Obesity Elicits Interleukin 1-Mediated Deficits in Hippocampal Synaptic Plasticity
Obesity Elicits Interleukin 1-Mediated Deficits in Hippocampal Synaptic Plasticity
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DOI：
10.1523/jneurosci.4200-13.2014
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发表时间：
2014-02-12
影响因子：
5.3
通讯作者：
Stranahan, Alexis M.
中科院分区：
文献类型：
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作者：
Erion, Joanna R.;Wosiski-Kuhn, Marlena;Stranahan, Alexis M.
在肥胖的人类和动物模型中，脂肪组织是已知的促炎细胞因子的来源，包括db/db小鼠，在这些模型中，肥胖是由于瘦素受体不敏感而产生的。炎性细胞因子在许多情况下都会导致认知障碍，但还没有研究确定肥胖诱导的炎症是否介导了突触功能障碍。为了解决这个问题，我们使用了跑步机训练范式，在跑步机训练范式中，小鼠暴露在每天的训练课程中或固定的腰带中，动机是通过在不遵守规定的情况下输送压缩空气来实现的。跑步机训练防止了海马区的小胶质细胞增生，取消了小胶质细胞激活标志物的表达，也阻断了体外暴露于脂多糖后在分离细胞中观察到的功能敏化。运动导致的小胶质细胞反应性降低与恢复海马区依赖记忆、逆转长时程增强缺陷和恢复海马树突棘密度有关。由于跑步机训练引起的广泛反应不限于免疫系统，我们接下来评估了通过脂肪切除和脂肪移植直接操纵肥胖是否影响炎症、认知和突触可塑性。脂肪切除术预防和脂肪移植促进全身性和中枢性炎症，并伴随认知和突触功能的改变。在跑步机和去脂术研究中，白介素1β(IL1β)水平都与肥胖和认知障碍相关，因此我们通过海马区内传递IL1受体拮抗剂(IL1ra)来操纵海马区IL1信号。在海马区IL1ra可预防突触功能障碍、促炎反应和认知障碍。这种模式支持IL1介导的神经炎症作为肥胖和糖尿病认知障碍的一种机制的核心作用。
Adipose tissue is a known source of proinflammatory cytokines in obese humans and animal models, including the db/db mouse, in which obesity arises as a result of leptin receptor insensitivity. Inflammatory cytokines induce cognitive deficits across numerous conditions, but no studies have determined whether obesity-induced inflammation mediates synaptic dysfunction. To address this question, we used a treadmill training paradigm in which mice were exposed to daily training sessions or an immobile belt, with motivation achieved by delivery of compressed air on noncompliance. Treadmill training prevented hippocampal microgliosis, abolished expression of microglial activation markers, and also blocked the functional sensitization observed in isolated cells after ex vivo exposure to lipopolysaccharide. Reduced microglial reactivity with exercise was associated with reinstatement of hippocampus-dependent memory, reversal of deficits in long-term potentiation, and normalization of hippocampal dendritic spine density. Because treadmill training evokes broad responses not limited to the immune system, we next assessed whether directly manipulating adiposity through lipectomy and fat transplantation influences inflammation, cognition, and synaptic plasticity. Lipectomy prevents and fat transplantation promotes systemic and central inflammation, with associated alterations in cognitive and synaptic function. Levels of interleukin 1 beta (IL1 beta) emerged as a correlate of adiposity and cognitive impairment across both the treadmill and lipectomy studies, so we manipulated hippocampal IL1 signaling using intrahippocampal delivery of IL1 receptor antagonist (IL1ra). Intrahippocampal IL1ra prevented synaptic dysfunction, proinflammatory priming, and cognitive impairment. This pattern supports a central role for IL1-mediated neuroinflammation as a mechanism for cognitive deficits in obesity and diabetes.