Chronic REM Sleep Deprivation Induces Metabolic and Neurotoxic Alterations Associated with Affective and Cognitive Deficit in Male Wistar Rats: Involvement of HPA Axis, Cholinergic, Inflammatory, and Oxidative Stress Pathways.

Diabetes is a metabolic condition characterized by increased blood glucose levels resulting from defects in insulin secretion, utilization, or both. Sleep deprivation (SD) can alter homeostasis, while the consequences of diabetes can disrupt sleep homeostasis. These findings support the hypothesis of a bidirectional interaction between sleep homeostasis, metabolic disorders, and neurological or behavioral disorders. The present study aims to investigate the bidirectional interaction between chronic REM-SD and metabolic disorders in rats by combining assessments of affective and cognitive behaviors (anxiety, depression, and memory function), metabolic (glucose homeostasis, glucose tolerance, insulin sensitivity), oxidative, cholinergic, cytotoxic, neuroinflammatory parameters, and histopathological change in hippocampus (HP), hypothalamus (HYP), and prefrontal cortex (PFC) in male Wistar rats. Eighteen male Wistar rats were divided into three groups (CON, WP, and CSD). The REM-SD was carried out for 18 h a day (from 4:00 p.m. to 10:00 a.m.) over a period of five weeks, using the modified multi-platform method (MMPM). Glucose (ipGTT) and insulin tolerance (ipITT), corticosterone and blood hs-CRP levels were evaluated, along with affective behaviors (anxiety- and depression-like) and cognitive functions, including spatial learning, recognition memory, working memory, and long-term memory. We also measured acetylcholinesterase (AchE) activity, neurotoxicity, and oxidative stress markers, as well as histopathological changes in the HP, HYP, and PFC of male Wistar rats. The results demonstrated that chronic REM-SD induced glucose intolerance and insulin resistance, leading to hyperglycemia, which was accompanied by low-grade inflammation and activation of the HPA axis. Regarding behavioral conditions, REM-SD induced anxiety, depression, and learning and memory impairments. Specifically, in relation to the brain region, REM-SD exhibited disruption in cholinergic neurotransmission, oxidative stress balance (increase in NO, MDA, and decrease in CAT and SOD activity), and neurotoxicity (increase in LDH levels). The r-Spearman correlation analysis showed that AchE activity and memory performance were strongly correlated in sleep-deprived rats. In addition, histological examination demonstrates that chronic REM-SD induced structural atrophy, neuronal degeneration, and a marked decrease in neuronal density in the PFC, HYP, and HP, specifically in the CA3 and DG. Briefly, this finding provides novel insight into the bidirectional interplay pathway between SD and metabolic disorders, and between the mechanisms linking sleep health, diabetes, and behavioral disorders. Consequently, our future studies aim to examine the effect of pharmacological treatments and sleep recovery on biochemical and neurobiochemical parameters, cholinergic neurotransmission, and brain architecture.