The role of CA2 in epilepsy and social comorbidity

CA2 在癫痫和社会共病中的作用

基本信息

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
项目类别：
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

项目摘要

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）的关键挑战是确定有助于的神经机制癫痫发作是因为目前的药物无法治疗所有癫痫发作，并且通常会带来令人衰弱的副作用。此外，目前的药物不治疗社会行为的改变通常由癫痫病人表现出来，包括增加社交侵略性。该项目将挑战当前的教条海马如何促进TLE癫痫发作的基础，该癫痫发作的重点是三个主要地区海马：齿状回，CA3和CA1。相反，我们检查了面积Ca2，一个相对较小的区域海马很少受到关注，但众所周知，在TLE患者和啮齿动物模型，可以作为癫痫发作的焦点或促进癫痫发作的传播。实验工具在两名主要研究人员的实验室中开发通过使用表达CRE重组酶的鼠标线，CA2在鼠标TLE模型中的重要性在CA2主神经元中相对有选择地。 Cre依赖性病毒载体将用于遗传表达 CA2主神经元中的编码工具，以检查TLE中Ca2电路的两种变化以及 Ca2急性或慢性沉默。因此，我们将确定CA2是否控制药理诱导健康大脑中急性癫痫发作和/或癫痫大脑中的慢性癫痫发作。我们也会确定CA2在鼠标模型中报道的社会认知和社会侵略性缺陷中的重要性我们发现CA2是社会识别记忆所必需的，并且与社会有关侵略。随着社会激素精氨酸加压素的促进社会记忆和社会侵略增强CA2的输入和输出，并已证明可以调节动物的癫痫发作，我们将检查该作用这种激素对癫痫小鼠社会行为改变的调节。通过评估 CA2在癫痫中，该项目提供了提供有关癫痫发作和的基本机械洞察力和社会行为合并症，并可能验证高度富含Ca2神经元的新型药物靶标。