that of control rats. The authors propose that the altered and correlated GABA, Gln, 5-HT, and DA concentrations/ratios could be considered key markers of neurological function in animal models of stress-induced sleep perturbation.
Highlights
A stressful event can significantly influence sleep—wake behavior in all animals [1,2]
The present study evaluated the uncertainty of data fitting with regard to spectral analysis and only utilized values with Cramer-Rao lower bounds (CRLBs) exhibiting less than 30% standard deviation
To the best of our knowledge, our study is the first to use in vivo 1H MRS in combination with in vitro LC-MS/MS in a rat model to quantitatively assess the influences of stress-induced sleep perturbation on the cerebral neurochemical and endogenous biomolecular profile of the hippocampal region
Summary
A stressful event can significantly influence sleep—wake behavior in all animals [1,2]. Stressinduced sleep perturbation (SSP) is a primary component of many pathophysiological conditions (i.e., those that cannot be attributed to psychiatric or medical disorders, substance abuse, or pain-related conditions), including post-traumatic stress disorder (PTSD) [2,3]. Brady and Sinha reported that excessive exposure to stress is associated with alterations in the neurobiology of the brain and may lead to an increased risk of various psychiatric illnesses in humans, including PTSD [7]. Insomnia in PTSD is associated with an impairment of prolonged sleep, difficulties in continuing/maintaining sleep, reduced alertness, fatigue, and other symptoms [8,9]. The present study will quantitatively assess the differences in neurochemical changes associated with sleep disturbance between sham controls and stress-induced models
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