Normal and Pathological Function of the Dentate Gyrus

齿状回的正常和病理功能

基本信息

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
项目类别：
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

项目摘要

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的齿状回内的神经元回路被严重破坏。这种疾病的实验模型建立在我们实验室之前的研究结果的基础上。证明癫痫海马内的齿状回电路保留了嵌入的编码齿状颗粒细胞网络，可以在以下情况下重新出现并恢复适当的认知功能抑制退化的病理活动的治疗。保持这种嵌入齿状的能力。尽管存在不受治疗影响的显着结构病理学，但颗粒细胞网络仍然存在在这个提案中，我们将在此基础上进行检查和操作齿状颗粒。癫痫动物和对照动物的细胞，以产生对这些癫痫如何发生的机械理解与正常电路功能相关的中断可以有针对性地恢复下游、紧急情况海马体的特性，例如学习和记忆以及情绪行为。本提案的假设是，与癫痫相关的编码特性退化齿状颗粒细胞对认知和行为合并症有显着影响，这些合并症构成为了检验这个中心假设，我们提出了颞叶癫痫核心表型的关键组成部分。围绕 3 个具体目标进行一系列实验：目标 1. 表征本地电路定义癫痫小鼠和对照小鼠的活性齿状颗粒细胞网络的特性目标 2. 确定长期齿状回回路的容量、时间进程和范围救援的具体干预策略目标 3. 评估齿状颗粒细胞的贡献。癫痫小鼠的过度兴奋导致海马空间编码被破坏，我们对此知之甚少。介导神经群体稀疏但确定性放电特性的机制我们知道，海马齿状回负责信息编码和可塑性。更不用说这些关键的齿状颗粒细胞特性与疾病相关的退化是如何发展的，反过来，这种兴奋性破坏如何侵蚀海马体的认知和情感功能除了导致癫痫发作的兴奋性增强之外，患者通常还支持。癫痫表现出严重的认知合并症，包括情绪、心境、学习和记忆缺陷，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针对新疗法方面很重要改善癫痫发作，还开发新的治疗方法以减少伴随的合并症癫痫的发展，是治疗发展中一个很大程度上未经探索的领域。