Depatment of Biochemistry, Medical, Pharmaceutical & Toxicological Chemistry, Krasnoyarsk State Medical University named after Prof. V.F. Voino-Yasenetsky, Krasnoyarsk, Russia; Research Institute of Molecular Medicine and Pathobiochemistry, Russia.
Depatment of Biochemistry, Medical, Pharmaceutical & Toxicological Chemistry, Krasnoyarsk State Medical University named after Prof. V.F. Voino-Yasenetsky, Krasnoyarsk, Russia; Research Institute of Molecular Medicine and Pathobiochemistry, Russia.
Brain Res. 2021 Feb 1;1752:147220. doi: 10.1016/j.brainres.2020.147220. Epub 2020 Dec 23.
Neuroinflammation has been classified as a trigger of behavioral alterations and cognitive impairments in many neurological conditions, including Alzheimer's disease, major depression, anxiety and others. Regardless of the cause of neuroinflammation, key molecules, which sense neuropathological conditions, are intracellular multiprotein signaling inflammasomes. Increasing evidence shows that the inflammatory response, mediated by activated nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3 (NLRP3) inflammasomes, is associated with the onset and progression of a wide range of diseases of the CNS. However, whether the NLRP3 inflammasome in the CNS is involved in the learning, development of anxiety and adult neurogenesis remains elusive. Therefore, the present study was designed to assess NLRP3 inflammasome contribution in anxiety and reveal its potential involvement in the experimental acquisition of fear responses and hippocampal neurogenesis. Behavioral, immunohistochemical and electrophysiological alterations were measured to evaluate role of neuroinflammation in the limbic system of mice. In this study, we describe interrelated neurophysiological mechanisms, which culminate in absence of NLRP3 inflammasome in young 4 months mice. These include the following: anxious behavior and deterioration in learning and memory of fear conditioning; impairment of adult neurogenesis; reduction and altered morphology of astrocytes in the brain; hyperexcitability in basolateral amygdala (BLA); impaired activation in axons of pyramidal cells of CA1 hippocampal zone in NLRP3 KO mice particularly via the Schaffer collateral pathway; and impaired synaptic transduction in pyramidal cells mediated by an embarrassment of neurotransmitter release from presynaptic site in CA3 hippocampal zone. The present study has demonstrated the novel findings that basal level of NLRP3 inflammasome in the brain of young mice is required for conditioning-induced plasticity in the ventral hippocampus and the basolateral amygdala. The deletion of NLRP3 impair synaptic transduction and caused anxiety-like behavior and labored fear learning, suggesting that low grade inflammation, mediated by NLRP3 expression, play a key role in memory consolidation.
神经炎症已被归类为许多神经疾病（包括阿尔茨海默病、重度抑郁症、焦虑症等）中行为改变和认知障碍的触发因素。无论神经炎症的原因是什么，能够感知神经病理状况的关键分子是细胞内多蛋白信号炎症小体。越来越多的证据表明，由激活的核苷酸结合寡聚结构域、富含亮氨酸重复序列和吡喃结构域包含 3（NLRP3）炎症小体介导的炎症反应与广泛的中枢神经系统疾病的发病和进展有关。然而，中枢神经系统中的 NLRP3 炎症小体是否参与学习、焦虑的发展和成年神经发生仍不清楚。因此，本研究旨在评估 NLRP3 炎症小体在焦虑中的作用，并揭示其在恐惧反应和海马神经发生的实验获得中的潜在作用。通过行为学、免疫组织化学和电生理学改变来评估神经炎症在小鼠边缘系统中的作用。在这项研究中，我们描述了相互关联的神经生理机制，这些机制最终导致年轻 4 个月的小鼠中缺乏 NLRP3 炎症小体。这些机制包括：焦虑行为和恐惧条件反射学习记忆的恶化；成年神经发生受损；大脑中的星形胶质细胞减少和形态改变；外侧杏仁核（BLA）的过度兴奋；NLRP3 KO 小鼠 CA1 海马区锥体神经元轴突的激活受损，特别是通过沙费尔侧支通路；以及 CA3 海马区锥体神经元突触传递的损伤，其原因是突触前部位神经递质释放的尴尬。本研究表明，年轻小鼠大脑中 NLRP3 炎症小体的基础水平对于腹侧海马体和外侧杏仁核的条件诱导可塑性是必需的。NLRP3 的缺失会损害突触传递，并导致焦虑样行为和费力的恐惧学习，这表明由 NLRP3 表达介导的低度炎症在记忆巩固中发挥关键作用。
