Remote effects of focal hippocampal seizures on neocortical function

描述(申请人提供)：癫痫发作对神经系统功能有局部和远程影响。颞叶癫痫(TLE)是一种常见的、令人衰弱的神经系统疾病，其特征是边缘结构(包括海马区)出现局灶性癫痫发作。有趣的是，部分颞叶癫痫发作经常导致意识受损等功能障碍，这不是仅从局部海马区损害就能预料到的。意识受损的人的局灶性颞叶癫痫与脑电(EEG)上的慢波和远离海马区的新皮质中的脑血流量(CBF)减少有关。海马局灶性癫痫发作导致新皮质功能抑制的机制尚不清楚。基于我们的初步研究，我们认为，发作期新皮质慢活动反映了皮质功能受抑的明显状态，比癫痫活动更类似于深度麻醉或睡眠。为了支持这一点，我们最近在一个大鼠模型中发现，自发性和诱发性边缘癫痫发作在海马区表现出高频放电，但在眼眶额叶皮质表现出1-3赫兹的缓慢活动。发作期新皮质慢活动的特点是神经元放电、脑血流量、血氧水平依赖的功能磁共振成像(BOLD FMRI)、脑血容量和代谢减少，而与此同时，海马区在所有这些指标上都显示出增加。我们还发现，可以通过破坏穹隆(海马体和皮质下核团之间对唤醒很重要的主要连接)和引入乙酰胆碱的替代品(皮质下觉醒核团的主要神经递质)来防止发作期新皮质缓慢活动。因此，我们的中心假设是，局灶性边缘癫痫发作抑制了皮质下觉醒系统(包括乙酰胆碱)，导致类似睡眠的新皮质功能受抑。我们计划在啮齿动物模型中从网络、神经递质和神经元的水平上研究这一假说。我们的目标是首先利用功能磁共振成像、局域场和多单位记录、局部刺激、断连和失活实验，确定导致部分边缘癫痫发作时新皮质迟缓活动的皮质和皮质下结构的网络。其次，我们将通过应用神经递质激动剂/拮抗剂来研究产生新皮质缓慢活动的神经递质，并使用体内生物传感器探针来测量神经递质。第三，我们将通过细胞旁和细胞内的记录，确定参与发作期新皮质慢活动的皮质和皮质下结构中已识别的神经元的放电模式和突触活动的变化。跨这些水平的信息整合将增加我们对TLE异常长期网络变化的理解，可能导致治疗这种疾病的新的治疗选择。

DESCRIPTION (provided by applicant): Seizures have both local and remote effects on nervous system function. Temporal lobe epilepsy (TLE) is a common and debilitating neurological disorder, characterized by focal seizures arising from limbic structures, including the hippocampus. Interestingly, partial 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 in which consciousness is impaired are associated with slow waves on electro- encephalography (EEG) and decreased cerebral blood flow (CBF) 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. Based on our preliminary studies, we propose that ictal neocortical slow activity reflects a distinct state of depressed cortical function, more closely resembling deep anesthesia or sleep than seizure activity. In support of this, we recently found in a rat model that spontaneous and induced limbic seizures exhibit high frequency discharges in the hippocampus, but slow 1-3 Hz activity in the orbital frontal cortex. Ictal neocortical slow activity was characterized by decreased neuronal firing, CBF, blood oxygen level dependent functional MRI (BOLD fMRI), cerebral blood volume, and metabolism, while at the same time the hippocampus showed increases in all of these measures. We also found that ictal neocortical slow activity could be prevented by disrupting the fornix (a main connection between the hippocampus and subcortical nuclei important for arousal) and by introducing a replacement for acetycholine (a major neurotransmitter of subcortical arousal nuclei). Therefore, our central hypothesis is that focal limbic seizures inhibit subcortical arousal systems (including acetylcholine) leading to depressed function in the neocortex resembling sleep. We plan to investigate this hypothesis at the level of networks, neurotransmitters, and neurons in a rodent model. Our aims are to first define the network of cortical and subcortical structures which cause ictal neocortical slow activity in partial limbic seizures using fMRI, local field and multiunit recordings, local stimulation, disconnection and inactivation experiments. Second, we will investigate the neurotransmitters producing neocortical slow activity through application of neurotransmitter agonists/antagonists, and neurotransmitter measurements using in vivo biosensor probes. Third, we will determine the changes in firing patterns and synaptic activity of identified neurons in the cortex and subcortical structures involved in ictal neocortical slow activity using juxtacellular and intracellular recordings. The integration of information across these levels will increase our understanding of abnormal long-range network changes in TLE, potentially leading to new therapeutic options in the treatment of this disorder.