Department of Neurosurgery, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi 710032, China.
Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, The National Key Clinical Specialty, The Neurosurgery Institute of Guangdong Province, The Engineering Technology Research Center of Education Ministry of China, Southern Medical University, Guangzhou, China.
Neuroscience. 2022 Jun 1;492:1-17. doi: 10.1016/j.neuroscience.2022.04.007. Epub 2022 Apr 8.
Toll-like receptor-4 (TLR4), a member of the TLR family, plays a key role in inflammation-related diseases of the nervous system. TLR4 knockout mice are widely used in various neurological disease studies, and there is a clear correlation between inflammation and behavior. Therefore, elucidating the effect of TLR4 on neurobehavioral function is essential, and the related mechanisms need to be explored. Male TLR4 knockout (TLR4) and wild-type (TLR4) mice of different ages (4, 8, and 16 months) were used for behavioral experiments. Synaptic spine, blood-brain barrier (BBB) integrity, memory regulatory proteins, cortical blood flow, and inflammatory factor examinations were also conducted to explore the possible mechanism by which TLR4 works. Here, we found that compared with 16-m-old TLR4 mice, age-matched TLR4 mice had better learning and memory abilities, increased expression of neuronal synaptic spines, and increased memory-related regulatory proteins in the hippocampus. TLR4 knockout significantly attenuated the fear response in 16-m-old mice. The TLR4 mice also had better blood-brain barrier integrity, increased expression of tight junction-associated proteins, increased cerebral cortical blood flow and reduced proinflammatory cytokine expression in the cortex and cerebrospinal fluid. Our results suggest that TLR4 deletion ameliorates significant neurobehavioral dysfunction during the aging stage, as well as multiple abnormalities in brain function and structure due to alterations in tight junction-associated proteins and inflammatory factors.
Toll 样受体-4（TLR4）是 TLR 家族的成员，在神经系统炎症相关疾病中发挥关键作用。TLR4 敲除小鼠广泛应用于各种神经疾病研究中，炎症与行为之间存在明显相关性。因此，阐明 TLR4 对神经行为功能的影响至关重要，需要探索相关机制。本研究使用不同年龄（4、8 和 16 个月）的 TLR4 敲除（TLR4）和野生型（TLR4）雄性小鼠进行行为实验，并进行突触小棘、血脑屏障（BBB）完整性、记忆调节蛋白、皮质血流和炎症因子检查，以探讨 TLR4 作用的可能机制。结果发现，与 16 个月龄的 TLR4 小鼠相比，同龄 TLR4 小鼠具有更好的学习和记忆能力，海马神经元突触小棘表达增加，记忆相关调节蛋白增加。TLR4 敲除显著减弱了 16 个月龄小鼠的恐惧反应。TLR4 小鼠还具有更好的血脑屏障完整性、紧密连接相关蛋白表达增加、大脑皮质血流增加以及皮质和脑脊液中促炎细胞因子表达减少。这些结果表明，TLR4 缺失可改善衰老阶段的显著神经行为功能障碍，以及与紧密连接相关蛋白和炎症因子改变相关的脑功能和结构的多种异常。
