Understanding the biological mechanisms of how pharmacologically-induced glucose dysregulation affects the brain and behavior

目的：* 传统上认为，大脑活动控制外周葡萄糖稳态的程度比其他方式更大。然而，最近的证据表明，葡萄糖稳态的变化可以深刻地影响大脑和认知功能。我们的NSERC资助的研究表明，非典型抗精神病药物（APD），这是多巴胺D2受体拮抗剂，可靠地损害葡萄糖稳态。这种影响可以通过抗糖尿病药物治疗来改善。在APD奥氮平的长期研究中，我们的大鼠在9周内表现出持续的血糖控制丧失。有趣的是，大鼠表现出海马体积的显著损失，这在日常锻炼中部分逆转。葡萄糖调节异常和海马体积变小之间有很强的相关性，表明慢性、不受控制的高水平葡萄糖可能导致海马体积的损失。* 假设：* 我们的主要假设是APD导致持续的葡萄糖调节异常，对大脑产生有害影响，导致海马体积损失。我们预测这将与严重的认知障碍有关。我们还预测，预防葡萄糖失调将防止APD的这些影响。研究计划：* 1/首先，我们将确定成年大鼠接受APD长期治疗后海马体积损失的持续时间。我们将评估APD治疗终止后不同持续时间后容量是否恢复。我们还将确定APD治疗是否唯一降低海马体积，或者是否有其他脑区显示体积变化。将检查体积损失的分子基质。* 2/将确定伴有血糖失调的慢性APD治疗对认知的影响。APD长期治疗后，将对无药物动物或适当对照动物进行海马依赖性行为任务训练和测试。* 3/我们将证实APD引起的容量损失和认知障碍是由于血糖控制丧失，而不是其他机制。动物将接受APD长期治疗，并将测试海马体积损失。单独的动物队列将被共同施用抗糖尿病药物，这将减少葡萄糖失调，我们预测这将改善海马体积的预测损失。意义：* 本系列实验将显著扩展我们对葡萄糖外周调节的糖皮质激素诱导的修饰如何在大脑水平改变中枢神经系统以及随后对行为和认知的影响的理解。受影响的关键生物学途径在很大程度上仍然未知，目前的研究将有助于开始了解可能涉及的机制。**

Objectives:***It has traditionally been believed that brain activity controls peripheral glucose homeostasis to a greater degree than the other way around. However, recent evidence indicates that changes in glucose homeostasis can profoundly affect the brain and cognitive function. Our NSERC-funded research has demonstrated that atypical antipsychotic drugs (APDs), which are dopamine D2 receptor antagonists, reliably impair glucose homeostasis. This effect can be ameliorated by treatment with antidiabetic drugs. In a chronic study with the APD olanzapine, our rats displayed sustained loss of glycemic control over 9 weeks. Interestingly, the rats showed significant loss of hippocampal volume, which was partially reversed by daily exercise. There was a strong association between glucose dysregulation and smaller hippocampal volumes, indicating that chronic, uncontrolled, high levels of glucose may contribute to loss of hippocampal volume. ***Hypotheses:***Our main hypothesis is that APDs cause sustained glucose dysregulation, with a deleterious effect on the brain, resulting in hippocampal volume loss. We predict that this will be associated with significant cognitive impairment. We also predict that preventing glucose dysregulation will prevent these effects of APDs.***Research Plan:***1/ Firstly, we will determine the duration of volume loss in the hippocampus following chronic treatment with APDs in adult rats. We will assess whether there is a recovery of volume following different durations after termination of APD treatment. We will also determine if hippocampal volume is uniquely decreased by APD treatment, or whether additional brain regions show volumetric changes. Molecular substrates for volume loss will be examined.***2/ The cognitive effects of chronic APD treatment with associated glucose dysregulation will be determined. Following chronic treatment with APDs, drug-free animals or appropriate controls will be trained and tested on a hippocampal dependent behavioral task.***3/ We will confirm that volume loss and cognitive impairment caused by APDs is due to loss of glycemic control, rather than other mechanisms. Animals will be treated chronically with an APD and will be tested for hippocampal volume loss. Separate cohorts of animals will be co-administered antidiabetic drugs, which will decrease glucose dysregulation, which we predict will ameliorate the predicted loss of hippocampal volume.******Significance:***The present series of experiments will significantly extend our understanding of how pharmacologically induced modification of the peripheral regulation of glucose can alter the central nervous system at the level of the brain, with subsequent effects on behavior and cognition. The key biological pathways affected remain largely unknown, and the current studies will help to begin to understand the mechanisms that may be involved.********* **