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：
10442117
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/10442117
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 (Brain)Human Image Intervention Laboratories Learning Limbic System Mediating Memory Moods Mus Neurons Pathologic Pathology Patients Performance Phenotype Play Population Predisposition Property Role Seizures Series Symptoms Techniques Temporal Lobe Epilepsy Testing Therapeutic Therapeutic Intervention Time Transgenic Organisms Treatment Efficacy Variant base 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 memory process 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.

在临时叶癫痫患者和中这种疾病的实验模型。该提议建立在我们实验室以前的发现上，证明癫痫海马内的齿状回电路保留了嵌入式编码可以重新出现并恢复适当认知功能的牙齿颗粒细胞网络治疗以抑制降解的病理活性。该嵌入式齿状的维持能力尽管存在明显的结构病理学，但仍未受到治疗影响，但仍会发生颗粒细胞网络干预措施。在此提案中，我们将建立在这个基础的基础上，并检查和操纵牙齿颗粒癫痫和控制动物中的细胞，以机械理解这些癫痫可以针对正常电路功能的相关干扰以恢复下游，紧急海马的特性，例如学习，记忆和情感行为。中央本提案的假设是在编码特性中与癫痫相关的降解牙齿颗粒细胞对构成的认知和行为合并症有显着贡献临时叶癫痫的核心表型的关键成分。为了检验这个中心假设，我们提出了进行一系列以3个特定目的为中心的实验：AIM 1。表征本地电路定义癫痫和对照小鼠中活性齿状颗粒细胞网络的特性。目标2。确定长期齿状回电路特定干预策略的能力，时间课程和程度癫痫小鼠的认知和行为功能。目标3。评估牙齿颗粒细胞的贡献癫痫小鼠的过度兴奋性破坏了海马空间编码。我们对介导神经元种群中稀疏但确定性的发射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。我们知道关于这些关键的齿状颗粒细胞特性中与疾病相关的降解的信息甚至更少，反过来，这种令人兴奋的破坏可能会侵蚀海马的认知和情感功能通常支持。除了增加癫痫发作的令人兴奋的增强之外，患有癫痫病暴露了严重的认知合并症，包括情绪，情绪，学习与记忆的缺陷，过程通常被视为边缘系统功能。了解癫痫发展如何改变边缘系统内的基本电路特性不仅在针对新疗法中很重要癫痫发作的改善，但也在开发新的治疗方法以减少参与的合并症条件癫痫发育，这是一个庞大的意外治疗发展领域。