ROLE OF CENTRAL AND PERIPHERAL SEROTONIN IN MIGRAINE PATHOPHYSIOLOGY

描述（由申请人提供）：偏头痛是最常见的神经血管疾病之一，具有明显的遗传倾向。了解偏头痛的机制将导致更具体的治疗。5-羟色胺（5-HT）是一种细胞外信号分子，在中枢神经系统（CNS）和外周中具有多种功能。有大量证据表明偏头痛可能是由慢性低5-HT倾向引起的。然而，5-羟色胺水平异常和偏头痛的表现之间的因果关系尚未确定。关于中枢与外周5-HT在偏头痛病理生理学中的作用，我们所知更少。Lmx1b条件性基因敲除小鼠（Lmx1bf/f/p）为解决这些问题提供了独特的机会。成年Lmx1bf/f/p小鼠缺乏脑干中几乎所有的中枢多巴胺能神经元，而外周中的5-HT表达不受影响。本研究拟利用Lmx1bf/f/p小鼠，结合分子和药理学方法，探讨5-HT系统在偏头痛病理生理学中的作用，着重阐明中枢与外周5-HT在偏头痛发生中的作用。我们假设慢性低5-HT状态导致以下部位的过度兴奋：1）对偏头痛触发物作出反应的脑区; 2）引起头痛的三叉神经血管通路或3）两者;从而增加偏头痛的易感性。在第一个目标中，我们将研究Lmx1bf/f/p小鼠是否表现出对皮质扩散性抑制（CSD）的易感性增加-一种模拟偏头痛触发的刺激。CSD属性将用作监测皮质兴奋性的标记。该提案的第二个目的是解决中央5-HT神经元的缺乏是否会影响三叉神经血管通路本身的兴奋性。Fos蛋白在颈/髓背角的表达模式将用于监测三叉神经伤害性通路的活性。最后，我们将间接耗尽Lmx1bf/f/p小鼠的外周5-HT，看看这是否会影响“偏头痛回路”的兴奋性。如果是，中枢和外周5-HT对偏头痛回路的作用是相加的、协同的还是拮抗的。总之，这些实验将提供有价值的见解中枢和外周5-HT系统的偏头痛的病理生理学的贡献。这里提出的工作将为我们进一步了解偏头痛的病理生理学和进展奠定基础。这将极大地促进偏头痛预防和姑息治疗药物的开发。 公共卫生相关性：偏头痛是最常见的神经系统疾病之一，是医疗保健系统的巨大负担。尽管偏头痛研究取得了新的进展，但我们对偏头痛的病理生理机制，尤其是进展的了解仍然有限。在这个项目中，我们建议使用小鼠缺乏中枢5-羟色胺能神经元作为一个模型系统，研究如何改变血清素水平影响的“偏头痛电路”的增益。这项研究的结果将极大地促进偏头痛的预防和姑息治疗药物的开发。

DESCRIPTION (provided by applicant): Migraine is one of the most common neurovascular disorders with noticeable genetic predisposition. Understanding the mechanisms of migraine will lead to more specific treatments. Serotonin (5-HT) is an extracellular signaling molecule with a multitude of functions in the central nervous system (CNS) and in the periphery. There is a significant body of evidence implicating that migraine may result from a chronic low 5-HT disposition. Nevertheless, the causal relationship between abnormal 5-HT level and the manifestation of migraine headache has not been firmly established. Even less is known about the contribution of central versus peripheral 5-HT to migraine pathophysiology. The Lmx1b conditional knock-out mice (Lmx1bf/f/p) offers a unique opportunity to address these questions. Adult Lmx1bf/f/p mice lack almost all the central serotonergic neurons in the brainstem, whereas 5-HT expression in the periphery is not affected. In this project we propose to use the Lmx1bf/f/p mice in combination with molecular and pharmacological approaches to explore the contribution of 5-HT system to migraine pathophysiology, emphasizing on elucidating the role of central versus peripheral 5-HT in the generation of migraine headache. We hypothesize that chronic low 5-HT state result in the hyperexcitation of: 1) the brain areas that respond to migraine triggers; 2) the trigeminovascular pathway subserving head pain or 3) both; thereby increasing the susceptibility to migraine headache. In the first aim we will investigate whether the Lmx1bf/f/p mice exhibit increased susceptibility to cortical spreading depression (CSD) - a stimulus that mimic migraine trigger. The CSD properties will be used as a marker to monitor cortical excitability. The second aim of the proposal addresses whether the lack of central 5-HT neurons affects the excitability of the trigeminovascular pathway per se. The pattern of Fos protein expression in cervical/medullary dorsal horn will be used to monitor the activity of the trigeminal nociceptive pathway. Finally, we will pharmacologically deplete the peripheral 5-HT in Lmx1bf/f/p mice to see if this affects the excitability of the 'migraine circuit'. And if so, whether the effects of central and peripheral 5-HT on migraine circuit is additive, synergistic or antagonistic. Together, these experiments will offer valuable insights into the contribution of central and peripheral 5-HT system to migraine pathophysiology. The work proposed here will set a stage that allows us to further advance our understanding of the migraine pathophysiology as well as progression. This will greatly facilitate drug development for both preventive and palliative therapies of migraine. PUBLIC HEALTH RELEVANCE: Migraine is one of the most common neurological disorders and is an enormous burden to the healthcare system. Despite the recent advances in migraine research, our understanding of the mechanisms underlying migraine pathophysiology, especially the progression, is still limited. In this project we propose to use mice that lack central serotonergic neurons as a model system to study how the alteration of serotonin level affects the gain of the 'migraine circuit'. The outcome of this study will greatly facilitate drug development for both preventive and palliative therapies of migraine headache.