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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