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一生中患上癫痫。三分之一的患者控制不良， 癫痫对药物治疗没有反应，使他们面临更大的突然意外死亡的风险， 癫痫（SUDEP）。虽然SUDEP的确切病因尚不清楚，但5-羟色胺（5-HT）系统的失调 与这些意外死亡有关5-HT在睡眠-觉醒调节和觉醒中起着关键作用。 发作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趴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 中缝背核（DRN）内5-HT神经元介导的。DRN是提升者的主要组成部分 产生兴奋的激活系统。DRN也是5-HT投射到其他神经元的关键来源。 个脑袋DRN中的神经元活动因癫痫发作而失调。DRN的结构变化与慢性 癫痫病有报道。我们假设癫痫患者DRN 5-HT活性失调 导致发作后觉醒丧失和SUDEP风险。在目标1中，我们将使用一个定制的光纤耦合微， 线阵列测量癫痫小鼠在不同睡眠状态和觉醒期间发作间期DRN 5-HT活性， 睡吧我们还将评估DRN 5-HT活性是否在不同时间诱导的癫痫发作后受到抑制。 睡眠-清醒状态目的2我们将利用钙成像与纤维光度法，以确定是否这些 癫痫动物对CO2暴露的反应使DRN 5-HT神经元活化减弱。我们将评估 与健康小鼠相比，癫痫小鼠是否表现出对CO2唤醒的潜伏期增加。参与 建议的培训计划和完成建议的实验将提高申请人的 神经科学培训，以成为一名独立的神经科学家。它还将决定神经元 参与导致某些癫痫发作的电路是致命的，并为临床医生提供了一个潜在的生物标志物，以确定 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.