Comorbid impairments of emotional and cognitive functions induced by different sleep deprivation durations

Sleep deprivation (SD) is a major risk factor for neuropsychiatric disorders and is known to induce comorbid emotional and cognitive impairments; however, the temporal dynamics and underlying mechanistic pathways remain poorly defined. Here, we established a standardized rotating rod-based SD model using male ICR mice (4-6 weeks old) to systematically investigate the effects of different SD durations. (1, 2, 3, or 7 days) on emotional and cognitive functions and the potential involvement of ferroptosis-related mechanisms. Emotional and cognitive functions were evaluated using a battery of behavioral tests. Hippocampal morphology was assessed by hematoxylin-eosin staining, while hippocampal ferrous iron content, systemic oxidative stress markers including total antioxidant capacity, glutathione, and malondialdehyde, together with ferroptosis-related protein expression were quantified. Our study demonstrated that 1-day SD induced anxiety-like behaviors and a stress-induced hyperactive state, accompanied by mild cognitive deficits. In contrast, prolonged SD (3- and 7-day SD) progressively promoted depressive-like behaviors accompanied by worsening cognitive deficits. Histological analysis revealed duration-dependent neuronal loss and structural damage in the hippocampal CA1 and CA3 regions. Biochemical analyses revealed duration-dependent alterations in hippocampal Fe²⁺ levels, with marked lipid peroxidation dysregulation emerging after 7-day SD. Western blotting analysis indicated that 7-day SD markedly disrupted hippocampal ferroptosis-related SIRT1/SLC7A11/GPX4 signaling pathways. In conclusion, SD induce duration-dependent comorbid emotional and cognitive dysfunction, accompanied by hippocampal injury and ferroptosis-related alterations. These findings provide preliminary evidence for a potential link between SD-induced neurobehavioral impairments and ferroptosis-related changes, warranting further mechanistic investigation.