Spinal Cord Injury Causes Brain Inflammation Associated with Cognitive and Affective Changes: Role of Cell Cycle Pathways
Spinal Cord Injury Causes Brain Inflammation Associated with Cognitive and Affective Changes: Role of Cell Cycle Pathways
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DOI：
10.1523/jneurosci.5110-13.2014
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发表时间：
2014-08
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影响因子：
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通讯作者：
Junfang Wu;Zaorui Zhao;B. Sabirzhanov;B. Stoica;Alok Kumar;Tao Luo;Jacob W. Skovira;A. Faden
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文献类型：
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作者：
Junfang Wu;Zaorui Zhao;B. Sabirzhanov;B. Stoica;Alok Kumar;Tao Luo;Jacob W. Skovira;A. Faden
实验性脊髓损伤（SCI）引起慢性神经病理性疼痛，与丘脑疼痛调节部位的炎症变化相关。我们最近研究了啮齿动物SCI后的慢性疼痛机制，发现不仅在丘脑，而且在其他区域，包括海马和大脑皮层，也有慢性炎症变化。由于这些变化与我们的啮齿动物TBI模型中与神经变性和神经行为功能障碍相关的变化相似，我们研究了小鼠SCI对认知，抑郁样行为和脑炎症的影响。SCI导致空间和保持记忆障碍和抑郁样行为，如在Morris水迷宫、Y-迷宫、新目标识别、步下被动回避、悬尾和蔗糖偏好测试中表现不佳所证明的。脊髓损伤引起海马和大脑皮层的慢性小胶质细胞活化，其中以肥大形态和M1表型的小胶质细胞为主。体视学分析显示，在12周，但不是8天损伤后海马神经元的损失显着。海马和大脑皮质细胞周期相关基因（cyclin A1，A2，D1，E2 F1和PCNA）和蛋白（cyclin D1和CDK 4）表达增加。SCI后全身给予选择性细胞周期蛋白依赖性激酶抑制剂CR 8可显著降低细胞周期基因和蛋白质表达、脑内小胶质细胞活化和神经变性、认知能力下降和抑郁症。这些研究表明，SCI可以引发慢性脑神经退行性反应，可能与延迟，持续诱导M1型小胶质细胞和相关的细胞周期激活有关，导致认知缺陷和生理抑郁。
Experimental spinal cord injury (SCI) causes chronic neuropathic pain associated with inflammatory changes in thalamic pain regulatory sites. Our recent studies examining chronic pain mechanisms after rodent SCI showed chronic inflammatory changes not only in thalamus, but also in other regions including hippocampus and cerebral cortex. Because changes appeared similar to those in our rodent TBI models that are associated with neurodegeneration and neurobehavioral dysfunction, we examined effects of mouse SCI on cognition, depressive-like behavior, and brain inflammation. SCI caused spatial and retention memory impairment and depressive-like behavior, as evidenced by poor performance in the Morris water maze, Y-maze, novel objective recognition, step-down passive avoidance, tail suspension, and sucrose preference tests. SCI caused chronic microglial activation in the hippocampus and cerebral cortex, where microglia with hypertrophic morphologies and M1 phenotype predominated. Stereological analyses showed significant neuronal loss in the hippocampus at 12 weeks but not 8 d after injury. Increased cell-cycle-related gene (cyclins A1, A2, D1, E2F1, and PCNA) and protein (cyclin D1 and CDK4) expression were found chronically in hippocampus and cerebral cortex. Systemic administration of the selective cyclin-dependent kinase inhibitor CR8 after SCI significantly reduced cell cycle gene and protein expression, microglial activation and neurodegeneration in the brain, cognitive decline, and depression. These studies indicate that SCI can initiate a chronic brain neurodegenerative response, likely related to delayed, sustained induction of M1-type microglia and related cell cycle activation, which result in cognitive deficits and physiological depression.