The role of CA2 in epilepsy and social comorbidity

CA2 在癫痫和社会共病中的作用

• 批准号: 10413857
• 负责人: STEVEN A SIEGELBAUM
• 金额: $ 52.76万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10413857
• 关键词: Acute; Address; Aggressive behavior; Animal Model; Animals; Area; Argipressin; Attention; Behavior; Behavioral; Brain; Brain region; Cell Death; Chronic; Clozapine; Complex; Disinhibition; Electrophysiology (science); Enterobacteria phage P1 Cre recombinase; Epilepsy; Epileptogenesis; Frequencies; Generations; Goals; Hippocampus (Brain); Hormones; Human; Individual; Investigation; Laboratories; Lead; Ligands; Memory; Modeling; Mus; Nerve Degeneration; Neurons; Output; Oxides; Patients; Pattern; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Pilocarpine; Principal Investigator; Property; Receptor Signaling; Reporting; Resistance; Rodent Model; Role; Sclerosis; Seizures; Signaling Molecule; Slice; Social Behavior; Temporal Lobe Epilepsy; Testing; Therapeutic; Viral Vector; base; behavior test; cognitive testing; cohort; comorbidity; dentate gyrus; designer receptors exclusively activated by designer drugs; drinking water; entorhinal cortex; experimental study; hippocampal pyramidal neuron; hormone regulation; in vivo; insight; kainate; laboratory development; memory recognition; mossy fiber; mouse model; neural circuit; neuromechanism; new therapeutic target; novel; novel therapeutic intervention; optogenetics; resilience; response; selective expression; side effect; social; social cognition; synaptic inhibition; tool

PROJECT ABSTRACT A key challenge in temporal lobe epilepsy (TLE) is to determine the neural mechanisms contributing to seizures because current drugs fail to treat all seizures and usually come with debilitating side effects. Moreover, current drugs do not treat alterations in social behavior often manifest by individuals with epilepsy, including increased social aggression. This project will challenge current dogma as to the pathophysiological bases of how the hippocampus contributes to seizures in TLE, which has focused on three major regions of the hippocampus: dentate gyrus, CA3 and CA1. Instead, we examine area CA2, a relatively small region of hippocampus that has received little attention but is known to survive relatively intact in TLE patients and rodent models, and may serve as a seizure focus or facilitate seizure propagation. Experimental tools developed in the laboratories of the two Principal Investigators now enable the direct investigation of the importance of CA2 in mouse TLE models by employing a mouse line that expresses Cre recombinase relatively selectively in CA2 principal neurons. Cre-dependent viral vectors will be used to express genetically encoded tools in CA2 principal neurons to examine both alterations in CA2 circuitry in TLE and the effects of CA2 acute or chronic silencing on seizures. Thus, we will determine whether CA2 controls the pharmacological induction of acute seizures in the healthy brain and/or chronic seizures in the epileptic brain. We will also determine the importance of CA2 in reported deficits in social cognition and social aggression in mouse models of acquired TLE, as we find that CA2 is required for social recognition memory and is implicated in social aggression. As the social hormone arginine vasopressin promotes social memory and social aggression by enhancing CA2 input and output, and has been shown to regulate seizures in animals, we will examine the role of CA2 regulation by this hormone on social behavioral alterations in epileptic mice. By evaluating the role of CA2 in epilepsy, this project offers the promise of providing both basic mechanistic insight into seizures and social behavioral comorbidity, and may validate novel drug targets highly enriched in CA2 neurons.

项目摘要 颞叶癫痫（TLE）的一个关键挑战是确定导致癫痫发作的神经机制。 癫痫发作，因为目前的药物不能治疗所有癫痫发作，通常伴随着使人衰弱的副作用。 此外，目前的药物不能治疗癫痫患者经常表现出的社会行为的改变， 包括社会攻击性的增加。这个项目将挑战目前的教条， 海马体如何在TLE癫痫发作中发挥作用的基础，该研究集中在海马体的三个主要区域， 海马：齿状回、CA 3和CA 1。相反，我们研究了CA 2区，一个相对较小的区域， 海马体很少受到关注，但已知在TLE患者中相对完整地存活， 啮齿动物模型，并可作为癫痫发作病灶或促进癫痫发作传播。实验工具 在两个主要研究人员的实验室中开发的，现在可以直接调查 通过使用表达Cre重组酶的小鼠系在小鼠TLE模型中CA 2的重要性 相对选择性地在CA 2主神经元。Cre依赖性病毒载体将用于基因表达 在CA 2主要神经元中的编码工具，以检查TLE中CA 2回路的改变和 癫痫发作时CA 2急性或慢性沉默。因此，我们将确定CA 2是否控制药理学作用。 诱导健康脑中的急性癫痫发作和/或癫痫脑中的慢性癫痫发作。我们还将 确定CA 2在小鼠模型中报告的社会认知和社会攻击缺陷中的重要性 对于获得性TLE，我们发现CA 2是社会识别记忆所需的，并且与社会认知有关。 侵略作为社会激素精氨酸加压素促进社会记忆和社会侵略， 增强CA 2的输入和输出，并已被证明可以调节动物的癫痫发作，我们将研究其作用 这种激素对癫痫小鼠社会行为改变的CA 2调节。通过评估 CA 2在癫痫中的作用，该项目提供了对癫痫发作的基本机制的见解， 社会行为共病，并可能验证高度富集在CA 2神经元的新药物靶点。