Remote effects of focal hippocampal seizures on neocortical function

局灶性海马癫痫发作对新皮质功能的远程影响

基本信息

批准号：
8415578
负责人：
HAL BLUMENFELD
金额：
$ 35.1万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8415578
关键词：
Acetylcholine Amnesia Anesthesia procedures Arousal Basal Nucleus of Meynert Biosensor Blood Volume Brain Stem Cell Nucleus Cerebral cortex Cerebrovascular Circulation Cerebrum Cognitive deficits Coma Conscious Data Depressed mood Disease Distant Electroencephalography Electrophysiology (science)Exhibits Focal Seizure Frequencies Functional Magnetic Resonance Imaging Functional disorder Glutamates Hippocampus (Brain)Histology Human Hypothalamic structure Impairment Interneurons Lead Maps Measurement Measures Membrane Potentials Metabolism Modeling Movement Neocortex Nervous System Physiology Neurons Neurotransmitters Operative Surgical Procedures Partial Epilepsies Pathway interactions Patients Pattern Pharmacotherapy Pyramidal Cells Quality of life Rattus Resolution Rodent Model Seizures Septal Nuclei Sleep Structure Synapses System Temporal Lobe Temporal Lobe Epilepsy Testing Thalamic structure Time Work awake base blood oxygen level dependent cholinergic neuron design encephalography extracellular frontal lobe hippocampal pyramidal neuron improved in vivo neocortical nervous system disorder neuroimaging neurotransmission neurotransmitter agonist neurotransmitter antagonist novel novel therapeutics prevent public health relevance research study

项目摘要

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.

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) 是一种常见且令人衰弱的神经系统疾病，其特征是由边缘结构（包括海马体）引起的局灶性癫痫发作。有趣的是，部分颞叶癫痫发作通常会导致意识障碍等功能缺陷，而仅局部海马损伤是不会出现这种情况的。意识受损的人类局灶性颞叶癫痫发作与脑电图（EEG）慢波和远离海马的新皮质脑血流量（CBF）减少有关。海马体局灶性癫痫发作导致新皮质功能抑制的机制尚不清楚。根据我们的初步研究，我们提出，发作期新皮质缓慢活动反映了皮质功能低下的独特状态，与癫痫发作活动更接近深度麻醉或睡眠。为了支持这一点，我们最近在大鼠模型中发现，自发性和诱发性边缘癫痫发作在海马体中表现出高频放电，但在眶额皮质中表现出缓慢的 1-3 Hz 活动。发作期新皮质缓慢活动的特点是神经元放电、CBF、血氧水平依赖性功能磁共振成像（BOLD fMRI）、脑血容量和代谢减少，而同时海马体在所有这些指标上都显示出增加。我们还发现，可以通过破坏穹窿（海马体和皮质下核之间的主要连接，对唤醒很重要）和引入乙酰胆碱（皮质下唤醒核的主要神经递质）的替代品来预防发作性新皮质缓慢活动。因此，我们的中心假设是局灶性边缘癫痫发作抑制皮质下唤醒系统（包括乙酰胆碱），导致新皮质功能下降，类似于睡眠。我们计划在啮齿动物模型的网络、神经递质和神经元水平上研究这一假设。我们的目标是首先使用功能磁共振成像、局部场和多单元记录、局部刺激、断开和失活实验来定义导致部分边缘癫痫发作的发作性新皮质缓慢活动的皮质和皮质下结构网络。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进行神经递质测量。第三，我们将使用细胞旁和细胞内记录来确定参与发作期新皮质慢活动的皮层和皮层下结构中已识别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 异常远程网络变化的理解，有可能为这种疾病的治疗带来新的治疗选择。