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”

基本信息

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
项目类别：
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

项目摘要

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个神经元动态相互作用的新兴属性。同样，病理性大脑状态，例如智力低下和自闭症，最终表现为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，导致人们建议也应该从异常网络功能的角度来研究精神发育迟滞和自闭症。然而，尽管在理解神经元功能的分子、突触和细胞机制以及识别与疾病相关的解剖和系统水平异常方面取得了重大进展，但在桥接这些水平的分析方面取得的进展相对较少。也就是说，对于正常或异常的程度知之甚少。行为、学习和认知源于复杂网络中神经元的相互作用。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补这一差距。最重要的假设是，在脆性 X 综合征中，协调控制网络动态的许多不同细胞和突触特性的能力存在缺陷。我们将扩展 Fmr1-/- 小鼠皮质回路网络异常的初步发现，并确定网络动态是否得到适当调节以响应慢性模式活动。此外，我们将确定 FXS 小鼠模型的皮质回路中的体外“学习”形式是否发生改变。如果我们确认 Fmr1-/- 小鼠的分离皮质网络中存在体外“学习”缺陷，我们将提供皮质回路功能和认知异常之间的重要联系。此外，建立可被视为体外学习形式的缺陷，为合理的治疗方法提供了策略。公共健康相关性：一些神经系统疾病（包括精神发育迟滞和自闭症）可能不仅仅是由分子或细胞水平上的孤立异常引起的，而是由分子水平上的多个相互作用因素如何改变神经元网络水平上的处理引起的。当前的项目旨在了解导致智力低下和自闭症（脆性 X 综合征）的最常见原因之一的网络水平异常。了解与认知缺陷因果相关的网络异常将为合理的治疗方法提供策略。