Regulation of blood flow in the brains of diabetic mice

项目总结 糖尿病是一种日益严重的公共健康危机，影响着美国29%的人口。一个 糖尿病的重要后果是认知能力下降和神经退行性变的发生率增加 疾病。这种下降的一个因素可能是血管功能障碍。在中枢神经系统，血流量增加作为响应 增加神经活动，这一过程称为功能性充血。在病理学上，这一过程可以成为 受损，这可能会阻止活跃的神经元获得所需的营养和氧气 他们不断增加的新陈代谢需求。糖尿病患者视网膜中的功能性充血在任何明显症状之前都受到了损害 有损坏的迹象。也有证据表明大脑的血流调节功能受损，但事实并非如此。 不清楚这些损害是否是由于功能性充血的丧失。对1型患者的研究 糖尿病和糖尿病动物模型显示，对刺激的反应导致血流增加减少。 然而，还没有研究同时记录血流和神经元活动，这是必要的 描述神经活动和血流、功能性充血之间的关系是如何改变的。一个缺口 我们仍然知道糖尿病时功能性充血是如何改变大脑的。我们假设 糖尿病患者的功能性充血将通过神经活动和血流的解偶联而改变，因此 神经活动的等量增加并不会引起同样的血流量增加。在目标1中，拟议 实验将同时测量1型糖尿病小鼠模型的功能性充血 测量血流量(使用激光多普勒血流仪)和诱发的神经活动(使用钙信号和 视觉皮层对漂移的格栅刺激的反应)。通过这种方式，它可以是 已确定糖尿病是否导致视皮层功能性充血的改变。 我们进一步假设糖尿病患者的血流改变是通过一氧化氮的过度表达来实现的。 (NO)由于诱导型一氧化氮合酶(INOS)表达增加。INOS的表达在 炎症和病理，以前的研究发现动物脑中iNOS表达增加 糖尿病模型。研究还表明，给糖尿病动物服用iNOS抑制剂可以恢复功能 视网膜充血。在目标2中，我们将通过给予选择性iNOS抑制剂来检验这一假设 氨基胍和1400W静脉给药对糖尿病小鼠的影响 诱发的神经活动和血流，以确定iNOS抑制如何影响功能性充血。我们会 同时给予1400W长期给予糖尿病诱导剂以研究iNOS的长期作用 抑制功能性充血。识别1型糖尿病患者功能性充血的损害是一种 在理解糖尿病所见损害的病因方面迈出了重要的一步，并提供了一个有希望的 治疗干预的目标。

PROJECT SUMMARY Diabetes mellitus is a growing public health crisis, affecting 29% of the population in the United States. An important consequences of diabetes is cognitive decline and increased incidence of neurodegenerative disease. One factor in this decline may be vascular dysfunction. In the CNS, blood flow increases in response to increased neural activity, a process called functional hyperemia. In pathology, this process can become impaired, which may prevent the active neurons from receiving the nutrients and oxygen they need to meet their increased metabolic needs. Functional hyperemia is impaired in the retina in diabetes before any overt signs of damage. There is also evidence to suggest impairment in blood flow regulation in the brain, but it is unclear if those impairments are due to a loss of functional hyperemia. Research in patients with type 1 diabetes and animal models of diabetes has shown reduced increases in blood flow in response to a stimulus. However, no studies have simultaneously recorded blood flow and neuronal activity, which is necessary to describe how the relationship between neural activity and blood flow, functional hyperemia, is altered. A gap remains in our knowledge of how functional hyperemia changes in the brain in diabetes. We hypothesize that functional hyperemia in diabetes will be altered through an uncoupling of the neural activity and blood flow, so that equivalent increases in neural activity do not elicit the same increase in blood flow. In aim 1, the proposed experiment will measure functional hyperemia in a mouse model of type 1 diabetes by simultaneously measuring blood flow (using laser Doppler flowmetry) and evoked neural activity (using Ca2+ signaling and electrocorticography) in the visual cortex in response to a drifting grating stimulus. In this way, it can be determined if there are alterations in functional hyperemia in the visual cortex as a consequence of diabetes. We further hypothesize that alterations in blood flow in diabetes are mediated by overexpression of nitric oxide (NO) due to increased expression of inducible nitric oxide synthase (iNOS). iNOS expression is increased in inflammation and pathology, and previous studies have found increased iNOS expression in the brain in animal models of diabetes. It has also been shown that giving diabetic animals inhibitors of iNOS restores functional hyperemia in the retina. In aim 2, we will test this hypothesis by giving the selective iNOS inhibitors aminoguanidine and 1400W intravenously to diabetic mice and examining the effects of the inhibitors on evoked neural activity and blood flow to determine how iNOS inhibition affects functional hyperemia. We will also give 1400W chronically from the induction of diabetes in order to study the effects of long term iNOS inhibition on functional hyperemia. Identifying impairments in functional hyperemia in type 1 diabetes is an essential step in understanding the etiology of the impairments seen in diabetes and provides a promising target for therapeutic intervention.