The neocortex consists of a constellation of functional areas that form a representation map of the external and internal world. These areas are strategically connected as processing networks to integrate multi-sensory information with internal goals, make decisions, and configure descending instructions that to guide intelligent behaviors. Across cortical areas, the basic core circuit architecture is a cortical-striatal-thalamic loop, which is duplicated and topographically organized along multiple functional systems according to the cortical representation map. We use forelimb motor control as a paradigm to explore the general principles of cortical circuit functional organization.
Among brain functions ranging from perception to cognition and action, the generation of complex movements enable animals to navigate and impact the world. In particular, the evolutionary elaboration of increasingly sophisticated forelimb behaviors, such as to reach, grasp, handle and manipulate objects, ultimately leads to uniquely human abilities. Previous studies of forelimb movements have largely been carried out in humans and non-human primates, but the neural circuit mechanisms remain difficult to explore. Rodents such as mice are capable of complex forelimb and orofacial movements, driven by the necessity of their omnivorous feeding on diverse food sources that require dexterous hand-mouth maneuvering. Thus mice present a powerful experimental system where our cell type genetic tools can integrate the full range of modern technologies for exploring cortical circuits underlying motor control.
We have established several mouse forelimb behavior paradigms that engage cortical function. In head-constrained setups, mice are trained to reach for a water drop at multiple spatial locations or to retrieve and eat food pellets. In a freely behaving setup, mice use highly coordinated and dexterous oro-manual movements to retrieve, handle, manipulate, and eat various food items. We apply machine learning based quantitative analysis to delineate ethograms of movement components and their organization. Guided by insights from behavior analysis, we then leverage our multiple genetic drive lines to carry out systematic screens to identify cortical areas and cell types involved in various aspects of sensorimotor control. We use wide-field mesoscopic imaging of genetically-encoded calcium indicator (GCaMP6f) across dorsal cortex to monitor the spatiotemporal activity patterns of molecular and projection defined neuron types; we use optogenetic activation and inhibition to probe their roles in different cortical areas during sensorimotor behaviors. Identification of key cortical areas and cell types allows us to apply cellular resolution two-photon imaging, optogenetic guided electrophysiological recording, and input-output viral tracing to explore neural circuit operations.
We begin to reveal projection neuron type and cortical circuit mechanisms that orchestrate coordinated forelimb and mouth movements during reach, grasp, handling, and manipulation. We have further discovered that dynamic areal and PN type-specific subnetworks are a key feature of cortical functional architecture linking microcircuit components with global brain networks. Together with our other research areas, we aim to integrate developmental genetic and functional definition of neuron types towards a more wholistic biological understanding of cortical circuit functional architecture.
Related Publications
Mohan, H., An, X., Kondo, H., Zhao, S., Musall, S., Mitra, P., Huang, Z.J. (2021) Cortical glutamatergic projection neuron types contribute to distinct functional subnetworks. bioRxiv doi: https://doi.org/10.1101/2021.12.30.474537
Abstracts
An X, Mohan H, Matho K, Kepecs A, Huang ZJ (2019) A cortical command circuit coordinates food handling and manipulation. Society of Neuroscience Abstract, 2019.
Li, Y, Qian Y, An X, Mohan H, Z. Huang ZJ (2020) Cortical circuits for forelimb reach-grasp-consume. Cold Spring Harbor Meeting on “Neuronal Circuits”, 2020.