Implication of the lateral hypothalamus in the comorbid sleep disorder of temporal lobe seizure

摘要 癫痫（Epilepsy）是一种常见的神经系统疾病，是一种反复发作的自发性疾病. 这些反复发作导致广泛的合并症，进一步降低患者的生活质量， 可能会干扰他们癫痫的诊断和治疗。特别是，患有颞叶疾病的患者 脑叶癫痫有频繁和严重的睡眠障碍，如白天过度嗜睡。众多的大脑 这些区域参与了觉醒的调节，并可能参与了这些共病睡眠的产生 紊乱其中，外侧下丘脑（LH）的食欲素能神经元已被证明控制 唤醒和觉醒，但也显示参与癫痫活动的调节。我们 假设颞叶癫痫发作可能会破坏LH的正常功能，导致 夜间睡眠结构和白天过度嗜睡。睡眠和癫痫之间的相互作用是 由于药物和环境等混杂因素，在患者中进行研究非常复杂和困难。而 在啮齿类动物研究中，环境是可以控制的，人与啮齿类动物之间存在明显的差异 昼夜节律周期和睡眠结构，限制了翻译价值。或者，恒河猴 非人类灵长类动物的睡眠结构与人类相似，有四个不同的睡眠阶段， 癫痫发作可以通过在颞叶注射青霉素来安全地诱发。急性癫痫发作将由 将青霉素局部注射到海马体中，这将导致连续的自发性癫痫发作， 发作间期活动持续4-6小时。在目标1中，我们将描述电生理变化的特点， 在这些颞叶癫痫发作时。我们将记录单位和当地的现场活动，并分析 癫痫发作和发作间期活动引起的放电频率和模式。我们希望看到LH的强烈参与 癫痫发作时的神经元在目标2中，我们将评估与颞叶癫痫相关的共病睡眠障碍， 脑叶癫痫我们将测试白天的过度嗜睡，并评估夜间睡眠的变化 癫痫发作诱导后不同时间点的睡眠结构，以及正常的睡眠结构如何 通过给予食欲素拮抗剂恢复。在诱导癫痫发作后，我们希望能找到一种干扰 睡眠结构，减少快速眼动持续时间，增加白天嗜睡，这可能是 通过给予suvorexant（一种食欲素拮抗剂）改善。这项工作将提供关键的初步数据 为后续研究更广泛地调查LH神经元和食欲素活性参与， 控制癫痫发作和与颞叶癫痫发作相关的睡眠障碍。

Abstract Epilepsy, the occurrence of spontaneous recurrent seizures, is one of the most common neurological disorders. These recurring seizures result in a wide range of comorbidities that further reduce a patient’s quality of life and could interfere with the diagnosis and treatment of their epilepsy. In particular, patients suffering from temporal lobe epilepsy have frequent and severe sleep disorders such as excessive daytime sleepiness. Numerous brain areas are involved in regulation of wakefulness and could be involved in the generation of these comorbid sleep disorders. Among them, the orexinergic neurons of the lateral hypothalamus (LH) have been shown to control arousal and wakefulness but have also been shown to be involved in the modulation of epileptic activity. We hypothesize that temporal lobe seizures may disrupt the normal function of the LH leading to changes in nocturnal sleep architecture and excessive daytime sleepiness. The interaction between sleep and epilepsy is complex and difficult to study in patients due to confounding factors such as medication and environment. While the environment can be controlled in rodent studies, there are distinct differences between the human and rodent circadian cycles and sleep architectures, limiting the translational value. Alternatively, rhesus macaque nonhuman primates have a sleep architecture like humans with four distinct sleep stages, and temporal lobe seizures can be safely induced by injecting penicillin into the temporal lobe. Acute seizures will be induced by local injection of penicillin into the hippocampus which will result in a succession of spontaneous seizures and interictal activity for a period of 4-6 hours. In Aim 1, we will characterize the electrophysiological changes of the LH during these temporal lobe seizures. We will record unit and local field activity and analyze the changes in firing rate and pattern induced by seizures and interictal activity. We expect to find a strong involvement of LH neurons during the seizures. In Aim 2, we will evaluate the comorbid sleep disorders associated with temporal lobe seizures. We will test the excessive daytime sleepiness and evaluate the changes in the nocturnal sleep architecture at different timepoints following seizure induction, and how normal sleep architecture can be restored with administration of an orexin antagonist. Following seizure induction, we expect to find a disruption of sleep architecture, reduction of REM duration, and an increase of daytime sleepiness, which can be ameliorated with administration of suvorexant, an orexin antagonist. This work will provide key preliminary data for a subsequent study to investigate more extensively the involvement of the LH neurons and orexin activity in the control of seizures and the comorbid sleep disorders associated with temporal lobe seizures.