Research On The Impact Of Cognitive Function In Mice The Role Of NMDA Receptor Subtype 2B And PSD-95 In Nociception Mechanisms

Part OneSurgical Incision-induced Nociception Causes Cognitive Impairment and Reduction in Synaptic NMDA Receptor2B in miceBackground:Postoperative cognitive dysfunction (POCD) is associated with impairments in daily functioning, and increased morbidity and mortality. However, the causes and neuropathogenesis of POCD remain largely unknown. Uncontrolled pain often occurs postoperatively.Objective:To determine the effects of surgical incision-induced nociception on the cognitive function and its underlying mechanisms in three and9-month-old mice.Methods:The mice had surgical incision in the hind paw and then were tested for nociceptive threshold, learning, and memory. Brain levels of NMDA receptor and phosphorylated Tau protein were also assessed.Results:We found that surgical incision-induced nociception in mice led to a decreased freezing time in the tone test (which assesses the hippocampus-independent learning and memory function), but not the context test, of Fear Conditioning System at3and7, but not30, days post-incision in9, but not three, month-old mice. Consistently, the surgical incision selectively decreased synaptic NMDA receptor2B levels in the medial prefrontal cortex, and increased levels of tumor necrosis factor-a and phosphorylated Tau protein in the cortex, but not hippocampus, of the mice. Finally, eutectic mixture of local anesthetics attenuated the surgical incision-induced reduction in the synaptic NMDA receptor2B levels and learning impairment.Conclusions:These results suggested that surgical incision-induced nociception reduced the synaptic NMDA receptor2B level in the medial prefrontal cortex of mice, which might lead to hippocampus-independent learning impairment, contributing to POCD. These findings call for further investigation to determine the role of surgical incision-induced nociception in POCD. Part TwoInflammatory Pain May Induce Cognitive Impairment Through an IL-6-Dependent and PSD-95-Associated MechanismBackground:Pain might be associated with cognitive impairment in humans. However, the characterization of such effects in a pre-clinical model and the investigation of the underlying mechanisms remain largely to be determined.Objective:To establish a system to determine the effect of pain on cognitive function in mice.Methods:Complete Freund’s adjuvant (CFA) was injected in the hind paw of5to8-month-old wild type and interleukin (IL)-6knockout (KO) mice. Learning and memory function, and the levels of IL6and postsynaptic density (PSD)-95in the cortex and hippocampus of mice were assessed.Results:We found that the CFA injection induced pain in the mice at3and7days post-injection, and decreased the freezing time [30.1(16.5) seconds versus56.8(28.1) seconds, P=0.023] in the tone test, which assesses the hippocampus-independent learning and memory function, but not a context test of Fear Conditioning System [15.8(6.7) seconds versus18.6(8.8) seconds, P=0.622], which assesses the hippocampus-dependent learning and memory function, at3days post-injection. Consistently, the CFA injection increased the interleukin-6[248%(11.6) versus100%(7.9), P<0.0001] and decreased the PSD-95[40%(10.0) versus100%(20.3), P<0.0001] level in the cortex, but not hippocampus [95%(8.6) versus100%(9.3), P=0.634], in the mice. The CFA injection induced neither reduction in the cortex PSD-95levels nor cognitive impairment in the interleukin-6knockout mice.Conclusions:These results suggest that pain induced by the CFA injection might increase interleukin-6levels and decrease PSD-95levels in the cortex, but not hippocampus, of mice, leading to hippocampus-independent cognitive impairment in mice. These findings call for further investigation to determine the role of pain in cognitive function.