CRCNS: Mapping and modeling multiscale lateral interactions in cortex

Processing complex sensory information requires highly interconnected cortical networks. A critical feature determining the behavior of these networks is the structure of lateral interactions between nearby neurons, which can, under certain circumstances, give rise to organized, modular functional activity. However, despite the clear importance of lateral interactions in a wide range of network models, we lack a clear understanding of their organization in vivo. To address this challenge, we propose a tight integration between computational modeling and optogenetic experiments at mesoscopic and cellular scales. We focus on a broad class of models explaining the emergence of highly organized modular patterns through structured local lateral interactions that exhibit local excitation—lateral inhibition (LELI) structure. The behavior of networks governed by such interactions depends critically on the spatial extent, heterogeneity, and net strength of these interactions, yet these essential parameters have not yet been examined in vivo. Here, we propose to directly probe local lateral interactions of cortical circuits, determine how these circuits transform local and large-scale inputs into output activity patterns, and develop computational models describing this transform to estimate these essential parameters of network interactions. By mapping functional interactions at mesoscopic and cellular resolution in vivo in a species with modular organization similar to that seen in humans, we will be able to provide the clearest evidence to date regarding the LELI- structure of lateral interactions. By applying specifically designed mesoscopic optogenetic stimuli in conjunction with widefield calcium imaging, we will map the transformation of input within the cortical network on millimeter scales, and shed light on the underlying lateral interactions. Further, by applying this framework to a brain area beyond visual cortex, our work has the potential to identify universal principles governing cortical development and function. The new insights from this proposed work will have broad implications, and will contribute to a deeper understanding of the circuit mechanisms responsible for the generation of cortical network activity states, providing fundamental knowledge that could serve as the basis for the development of next generation prosthetics and novel treatments for a host of neurological disorders. RELEVANCE (See instructions): The research in this proposal will provide new insights into how circuits within a nonmurine cortex transform incoming information. We will gain insights into how network interactions and their transformation of information may be perturbed in neurological disease. Ultimately, understanding the mechanisms underlying activity transformation within the cortex may provide avenues for potential therapeutic interventions in these diseases.