The purpose of this RFA is to promote the integration of experimental, analytic and theoretical capabilities for the examination of neural circuits and systems. This proposal is highly responsive to the RFA in that it links several different neuroscience labs to develop new technologies that provide for simultaneous multistate imaging and applies these technologies to the examination of how neuronal dynamics in mammalian cortex varies as a function of brain state and development. Paired imaging modalities will bridge the gap from imaging activity in individual neurons to whole brain circuit level analyses. The different scales will be linked with a comprehensive model such that each level of experimentation can inform the other. We will develop the technology to allow simultaneous single cell (two-photon) Ca2+ imaging of a local circuit and cortex-wide mesoscopic (single-photon) Ca2+ imaging across the entire neocortex. In separate paired studies in the same animals we will develop simultaneous mesoscopic Ca2+ imaging across the cortex with whole-brain functional MRI. Whole cortex mesoscopic Ca2+ imaging represents an innovative technology developed by one of the PIs (Crair) that uses mice expressing a genetically encoded Ca2+ indicator (GCaMP6) in all neurons or in select populations of neurons to allow both local neuronal and transcranial population level mesoscopic scale imaging across the cortex in the intact, unanesthetized developing mouse brain. This Ca2+ imaging technique will allow us to directly link single cell imaging to gross circuit level activity across the cortex and whole brain An integrative model is proposed to link these different modalities in order to understand the neural source of macroscopic circuit changes and the factors that influence this organization through development and as a function of behavioral brain state. This work is innovative in the novel Ca2+ imaging strategies to be further developed, and in the design of paired scale imaging to establish links between single neuron activity and circuit level organization. The work is significant in that it will provide a set of tools for detailed investigations of the impact of specific neuronal cell populations on brain circuit functional organization in healthy development and disease models. It is also significant in that new insights into the source and flow of neuronal activity will be obtained that will improve our understanding of the principles guiding self-organization in the developing brain and its dynamic modulation by brain state.

Public Health Relevance

In this project, we develop and apply experimental and analytic methods to examine neuronal activity across spatiotemporal scales, including the single cell, cortex-wide and whole brain, using genetically encoded calcium indicators and functional magnetic resonance imaging in rodents. The development of these experimental technologies and associated models will be used to examine the development of cortical circuits at the local and mesoscopic scale, and specifically address how behavioral brain state modulates local cortical circuits and network architecture through development. The work will provide a novel set of tools for detailed investigations of the role of specific neuronal cell populations on brain ciruit functional organization in healthy development and disease models.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZNS1)
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Gnadt, James W
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Yale University
Schools of Medicine
New Haven
United States
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Salehi, Mehraveh; Karbasi, Amin; Shen, Xilin et al. (2018) An exemplar-based approach to individualized parcellation reveals the need for sex specific functional networks. Neuroimage 170:54-67
Seabrook, Tania A; Burbridge, Timothy J; Crair, Michael C et al. (2017) Architecture, Function, and Assembly of the Mouse Visual System. Annu Rev Neurosci 40:499-538