CX3C-Chemokine Receptor 1 Modulates Cognitive Dysfunction Induced by Sleep Deprivation

CX3C-Chemokine Receptor 1 Modulates Cognitive Dysfunction Induced by Sleep Deprivation

Sleep is a fundamental physiological process essential for maintaining human health. However, the fast-paced modern lifestyle often disrupts sleep cycles, leading to widespread sleep deprivation (SD), particularly among middle-aged individuals who face significant societal pressures. Sleep deprivation has been linked to various adverse health outcomes, including declined immunity, increased incidence of cerebrovascular diseases, and cognitive impairments. Notably, individuals with sleep disorders are at a higher risk of developing Alzheimer’s disease (AD) and other neurodegenerative conditions. The relationship between sleep deprivation and cognitive dysfunction has been increasingly studied, with microglia, the brain’s resident immune cells, emerging as key players in this process.

Microglia are critical for maintaining brain homeostasis and responding to pathological stimuli. Recent research has highlighted the role of microglial CX3C-chemokine receptor 1 (CX3CR1) in modulating neuroinflammation and synaptic pruning, processes that are implicated in cognitive decline. CX3CR1 is the sole receptor for CX3C-chemokine ligand 1 (CX3CL1), a chemokine highly expressed in the hippocampus, a brain region crucial for learning and memory. The CX3CL1/CX3CR1 signaling axis is essential for neuron-microglia communication, influencing microglial activation, synaptic pruning, and neuroinflammation.

This study aimed to investigate the role of CX3CR1 in modulating cognitive dysfunction induced by sleep deprivation. Middle-aged wild-type (WT) C57BL/6 mice and CX3CR1 knockout (CX3CR1⁻/⁻) mice were subjected to either 8 hours of sleep deprivation or normal sleep. Behavioral tests, histological analyses, and molecular assays were conducted to evaluate cognitive function, microglial activity, synaptic pruning, and inflammatory responses.

The findings revealed that CX3CR1 deficiency prevented sleep deprivation-induced cognitive impairments. Unlike WT mice, CX3CR1⁻/⁻ mice exhibited improved cognitive function following sleep deprivation. This was associated with reduced microglial activation, decreased expression of pro-inflammatory cytokines, and increased levels of anti-inflammatory cytokines in the hippocampus. Additionally, CX3CR1⁻/⁻ mice showed enhanced synaptic plasticity, as evidenced by increased dendritic spine density in the dentate gyrus (DG) region of the hippocampus. These results suggest that CX3CR1 plays a pivotal role in mediating the cognitive effects of sleep deprivation through its influence on microglial activity and synaptic pruning.

The study employed a comprehensive approach to assess the impact of CX3CR1 deficiency on sleep deprivation-induced cognitive dysfunction. Behavioral tests, including the fear conditioning test and open field test, were used to evaluate cognitive function and anxiety-like behavior. The fear conditioning test, which measures hippocampus-dependent learning and memory, showed that sleep deprivation significantly impaired cognitive function in WT mice but not in CX3CR1⁻/⁻ mice. The open field test, used to assess anxiety-like behavior, revealed no significant differences in activity levels among the groups, indicating that the observed cognitive effects were not confounded by stress or anxiety.

Histological analyses focused on microglial density and neuronal activity in the hippocampus. Immunohistochemistry for ionized calcium-binding adaptor molecule-1 (Iba-1), a microglial marker, showed that sleep deprivation increased microglial density in the DG region of WT mice. In contrast, CX3CR1⁻/⁻ mice exhibited reduced microglial activation following sleep deprivation. Similarly, the expression of c-fos, an immediate early gene indicative of neuronal activity, was elevated in WT mice after sleep deprivation but decreased in CX3CR1⁻/⁻ mice. These findings suggest that CX3CR1 deficiency attenuates microglial activation and neuronal stress responses induced by sleep deprivation.

Molecular assays were conducted to evaluate the expression of neurotrophic factors and inflammatory cytokines in the hippocampus. Western blot analysis revealed that CX3CR1⁻/⁻ mice had elevated levels of brain-derived neurotrophic factor (BDNF) and phosphorylated cAMP-responsive element binding protein (p-CREB) following sleep deprivation, indicating enhanced synaptic plasticity and neuroprotection. Real-time quantitative polymerase chain reaction (qRT-PCR) showed that CX3CR1⁻/⁻ mice had reduced expression of pro-inflammatory cytokines, such as interleukin-1 beta (IL-1β), and increased expression of anti-inflammatory cytokines, including arginase-1 (Arg-1) and interleukin-4 (IL-4). These changes in the inflammatory milieu likely contribute to the protective effects of CX3CR1 deficiency against sleep deprivation-induced cognitive dysfunction.

Synaptic pruning, a process by which microglia eliminate excess or dysfunctional synapses, is essential for maintaining synaptic plasticity and cognitive function. The study used Golgi staining to assess dendritic spine density in the DG region of the hippocampus. Sleep deprivation reduced spine density in WT mice, but this effect was reversed in CX3CR1⁻/⁻ mice, which exhibited increased spine density following sleep deprivation. This suggests that CX3CR1 deficiency prevents the excessive synaptic pruning induced by sleep deprivation, thereby preserving synaptic integrity and cognitive function.

The study also explored the role of other microglial factors involved in synaptic pruning, including triggering receptor expressed on myeloid cells 2 (TREM2) and complement component 3 (C3). qRT-PCR analysis showed that sleep deprivation increased the expression of TREM2 and C3 in WT mice, but these changes were attenuated in CX3CR1⁻/⁻ mice. This indicates that CX3CR1 deficiency reduces the phagocytic activity of microglia, further supporting the hypothesis that CX3CR1 modulates synaptic pruning and cognitive function in response to sleep deprivation.

The findings of this study have important implications for understanding the mechanisms underlying sleep deprivation-induced cognitive dysfunction. The CX3CL1/CX3CR1 signaling axis emerges as a critical regulator of microglial activity, neuroinflammation, and synaptic pruning. By targeting this pathway, it may be possible to develop therapeutic strategies to mitigate the cognitive impairments associated with sleep deprivation and related sleep disorders.

In conclusion, this study demonstrates that CX3CR1 deficiency protects against sleep deprivation-induced cognitive dysfunction by attenuating microglial activation, reducing neuroinflammation, and preserving synaptic plasticity. These findings highlight the potential of CX3CR1 as a therapeutic target for preventing cognitive decline in individuals with sleep disorders. Further research is needed to explore the translational potential of these findings and to develop interventions that modulate the CX3CL1/CX3CR1 signaling pathway to improve cognitive outcomes in sleep-deprived individuals.

doi.org/10.1097/CM9.0000000000001769

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