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

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.