Cognitive outcomes of optogenetic seizure intervention in epileptic mice

项目摘要 除了癫痫发作，颞叶癫痫（TLE）患者还患有一系列合并症，包括 认知能力下降TLE本身大约每1000人中有1.7人受到影响，不幸的是，这一重大疾病的三分之一 患者群体经历了当前药理学治疗选择的不受控制的癫痫发作。 纵向证据表明，癫痫发作缺乏控制是认知功能恶化的主要预测因素， TLE患者然而，癫痫干预对认知结果的影响-以及它们与 TLE的解剖学变化-仍有待研究。如果没有这些知识， 将极大地抑制针对与TLE相关的认知下降的治疗。确定经常项目的作用 癫痫发作和重要的神经元群体将为未来旨在治疗认知障碍的临床治疗提供信息。 合并症。我们的初步数据表明，特定的和强大的记忆缺陷， 癫痫小鼠的异常解剖表型。这些结果基本上与 报告解剖病理学和记忆缺陷的人类TLE患者。其他检查患者的研究 癫痫缓解患者的认知功能稳定或改善。这表明，停止 癫痫发作会导致积极的认知结果。因此，我们假设慢性按需光遗传学 干预可以减轻癫痫小鼠的认知缺陷。我们将通过以下内容来解决这个假设 具体目的：1A）确定海马、小脑外侧和小脑蚓部靶向治疗的相对有效性， 1B）比较慢性光遗传学癫痫发作干预在认知功能方面的策略; 抢救; 2）确定TLE的神经病理学、癫痫发作干预和认知功能之间的关系。 损伤我们将利用海马内海人酸（IKKA）小鼠模型诱导TLE， 自发性癫痫在这些小鼠中，我们将实施一种光遗传学癫痫干预系统， 控制癫痫发作干预的模式和位置。从该项目获得的信息将告知 慢性癫痫自发性发作是否累积损伤并导致癫痫发作， 认知能力下降此外，这些结果将确定癫痫干预的关键要素， 与认知结果相关的神经病理学，为未来的研究提供方向，以治疗这种疾病。 使人衰弱的疾病

Project Summary In addition to seizures, temporal lobe epilepsy (TLE) patients suffer from a range of comorbidities, including cognitive decline. TLE itself afflicts approximately 1.7 per 1000 people, and tragically, one-third of this substantial patient population experiences uncontrolled seizures with current pharmacological treatment options. Longitudinal evidence suggests that lack of seizure control is a leading predictor of cognitive deterioration in patients with TLE. Yet the impact of seizure intervention on cognitive outcomes – and their mutual relationship to anatomical changes in TLE – remains to be investigated. Without this knowledge, the ability to implement therapies addressing TLE-associated cognitive decline will be greatly inhibited. Identifying the role of recurrent seizures and important neuronal populations will inform future clinical therapies aimed at treating cognitive comorbidities. Our preliminary data demonstrate specific and robust memory deficits in conjunction with abnormal anatomical phenotypes in epileptic mice. These results are in general agreement with observations in human TLE patients that report anatomical pathologies and memory deficits. Other studies examining patients that achieve seizure remission report stabilized or improved cognitive functioning. This suggests that stopping seizures will lead to positive cognitive outcomes. Therefore, we hypothesize that chronic on-demand optogenetic intervention can alleviate cognitive deficits in epileptic mice. We will address this hypothesis through the following Specific Aims: 1A) determine the relative effectiveness of hippocampal, lateral cerebellar, and vermal targeting at cognitive rescue in epileptic mice; 1B) compare strategies of chronic optogenetic seizure intervention at cognitive rescue; and 2) determine the relationship between neuropathologies of TLE, seizure intervention, and cognitive impairment. We will utilize in the intrahippocampal kainic acid (IHKA) mouse model of TLE to induce spontaneous seizures. In these mice, we will implement an optogenetic seizure intervention system to specifically control the pattern and location of seizure intervention. The information obtained from this project will inform the controversy of whether or not spontaneous seizures in chronic epilepsy accumulate damage and result in cognitive decline. Furthermore, these results will identify key elements of seizure intervention and neuropathologies that correlate with cognitive outcomes, providing direction for future investigations to treat this debilitating disorder.