Normal and Pathological Function of the Dentate Gyrus

齿状回的正常和病理功能

• 批准号: 10609505
• 负责人: DOUGLAS A COULTER
• 金额: $ 56.81万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609505
• 关键词: Affective; Aftercare; Anxiety; Area; Behavioral; Calcium; Code; Cognitive; Competence; Control Animal; Development; Disease; Disease model; Emotional; Emotional Disturbance; Emotions; Epilepsy; Exhibits; Experimental Models; Foundations; Generations; Health; Hippocampus; Human; Image; Intervention; Laboratories; Learning; Limbic System; Mediating; Memory; Moods; Mus; Neurons; Pathologic; Pathology; Patients; Performance; Phenotype; Play; Population; Predisposition; Process; Property; Role; Seizures; Series; Symptoms; Techniques; Temporal Lobe Epilepsy; Testing; Therapeutic; Therapeutic Intervention; Time; Transgenic Organisms; Treatment Efficacy; Variant; cognitive function; comorbidity; dentate gyrus; designer receptors exclusively activated by designer drugs; disabling symptom; emotional behavior; experimental study; granule cell; improved; in vivo; memory encoding; neuronal circuitry; new therapeutic target; patch clamp; recruit; spatial memory; therapeutic target; therapy development

The neuronal circuitry within the dentate gyrus is massively disrupted in temporal lobe epilepsy patients and in experimental models of this disorder. This proposal builds upon our laboratory’s previous findings, which demonstrate that the dentate gyrus circuitry within the epileptic hippocampus retains an embedded coding network of dentate granule cells which can reemerge and restore appropriate cognitive function following treatments to suppress degraded pathologic activity. The maintained competence of this embedded dentate granule cell network occurs despite the significant structural pathology which is unaffected by therapeutic interventions. In this proposal, we will build upon this foundation, and examine and manipulate dentate granule cells in both epileptic and control animals to generate a mechanistic understanding of how these epilepsy- associated disruptions to normal circuit functioning can be targeted to restore downstream, emergent properties of the hippocampus, such as learning and memory and emotional behaviors. The CENTRAL HYPOTHESIS of the present proposal is that the epilepsy-associated degradation in coding properties of dentate granule cells contributes significantly to both the cognitive and behavioral comorbidities that constitute key components of the core phenotypes of temporal lobe epilepsy. To test this Central Hypothesis, we propose to conduct a series of experiments centered on 3 SPECIFIC AIMS: Aim 1. Characterize the local circuit properties defining the active dentate granule cell network in epileptic and control mice. Aim 2. Determine the capacity, time course, and extent of long-term dentate gyrus circuit specific intervention strategies to rescue cognitive and behavioral function in epileptic mice. Aim 3. Assess the contribution of dentate granule cell hyperexcitability in epileptic mice to disrupted hippocampal spatial coding. We know little about the mechanisms that mediate the sparse yet deterministic firing properties of neuronal populations in the hippocampal dentate gyrus that are responsible for their role in information coding and plasticity. We know even less about how disease-associated degradation in these critical dentate granule cell properties develop, and in turn how this excitability disruption may erode cognitive and affective functions that the hippocampus normally supports. In addition to the enhanced excitability responsible for seizure generation, patients with epilepsy exhibit severe cognitive comorbidities, including deficits in emotion, mood, and learning and memory, processes typically thought of as limbic system functions. Understanding how epilepsy development alters the basic circuit properties within the limbic system may be important not only in targeting new therapies for seizure amelioration, but also in developing new treatments to reduce comorbid conditions accompanying epilepsy development, a largely unexplored area of therapy development.

颞叶癫痫患者和癫痫患者齿状回内的神经元回路被大量破坏， 这种疾病的实验模型。这项建议建立在我们实验室以前的发现之上， 证明癫痫海马内的齿状回回路保留了嵌入式编码， 齿状颗粒细胞的网络，可以重新出现，并恢复适当的认知功能， 治疗以抑制退化的病理活性。这种嵌入式齿状的能力 尽管存在显著的结构病理学，但颗粒细胞网络的出现不受治疗性药物的影响。 干预措施。本研究拟在此基础上，对齿状颗粒进行研究和操作 癫痫和对照动物的细胞，以产生对这些癫痫的机制的理解- 正常电路功能的相关中断可以有针对性地恢复下游，紧急 海马体的特性，如学习和记忆以及情绪行为。中央 本提案的假设是癫痫相关的编码特性的退化， 齿状颗粒细胞对认知和行为共病有重要作用， 颞叶癫痫核心表型的关键组成部分。为了验证这一中心假设，我们建议 进行一系列实验，围绕3个具体目标：目标1。描述本地电路的特性 定义癫痫和对照小鼠中活性齿状颗粒细胞网络的性质。目标2.确定 容量、时间进程和长期齿状回回路特定干预策略的程度，以挽救 癫痫小鼠的认知和行为功能。目标3.评估齿状回颗粒细胞的贡献 癫痫小鼠对海马空间编码破坏的过度兴奋性。我们对这一点知之甚少。 调节神经元群体稀疏但确定性放电特性的机制， 海马齿状回负责其在信息编码和可塑性中的作用。我们知道 更不用说这些关键的齿状颗粒细胞特性的疾病相关退化是如何发展的， 以及这种兴奋性的破坏如何侵蚀海马体的认知和情感功能， 通常支持。除了负责癫痫发作的兴奋性增强外， 癫痫表现出严重的认知共病，包括情感、情绪、学习和记忆的缺陷， 通常被认为是边缘系统功能的过程。了解癫痫的发展如何改变 边缘系统内的基本回路特性可能不仅在靶向新疗法中是重要的， 癫痫发作改善，而且还在开发新的治疗方法，以减少伴随 癫痫的发展，一个很大程度上未探索的治疗发展领域。