CCR3 contributes to neuroinflammation and cognitive impairment induced by prolonged underwater exercise

Abstract Underwater operations are widely used in diverse fields such as marine exploration, underwater construction and infrastructure maintenance, and military missions. Previous research has emphasized the significance of maintaining cognitive function during these tasks. However, the impact of underwater operations on cognitive function and the underlying mechanisms remain unclear. Hence, this study aimed to investigate the effects of underwater operations on cognitive function and explore the potential molecular mechanisms involved. We accomplished this first by assessing underwater operators’ stress response, anxiety, and cognitive function before and after a single underwater operation of two different durations and found that 30 min underwater operation improved cognitive function while 3 h underwater operation induced significant cognitive decline. Then, an animal model of swimming in a hyperbaric environment at 2.0ATA (atmospheres absolute) for varying durations was applied to simulate underwater operations. Behavioral tests, histological examinations, biochemical assays were conducted, and results indicated that the effect of a single underwater exercise on cognitive function was time-dependent and prolonged underwater exercise caused significant cognitive impairment. Furthermore, RNA-sequencing was conducted for the normal control group and the most significantly impaired group, leading to the focus on neuroinflammation and the identification of C-C chemokine receptor type 3(CCR3) as a potential target for further investigation. Finally, knockdown experiment was performed using an adeno-associated virus (AAV) vector containing shRNA (CCR3)-EGFP injected to the rats’ hippocampus to explore the involvement of CCR3 in cognitive impairment induced by prolonged underwater exercise. Results revealed that CCR3 knockdown significantly alleviated neuroinflammation and cognitive impairment. Moreover, prolonged underwater exercise activated microglia and promotes their polarization towards the pro-inflammatory phenotype. Conversely, CCR3 knockdown switched the activated microglia to the anti-inflammatory phenotype. Taken together, these results highlight the time-dependent effect of a single underwater operation on cognitive function and shed insight on alleviating CCR3-mediated neuroinflammation as potential intervention targets to protect the brain during underwater operations.