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Experimentally-induced total sleep deprivation (TSD) and chronic partial sleep restriction (CPSR) leads to the emergence of cognitive impairments. This is hypothesized to result from a consequent neuroinflammation which may also hasten the neurodegenerative processes. Neuroinflammatory markers such as tumor necrosis factor-alpha (TNFα) are thought to be potential culprits in SD-induced neurodegeneration. The effect of TSD and CPSR on memory and anxiety-related behaviors (using the Elevated Plus-Maze test-retest protocol) and serum level of brain derived neurotrophic factor (BDNF) and corticosterone were assessed in male Wistar rats subjected to the modified disk-over-water (DOW) apparatus. In addition, an immunohistochemical (IHC) study was done to possibly detect the amyloid-beta (Aβ) and hyper-phosphorylated tau protein (HPτ) deposition in the dentate gyrus (DG) of the examined rats' hippocampi. Histomorphology and neuronal numerical density assessments were done at the same level across control and experimental animals. We also studied the above parameters in rats after intraperitoneal injection of the TNFα neutralizing antibody, infliximab (IFX). Rats subjected to TSD and CPSR which did not receive IFX, showed a more pronounced impairment of memory, elevated serum corticosterone and decreased BDNF levels. CPSR rats which underwent delayed brain excision following behavioral testing, showed deposition of the HPτ and revealed the least numerical density in the hippocampal DG neurons. Meanwhile, IHC study revealed no Aβ deposition in the hippocampal DG of all examined rats. Interestingly, treatment with IFX, abrogated sleep restriction-induced cognitive decline, biochemical changes and the immunohistopathology in the hippocampal DG. Taken together, our findings indicated that CPSR (the SD model mimicking shift work) induces not only cognitive and biochemical changes, but also pathology in the hippocampal DG. This is possibly via activation of the inflammatory mechanisms in part through TNFα-dependent pathways.