The cortex constitutes the primary site of higher cognitive functions and mental disease. No unified theory of how the cortex works exists yet, due to our basic ignorance about its microcircuits (i.e. the detailed connectivity patterns of any cortical area), and also because it is likely that its function is based on an emergent level, determined by the states of activity of large neuronal ensembles. Two-photon calcium imaging and photo-activation techniques enable us to simultaneous record and optically manipulate the activity of larger neuronal populations, while maintaining single cell resolution. Using such techniques we have encountered signs of what could be a highly distributed and essentially random cortical microcircuit. Based on these results, we propose the idea that the cortex is a random circuit, meaning that each synaptic connection is chosen by chance, independently from others. These circuits, mathematically analogous to completely connected ones, would maximize the distribution of information and enable the appearance of emergent functional states. This model runs contrary to the traditional view of the cortex, one that arose from sampling individual neurons, as a very specific machine where the connectivity and function of each neuron is precisely determined. Using this award, I want to test the hypothesis that the cortex is a random network, applying novel two-photon methods in a large-scale and systematic study of the mouse cortical microcircuit. I propose a three-pronged approach: 1- Image the activity of an entire cortical module in a mouse, to detect all spikes from all cells. 2- Perform Circuit Cracker analysis to obtain the blueprint of connectivity of the module. 3- Optically manipulate the population activity to test whether it behaves as a random circuit. Experiments will be done in mouse cortex in vivo, with awake, head-restrained preparations, under sensory stimulation and rest. Transgenic strains will b
Functional Connectomics of the Neocortical Microcircuit The structure and function of the circuits in the cerebral cortex are still mysterious. I propose to use novel two-photon optical methods in a large-scale effort to image every spike from every neuron in a cortical area of an awake mouse circuit, map every connection in this region and manipulate their activity of the neurons to understand how the circuit works. These data will reveal the blueprint and the computational logic of the cortical circuit and help to better understand the pathophysiology of diseases that affect the cortex, such as epilepsy or mental illnesses.
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| Migliori, Bianca; Datta, Malika S; Dupre, Christophe et al. (2018) Light sheet theta microscopy for rapid high-resolution imaging of large biological samples. BMC Biol 16:57 |
| Liou, Jyun-You; Ma, Hongtao; Wenzel, Michael et al. (2018) Role of inhibitory control in modulating focal seizure spread. Brain 141:2083-2097 |
| Agetsuma, Masakazu; Hamm, Jordan P; Tao, Kentaro et al. (2018) Parvalbumin-Positive Interneurons Regulate Neuronal Ensembles in Visual Cortex. Cereb Cortex 28:1831-1845 |
| Izquierdo-Serra, Mercè; Hirtz, Jan J; Shababo, Ben et al. (2018) Two-Photon Optogenetic Mapping of Excitatory Synaptic Connectivity and Strength. iScience 8:15-28 |
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| Baird-Daniel, Eliza; Daniel, Andy G S; Wenzel, Michael et al. (2017) Glial Calcium Waves are Triggered by Seizure Activity and Not Essential for Initiating Ictal Onset or Neurovascular Coupling. Cereb Cortex 27:3318-3330 |
| Fang, Wei-Qun; Yuste, Rafael (2017) Overproduction of Neurons Is Correlated with Enhanced Cortical Ensembles and Increased Perceptual Discrimination. Cell Rep 21:381-392 |
| Wenzel, Michael; Hamm, Jordan P; Peterka, Darcy S et al. (2017) Reliable and Elastic Propagation of Cortical Seizures In Vivo. Cell Rep 19:2681-2693 |
| Dupre, Christophe; Yuste, Rafael (2017) Non-overlapping Neural Networks in Hydra vulgaris. Curr Biol 27:1085-1097 |
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