Remote effects of focal hippocampal seizures on neocortical function

描述（由申请人提供）：癫痫发作对神经系统功能有局部和远程影响。颞叶癫痫（TLE）是一种常见的神经系统疾病，其特征是由边缘系统结构（包括海马）引起的局灶性癫痫发作。有趣的是，部分颞叶癫痫发作往往会导致功能缺陷，如意识障碍，这是不期望从局部海马损伤单独。其中意识受损的人类局灶性颞叶癫痫发作与脑电图（EEG）上的慢波和远离海马的新皮质中的脑血流量（CBF）减少相关。海马局灶性癫痫发作导致新皮层功能下降的机制尚不清楚。基于我们的初步研究，我们提出，发作性新皮层缓慢活动反映了一种独特的状态，抑郁的皮层功能，更接近深度麻醉或睡眠比癫痫发作活动。为了支持这一点，我们最近在大鼠模型中发现，自发性和诱导性边缘系统癫痫发作在海马中表现出高频放电，但在眶额皮质中表现出缓慢的1-3 Hz活动。发作期新皮层缓慢活动的特征是神经元放电减少，CBF，血氧水平依赖性功能性MRI（BOLD fMRI），脑血容量和代谢，而在同一时间，海马在所有这些措施中表现出增加。我们还发现，可以通过破坏穹窿（海马和皮层下核团之间的主要联系，对唤醒很重要）和引入乙酰胆碱（皮层下唤醒核团的主要神经递质）的替代品来防止发作性新皮层缓慢活动。因此，我们的中心假设是，局灶性边缘系统癫痫发作抑制皮层下唤醒系统（包括乙酰胆碱），导致类似睡眠的新皮层功能下降。我们计划在啮齿动物模型中的网络，神经递质和神经元水平上研究这一假设。我们的目的是首先定义网络的皮质和皮质下结构，导致发作性新皮质缓慢活动的部分边缘癫痫发作，使用功能磁共振成像，局部领域和多单元记录，局部刺激，断开和失活实验。其次，我们将通过应用神经递质激动剂/拮抗剂以及使用体内生物传感器探针测量神经递质来研究产生新皮质缓慢活动的神经递质。第三，我们将确定的放电模式和突触活动的变化，确定神经元在皮层和皮层下结构参与发作的新皮层慢活动，使用细胞内和细胞内记录。跨这些水平的信息整合将增加我们对TLE异常长程网络变化的理解，可能导致治疗这种疾病的新治疗选择。

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.