Moderate Recurrent Hypoglycemia Markedly Impairs Set-Shifting Ability in a Rodent Model: Cognitive and Neurochemical Effects.
Moderate Recurrent Hypoglycemia Markedly Impairs Set-Shifting Ability in a Rodent Model: Cognitive and Neurochemical Effects.
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DOI：
10.2174/1876524601205010001
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
McNay EC
中科院分区：
文献类型：
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作者：
Jahagirdar V;Ramcharitar J;Cotero VE;McNay EC
复发性低血糖(RH)是糖尿病胰岛素强化治疗的主要并发症。尤其值得关注的是RH对认知产生长期影响的潜在可能。由于有报道称糖尿病患者存在心理灵活性和判断力的缺陷，通常认为这两者主要是由前额叶皮质调节的，因此本研究的目的是确定RH是否会影响前额叶皮质功能。采用类似于威斯康星卡片分类任务的迷宫、食物奖赏集转移任务，在雄性SD大鼠上测试了内侧前额叶皮质(MPFC)介导的集转移能力。绩效衡量标准是在第1天(最初的规则学习)和第2天(对变化的偶然性做出反应的集合转移)两天都要确定标准的试验次数。在体微透析法测定mPFC胞外葡萄糖、乳酸、丙酮酸、谷氨酸和多巴胺。MPFC内的死后测量包括葡萄糖转运蛋白3(GLUT3)和c-Fos。RH动物在第一天的表现有所增强，这与之前的工作一致，该工作表明RH在正常血糖时可以改善随后的海马区功能。这项研究的关键发现是，在第二天，RH导致了定势转换表现的损害，这意味着精神灵活性方面的损害。与这一发现一致的是，与对照组相比，RH动物在第2天表现出mPFC糖酵解减少。我们的数据显示，RH可导致随后的判断受损，并伴随着前额叶皮质功能的降低。这些发现表明了糖尿病患者判断力受损的潜在机制。
Recurrent hypoglycemia (RH) is the major complication of intensive insulin treatment for diabetes mellitus. Of particular concern is the perceived potential for long-term impact of RH on cognition. Because diabetic patients have been reported to have deficits in mental flexibility and judgment, both generally considered to be mediated predominantly by the prefrontal cortex, the purpose of the present study was to determine whether RH would affect prefrontal cortex function. Medial prefrontal cortex (mPFC)-mediated set-shifting ability was tested in male Sprague-Dawley rats using a maze-based, food-reward Set-Shift task analogous to the Wisconsin card-sorting task. The performance measure was the number of trials to criterion on both day 1 (initial rule-learning) and day 2 (set-shifting in response to a changed contingency). In vivo microdialysis was used to measure mPFC extracellular glucose, lactate, pyruvate, glutamate, and dopamine. Post-mortem measures within the mPFC included glucose transporter 3 (GluT3) and c-Fos. RH animals had enhanced performance on day 1, consistent with previous work that showed RH to improve subsequent hippocampal function when euglycemic. The key finding of the present work is that RH led to impaired set-shifting performance on day 2, suggesting impairment in e.g. mental flexibility. Consistent with this finding, RH animals show decreased mPFC glycolysis on day 2 compared to controls. Our data show that RH can lead to subsequent impaired judgment, accompanied by reduced prefrontal cortex function. The findings suggest a potential underlying mechanism for the impaired judgment seen in diabetic patients.