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: 8547831
• 负责人: DEAN V BUONOMANO
• 金额: $ 22.18万
• 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 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8547831
• 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; learned behavior; 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.

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的动态相互作用的新兴特性。同样，病理性大脑状态，如智力迟钝和自闭症，最终表现为异常网络功能的结果。一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，导致了一种建议，即精神发育迟滞和自闭症也应该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小。也就是说，相对而言，我们对正常或异常的程度 行为、学习和认知是由嵌入复杂网络中的神经元的相互作用产生的。 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，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。我们将扩展从Fmr 1-/-小鼠皮层电路网络异常的初步研究结果，并确定网络动态是否适当调节慢性模式化活动。此外，我们将确定是否有一种形式的体外“学习”是改变皮质crystallium从小鼠模型的FXS。如果我们证实，赤字在体外“学习”存在于孤立的皮层网络从Fmr 1-/-小鼠，我们将提供一个重要的联系皮层电路功能和认知异常。此外，建立可以被认为是体外学习形式的缺陷，为合理的治疗方法提供了一种策略。