Role of spontaneous activity towards the assembly and function of neocortical circuits

修改后的项目摘要/摘要部分 自发的活动模式被认为对几个物种的多个大脑回路的组装和成熟具有指导意义。自发驱动的活动有望引导新生儿结构回路模板的形成，进而影响一生中的新皮质功能。自发活动模式的紊乱具有很大的临床意义，因为它们容易导致新皮质回路的永久性错误连接，这是神经发育和精神障碍的主要原因。因此，各种研究表明，在新生儿发育过程中，遗传和环境因素的干扰会导致神经发育和精神障碍的高风险。然而，关于自发活动模式如何控制新皮质连接的出现和维持，以及它最终如何影响体内电路功能，人们知之甚少。我们的目标是了解自发的网络活动模式如何协调视觉皮质的适当成熟和功能。中心假设是，新生儿的自发活动，如视网膜波，对于建立精确的远程和局部新皮质回路至关重要，当初级视觉皮质早期活动依赖的连接中断时，视觉处理和认知功能会发生变化。这些研究的基本原理是，它们将为神经发育和精神障碍中的新皮质功能障碍提供新的见解。具体目的是：1)评估自发活动对新生脑视皮质基因表达的影响。2)评估自发活动在视皮层突触连接中的作用。3)确定新生儿自发活动模式对以后的视觉加工的影响。在第一个目标下，将进行单细胞RNA测序实验，以阐明自发活动如何影响新生儿年龄的基因表达。在第二个目标下，将进行切片电生理学实验，以阐明自发活动如何影响突触成熟。在第三个目标下，将进行体内记录，以研究自发活动对视觉皮质体内功能的作用。这项申请中提出的研究具有创新性，因为它将为研究自发活动对新皮质转录、连接和体内功能的作用开辟新的途径。这项拟议的研究意义重大，因为它将为自发活动如何引导新生儿结构电路模板的形成提供新的机械论见解，而这反过来又会影响一生中的新皮质功能。

Modified Project Summary/Abstract Section Spontaneous patterns of activity is thought to be instructive for the assembly and maturation of multiple brain circuits across several species. Spontaneously driven activity is expected to guide the formation of a neonatal architectural circuit template, which in turn impacts neocortical function throughout life. Disturbances of spontaneous activity patterns have great clinical relevance, as they are liable to lead to permanent miswiring of neocortical circuits, a leading cause for neurodevelopmental and psychiatric disorders. Accordingly, various studies reveal that disturbances in genetic and environmental factors during neonatal development present high risk for neurodevelopmental and psychiatric disorders. Yet little is known about how spontaneous patterns of activity control the emergence and maintenance of neocortical connectivity, and how it ultimately impacts in vivo circuit function. Our goal is to understand how spontaneous patterns of network activity orchestrate the proper maturation and function of the visual cortex. The central hypothesis is that spontaneous neonatal activity, such as retinal waves, is critical for the establishment of precise long-range and local neocortical circuits, and that altered visual processing and cognitive functions develop when activity dependent connectivity is disrupted early in life in the primary visual cortex. The rationale for these studies is that they will provide novel insights into neocortical dysfunction in neurodevelopmental and psychiatric disorders. The specific aims are: 1) Assess the role of spontaneous activity on neonatal gene expression in the visual cortex. 2) Assess the role of spontaneous activity on visual cortex synaptic connectivity. 3) Determine the impact of neonatal spontaneous patterns of activity on visual processing at later ages. Under the first aim, single-cell RNA sequencing experiments will be performed in order to elucidate how spontaneous activity impact gene expression at neonatal ages. Under the second aim, slice electrophysiology experiments will be performed in order to elucidate how spontaneous activity impact synaptic maturation. Under the third aim, in vivo recordings will be performed in order to investigate the role of spontaneous activity for the in vivo function of the visual cortex. The research proposed in this application is innovative because it will open new avenues for studying the role of spontaneous activity for transcriptomics, connectivity, and in vivo function of the neocortex. The proposed research is significant because it will provide novel mechanistic insights into how spontaneous activity might guide the formation of a neonatal architectural circuit template, which in turn impacts neocortical function throughout life.