Remote effects of focal hippocampal seizures on neocortical function

项目摘要/摘要 癫痫发作对神经系统功能既有局部影响，也有远程影响。颞叶癫痫是一种常见的 和衰弱的神经障碍，其特征是边缘结构引起的局灶性癫痫，包括 海马体。有趣的是，局灶性颞叶癫痫发作经常导致功能缺陷，如受损 意识，这不是单单由局部海马区损伤引起的。人局灶性颞叶 意识受损的癫痫发作在脑电(EEG)上表现为慢波并降低 大脑血流在远离海马体的新皮质。局灶性癫痫发作的机制 在海马区，导致新皮质功能受抑的原因尚不清楚。我们建立了一个大鼠模型 局灶性边缘惊厥在海马区表现为高频放电，但在海马区1-3赫兹活动减慢 新皮质，皮质血流量和代谢减少，以及行为反应性降低 类似于人类的疾病。在这个模型中，我们发现重要的皮质下觉醒系统包括 脑干和基底前脑胆碱能神经元受到抑制。这些发现表明，类似睡眠的大脑皮质 由于皮质下觉醒减少，局灶性边缘癫痫可出现慢波。此外，我们发现 推测的下行GABA能系统包括外侧隔和下丘脑前部 因局灶性边缘癫痫发作而强烈激活。基于这些发现，我们的中心假设是大脑边缘 癫痫发作激活抑制系统，抑制皮质下觉醒，导致睡眠样皮质慢波 以及意识受损。我们计划在神经元、网络和 啮齿动物模型中的行为。最近的研究也提出了恢复皮质下觉醒的令人兴奋的前景 以改善癫痫发作期间的皮质功能。因此，我们的目标是首先研究皮层下的输入 唤醒系统使用全细胞电生理学来确定传入的突触活动；并使用 光遗传学选择性地激活或抑制输入通路的光遗传学第二，我们将确定哪个皮质下 唤醒系统是通过电或光基因恢复输出而抑制皮质功能的关键 在局灶性边缘癫痫发作期间从这些系统获得，并通过电生理学测量对皮质的影响 记录和高场功能磁共振成像(FMRI)。第三，我们将研究 局灶性边缘惊厥对注意和决策任务的影响及皮层下恢复能力的研究 唤醒以改善癫痫发作期间的行为反应。这些应用程序之间的信息集成 水平将增加我们对癫痫异常远程网络变化的理解，潜在地导致 为治疗这种疾病提供了新的治疗选择。

PROJECT SUMMARY / ABSTRACT Seizures have both local and remote effects on nervous system function. Temporal lobe epilepsy is a common and debilitating neurological disorder, characterized by focal seizures arising from limbic structures, including the hippocampus. Interestingly, focal temporal lobe seizures often cause functional deficits such as impaired consciousness, which is not expected from local hippocampal impairment alone. Human focal temporal lobe seizures with impaired consciousness show slow waves on electro-encephalography (EEG) and decreased cerebral blood flow in the neocortex, distant from the hippocampus. The mechanisms by which focal seizures in the hippocampus cause depressed function in the neocortex are not known. We established a rat model with focal limbic seizures exhibiting high frequency discharges in the hippocampus, but slow 1-3 Hz activity in the neocortex, decreased cortical blood flow and metabolism, as well as decreased behavioral responsiveness resembling the human disorder. In this model we found that important subcortical arousal systems including brainstem and basal forebrain cholinergic neurons are depressed. These finding suggest that sleep-like cortical slow waves may occur in focal limbic seizures because of decreased subcortical arousal. In addition we found that putative descending GABAergic systems including the lateral septum and anterior hypothalamus are strongly activated by focal limbic seizures. Based on these findings, our central hypothesis is that focal limbic seizures activate inhibitory systems which depress subcortical arousal leading to sleep-like cortical slow waves and impaired consciousness. We plan to investigate this hypothesis at the level of neurons, networks, and behavior in a rodent model. Recent work has also raised the exciting prospect of restoring subcortical arousal to improve cortical function during seizures. Therefore, our aims are to first investigate the inputs to subcortical arousal systems using whole-cell electrophysiology to determine incoming synaptic activity; and using optogenetics to selectively activate or inhibit input pathways. Second, we will determine which subcortical arousal systems are critical for depressed cortical function by electrically or optogenetically restoring outputs from these systems during focal limbic seizures, and measure effects on the cortex through electrophysiology recordings and high-field functional magnetic resonance imaging (fMRI). Third, we will examine the effects of focal limbic seizures on attention and decision-making tasks and investigate the ability of restored subcortical arousal to improve behavioral responsiveness during seizures. The integration of information across these levels will increase our understanding of abnormal long-range network changes in epilepsy, potentially leading to new therapeutic options in the treatment of this disorder.