The effect of epilepsy and seizures on dorsal raphe serotonin neuron activity and arousal

项目摘要 每26个美国人中就有一个会在有生之年患上癫痫。这些患者中有三分之一的人控制不良 对药物没有反应的癫痫，使他们处于更大的猝死风险中 癫痫(SUDEP)。虽然SUDEP的确切病因尚不清楚，但5-羟色胺(5-HT)系统的调节失调 与这些过早死亡有关。5-羟色胺在睡眠-觉醒调节和觉醒过程中起着关键作用。 性后觉醒受损发生在癫痫发作后，被认为是SUDEP的危险因素。大多数SUDEP病例 发生在晚上，受害者被发现俯卧在床上。这意味着受害者无法唤醒，尽管 增加二氧化碳(CO2)水平，这通常会引发保护性唤醒反射。这种反射是 由中缝背核(DRN)内的5-羟色胺(5-HT)神经元介导。DRN是提升的主要组成部分 产生唤醒的激活系统。DRN也是5-HT投射到其余部分的关键来源。 大脑。DRN中的神经元活动因癫痫发作而失控。慢性背根神经节的结构变化 有癫痫的报道。我们假设癫痫患者DRN 5-羟色胺活性失调 有助于丧失后遗症唤醒和SUDEP风险。在目标1中，我们将使用定制的光纤耦合微 导线阵列检测癫痫小鼠不同睡眠状态和清醒后发作间期DRN 5-羟色胺的活性 睡吧。我们还将评估在不同时期诱导的癫痫发作后DRN 5-羟色胺活性是否受到抑制 睡眠-唤醒状态。目的2我们将利用钙成像和纤维光度法来确定这些 癫痫动物对二氧化碳暴露的反应减弱了DRN 5-羟色胺神经元的激活。我们将评估 癫痫小鼠是否表现出比健康小鼠更长的二氧化碳唤醒潜伏期。参与 建议的培训计划和建议的实验的完成将推进申请人的 为成为一名独立的神经科学家而接受的神经科学培训。它还将决定神经细胞 导致某些癫痫发作的回路是致命的，并为临床医生提供了一个潜在的生物标志物来识别 SUDEP风险最高的患者。

Project Abstract One in 26 Americans will develop epilepsy during their lifetime. One third of these patients have poorly controlled epilepsy that does not respond to medication, placing them at greater risk for sudden unexpected death in epilepsy (SUDEP). While the exact etiology of SUDEP is unknown, dysregulation of the serotonin (5-HT) system has been linked to these untimely deaths. 5-HT plays a critical role in sleep-wake regulation and arousal. Impaired postictal arousal occurs after seizures and is considered a risk factor for SUDEP. Most cases of SUDEP occur at night with the victim found prone in bed. This implies that the victim was unable to arouse, despite the increasing carbon dioxide (CO2) levels which would normally trigger a protective arousal reflex. This reflex is mediated by 5-HT neurons in the dorsal raphe nucleus (DRN). The DRN is a major component of the ascending activating system that produces arousal. The DRN is also a key source of 5-HT projections to the rest of the brain. Neuronal activity in the DRN is dysregulated by seizures. Structural changes in the DRN with chronic epilepsy have been reported. We hypothesize that dysregulation of DRN 5-HT activity in epilepsy patients contributes to loss of postictal arousal and SUDEP risk. In Aim 1 we will use a custom optical fiber-coupled micro- wire array to measure interictal DRN 5-HT activity in epileptic mice during different sleep states and arousal from sleep. We will also assess whether DRN 5-HT activity is suppressed following seizures induced during different sleep-wake states. Aim 2 we will utilize calcium imaging with fiber photometry to determine whether these epileptic animals have blunted DRN 5-HT neuronal activation in response to CO2 exposure. We will assess whether epileptic mice exhibit an increased latency to arouse to CO2 compared to healthy mice. Participation in the proposed training plan and completion of the proposed experiments will advance the applicant's neuroscience training towards a career as an independent neuroscientist. It will also determine the neuronal circuitry involved in causing some seizures to be fatal and provide clinicians a potential biomarker to identify patients at the highest risk for SUDEP.