Acute fasting inhibits central caspase-1 activity reducing anxiety-like behavior and increasing novel object and object location recognition.
Acute fasting inhibits central caspase-1 activity reducing anxiety-like behavior and increasing novel object and object location recognition.
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DOI：
10.1016/j.metabol.2017.03.005
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发表时间：
2017-06
期刊：
影响因子：
--
通讯作者：
Freund GG
中科院分区：
文献类型：
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作者：
Towers AE;Oelschlager ML;Patel J;Gainey SJ;McCusker RH;Freund GG
中枢神经系统（CNS）的炎症通常与焦虑共病。重要的是，与焦虑最相关的促炎细胞因子是IL-1β。IL-1β的生物利用度和活性受caspase-1依赖性蛋白水解对炎性体的调节。因此，干预调节caspase-1的激活或活性应该减少焦虑，特别是在促进IL-1β成熟的状态下。雄性C57BL/6j、C57BL/6j小鼠经capase-1抑制剂生物素- yvad -cmk、caspase-1敲除（KO）小鼠和IL-1R1 KO小鼠禁食24小时或允许自由进食。禁食后立即在脑区匀浆中测量caspase-1活性，并通过免疫组织化学方法定位激活的caspase-1在脑中的位置。分别采用高架零迷宫和新物体/物体定位任务测试小鼠的类焦虑行为和认知。小鼠禁食24小时，全脑和前额叶皮层、杏仁核、海马和下丘脑的caspase-1活性分别降低35%、25%、40%、40%和40%。禁食24小时还能减少40%的焦虑样行为，并分别提高21%和31%的新物体和物体位置识别能力。然而，禁食后大脑中的IL-1β蛋白并未减少。YVAD的ICV管理使前额叶皮层和杏仁核的caspase-1活性分别降低了55%，导致焦虑样行为减少了64%。重要的是，当caspase-1 KO或IL1-R1 KO小鼠禁食时，没有观察到禁食依赖性的焦虑样行为减少。研究结果表明，禁食可以减少焦虑样行为，提高记忆力，其机制与减少大脑中caspase-1的活性有关。
Inflammation within the central nervous system (CNS) is frequently comorbid with anxiety. Importantly, the pro-inflammatory cytokine most commonly associated with anxiety is IL-1β. The bioavailability and activity of IL-1β is regulated by caspase-1-dependent proteolysis vis-a-vis the inflammasome. Thus, interventions regulating the activation or activity of caspase-1 should reduce anxiety especially in states that foster IL-1β maturation. Male C57BL/6j, C57BL/6j mice treated with the capase-1 inhibitor biotin-YVAD-cmk, caspase-1 knockout (KO) mice and IL-1R1 KO mice were fasted for 24 hours or allowed ad libitum access to food. Immediately after fasting, caspase-1 activity was measured in brain region homogenates while activated caspase-1 was localized in the brain by immunohistochemistry. Mouse anxiety-like behavior and cognition were tested using the elevated zero maze and novel object/object location tasks, respectively. A 24 h fast in mice reduced the activity of caspase-1 in whole brain and in the prefrontal cortex, amygdala, hippocampus, and hypothalamus by 35%, 25%, 40%, 40%, and 40% respectively. A 24 h fast also reduced anxiety-like behavior by 40% and increased novel object and object location recognition by 21% and 31%, respectively. IL-1β protein, however, was not reduced in the brain by fasting. ICV administration of YVAD decreased caspase-1 activity in the prefrontal cortex and amygdala by 55%, respectively leading to a 64% reduction in anxiety like behavior. Importantly, when caspase-1 KO or IL1-R1 KO mice are fasted, no fasting-dependent reduction in anxiety-like behavior was observed. Results indicate that fasting decrease anxiety-like behavior and improves memory by a mechanism tied to reducing caspase-1 activity throughout the brain.