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数百万神经元的动态相互作用的新兴特性。同样，病理大脑状态，例如智力低下和自闭症，最终是由于网络功能异常而表达的。表征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，而是来自多个相互作用的分子和细胞异常对网络功能的影响。实际上，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以下建议：智力低下和自闭症也应从异常网络功能的角度进行研究。然而，尽管在理解神经元功能的分子，突触和细胞机制方面取得了重大进展，以及确定与疾病相关的解剖学和系统水平异常，但在弥合这些分析水平方面取得了相对较少的进展。也就是说，关于正常或异常的知之甚少 从嵌入复杂网络中的神经元的相互作用中出现了行为，学习和认知。 此处描述的研究旨在通过研究缺乏引起脆弱X综合征的基因的小鼠中的异常网络特性来弥合这一差距。总体假设是，在脆弱的X综合征中，协调许多控制网络动力学的许多不同的细胞和突触特性的能力存在不足。我们将扩展FMR1 - / - 小鼠皮质回路中网络异常的初步发现，并确定是否针对慢性图案活动进行了适当调节网络动力学。此外，我们将确定在FXS小鼠模型的皮质CRCUT中，体外“学习”的形式是否改变。如果我们确认从FMR1 - / - 小鼠的孤立皮质网络中存在体外“学习”缺陷，我们将提供皮质电路功能与认知异常之间的重要联系。此外，确定可以被认为是体外学习形式的缺陷，为理性治疗方法提供了一种策略。 公共卫生相关性：一些神经疾病，包括精神障碍和自闭症 - 可能仅仅是由于分子或细胞水平上的孤立异常引起的，而是由于分子水平的多个相互作用因子如何改变神经元网络水平的多个相互作用因子。当前的项目旨在理解网络级别的异常，这是智力低下和自闭症，脆弱X综合征的最常见原因之一。了解与认知缺陷有因果关系的网络异常将为理性治疗方法提供一种策略。