Department of Neurology, Zhongnan Hospital, Wuhan University, No.169, Donghu Road, Wuhan 430071, Hubei, China; Department of Neurology, The Third People's Hospital of Chengdu, China.
Clinical Medicine Research Center of Dementia and Cognitive Impairment, Hubei Province, China.
Brain Res Bull. 2022 Sep;187:98-110. doi: 10.1016/j.brainresbull.2022.07.001. Epub 2022 Jul 4.
People exposed to prolonged chronic unpredictable mild stress (CUMS) are easy to suffer from depression and cognitive impairment. Environmental enrichment (EE) had a beneficial effect on depressive-like and cognition-like behaviors by inhibiting inflammation. However, the specific mechanism involved in the inflammation inhibition that occurs after EE treatment for the depression and cognitive decline induced by CUMS remains unclear. In this study, we evaluated the possible mechanism of the beneficial effects on depression and cognition by EE.
Rats were randomly divided into 5 groups as follows: (1) Control + standard environment (SE), (2) CUMS + SE, (3) CUMS + EE, (4) CUMS + EE+ 3-methiladenine (3-MA), (5) CUMS + SE + 3-MA. They were exposed to CUMS procedure for 5 weeks except the control group. After CUMS procedure, rats were housed in the EE or SE for 3 weeks. During EE or SE treatment, rats were injected with normal saline or 3-MA every day. 3-MA as an autophagy inhibitor suppresses autophagy via inhibition of class III PI3K. Behavioral tests were used to investigate depressive-like and cognition-like behaviors after EE treatment. Then, autophagy-related proteins, inflammation-related molecules, transmission electron microscopy (TEM) and immunofluoresence were determined.
We found that CUMS induced depressive-like behaviors and cognitive impairment, reflected in worse behavioral test, such as reduced sucrose preference ratio, decreased locomotor and exploratory activity, prolonged immobility and spatial learning and memory impairment. In addition, CUMS rats exhibited the reduced expression of autophagy related proteins including LC3 and Beclin-1 and the increased inflammation activation including microglia cells, NLRP3 inflammasome and proinflammatory cytokines (IL-1β, IL-6 and TNF-α). After EE treatment, these changes were reversed. However, 3-MA, the inhibitor of autophagy, eliminated the neuroprotective effects of EE on depressive-like behaviors and cognitive decline.
This study demonstrates that EE can play neuroprotective effects on depression and cognitive impairment by inducing autophagy-mediated inflammation inhibition, which accounts for the reduction of proinflammatory cytokines, including IL-1β, IL-6 and TNF-α.
长期慢性不可预测轻度应激（CUMS）暴露的人容易患抑郁症和认知障碍。环境丰富（EE）通过抑制炎症对抑郁样和认知样行为有有益的影响。然而，EE 治疗 CUMS 引起的抑郁和认知下降后发生的炎症抑制的具体机制尚不清楚。在这项研究中，我们评估了 EE 对抑郁和认知有益的可能机制。
大鼠随机分为 5 组：（1）对照+标准环境（SE），（2）CUMS+SE，（3）CUMS+EE，（4）CUMS+EE+3-甲基腺嘌呤（3-MA），（5）CUMS+SE+3-MA。除对照组外，它们均接受 CUMS 程序 5 周。CUMS 程序后，大鼠在 EE 或 SE 中饲养 3 周。在 EE 或 SE 治疗期间，大鼠每天注射生理盐水或 3-MA。3-MA 作为自噬抑制剂通过抑制 III 类 PI3K 来抑制自噬。行为测试用于研究 EE 治疗后的抑郁样和认知样行为。然后，测定自噬相关蛋白、炎症相关分子、透射电镜（TEM）和免疫荧光。
我们发现 CUMS 诱导了抑郁样行为和认知障碍，表现在行为测试中更差，例如蔗糖偏好比降低、运动和探索性活动减少、不动时间延长以及空间学习和记忆障碍。此外，CUMS 大鼠表现出自噬相关蛋白表达减少，包括 LC3 和 Beclin-1，炎症激活增加，包括小胶质细胞、NLRP3 炎性体和促炎细胞因子（IL-1β、IL-6 和 TNF-α）。EE 治疗后，这些变化得到逆转。然而，自噬抑制剂 3-MA 消除了 EE 对抑郁样行为和认知下降的神经保护作用。
这项研究表明，EE 通过诱导自噬介导的炎症抑制对抑郁和认知障碍发挥神经保护作用，这解释了促炎细胞因子（包括 IL-1β、IL-6 和 TNF-α）的减少。
