Abnormal network dynamics and "learning" in neural circuits from Fmr1-/- mice

Fmr1-/- 小鼠神经回路中的异常网络动态和“学习”

• 批准号: 8445001
• 负责人: DEAN V BUONOMANO
• 金额: $ 19.25万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-19 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8445001
• 关键词: Autistic Disorder; Behavior; Behavioral; Brain; Chronic; Cognition; Cognitive deficits; Complex; Dendritic Spines; Development; Disease; Event; Exhibits; Failure; Fragile X Syndrome; Frequencies; Generations; Genes; Genetic; Goals; In Vitro; Learning; Light; Link; Mental Retardation; Molecular; Morphology; Mus; Neurons; Pattern; Penetrance; Phenotype; Physiologic pulse; Potassium Channel; Process; Property; Proxy; Regulation; Reporting; Reproducibility; Research; Sensory; Slice; Stimulus; Suggestion; Synapses; System; Therapeutic; Time; Training; cognitive function; density; experience; in vitro Model; mouse model; nervous system disorder; neural circuit; neurophysiology; novel; relating to nervous system; response; simulation; therapeutic target

DESCRIPTION (provided by applicant): Learning, behavior, and cognition, are ultimately an emergent property of the dynamic interactions of millions of neurons embedded within complex networks. Similarly, pathological brain states, such as mental retardation and autism, are ultimately expressed as a result of abnormal network function. The cognitive deficits that characterize some neurological diseases may not be caused by isolated molecular or cellular abnormalities, but rather from the effects of multiple interacting molecular and cellular abnormalities on network function. Indeed, the complexity and diversity of the neural and behavioral phenotypes associated with some diseases, have led to the suggestion that mental retardation and autism should also be studied from the perspective of abnormal network function. However, despite significant advances towards understanding the molecular, synaptic, and cellular mechanisms of neuronal function, as well as towards identifying the anatomical and systems level abnormalities associated with diseases, relatively little progress has been made in bridging these levels of analysis. That is, relatively little is known about how normal or abnormal behavior, learning, and cognition emerge from the interaction of neurons embedded in complex networks. The research described here is aimed at bridging this gap by studying the abnormal network properties in mice lacking the gene that causes Fragile X syndrome. The overarching hypothesis is that in Fragile X syndrome there is a deficit in the ability to coordinate the many different cellular and synaptic properties that govern network dynamics. We will extend preliminary findings on network abnormalities in cortical circuits from Fmr1-/- mice, and determine if the network dynamics is appropriately regulated in response to chronic patterned activity. Additionally, we will determine if a form of in vitro 'learning' is altered in cortical crcuits from the mouse model of FXS. If we confirm that deficits in in vitro 'learning' are present in isolated cortical networks from Fmr1-/- mice we will provide an important link between cortical circuit function and cognitive abnormalities. Furthermore, establishing deficits in what can be considered a form of in vitro learning, offers a strategy for rational therapeutic approaches for treatment. PUBLIC HEALTH RELEVANCE: Some neurological diseases-including mental retardation and autism-may not arise simply from isolated abnormalities at the molecular or cellular level, but from how multiple interacting factors at the molecular level alter processing at the level of networks of neurons. The current project is aimed at understanding network level abnormalities in what is among the most common causes of mental retardation and autism, Fragile X syndrome. Understanding the network abnormalities that are causally related to cognitive deficits will provide a strategy for rational therapeutic approaches for treatment.

描述(由申请人提供)：学习、行为和认知，最终是嵌入复杂网络中的数百万神经元动态交互的一个新特性。同样，病理性的大脑状态，如智力低下和自闭症，最终都是网络功能异常的结果。某些神经系统疾病的认知缺陷可能不是由孤立的分子或细胞异常引起的，而是由多种相互作用的分子和细胞异常对网络功能的影响引起的。事实上，与某些疾病相关的神经和行为表型的复杂性和多样性，导致了人们建议也应该从网络功能异常的角度来研究智力低下和自闭症。然而，尽管在理解神经功能的分子、突触和细胞机制以及识别与疾病相关的解剖学和系统水平的异常方面取得了重大进展，但在连接这些分析水平方面进展相对较小。也就是说，人们对正常或异常的程度知之甚少 行为、学习和认知来自嵌入复杂网络的神经元的相互作用。这里描述的研究旨在通过研究缺乏导致脆性X综合征的基因的小鼠的异常网络特性来弥合这一差距。最重要的假设是，在脆性X综合征中，缺乏协调支配网络动力学的许多不同细胞和突触属性的能力。我们将扩展关于Fmr1-/-小鼠大脑皮质回路网络异常的初步发现，并确定网络动态是否针对慢性模式活动进行了适当的调节。此外，我们还将确定FXS小鼠模型的大脑皮层中是否存在某种形式的体外“学习”。如果我们证实Fmr1-/-小鼠的孤立皮层网络存在体外‘学习’缺陷，我们将提供皮层回路功能和认知异常之间的重要联系。此外，建立可被认为是一种体外学习形式的缺陷，为合理的治疗方法提供了一种策略。 与公共卫生相关：一些神经疾病--包括智力低下和自闭症--可能不仅仅是由于分子或细胞水平上的孤立异常，而是因为分子水平上的多种相互作用因素如何改变神经元网络水平上的处理。目前的项目旨在了解网络水平的异常，这是导致智力低下和自闭症的最常见原因之一，脆性X综合征。了解与认知缺陷相关的网络异常将为合理的治疗方法提供策略。