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

National Institute of Health (NIH)
National Eye Institute (NEI)
NIH Director’s Pioneer Award (NDPA) (DP1)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BCMB-N (50))
Program Officer
Steinmetz, Michael A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Columbia University (N.Y.)
Other Domestic Higher Education
New York
United States
Zip Code
Carrillo-Reid, Luis; Yang, Weijian; Kang Miller, Jae-Eun et al. (2017) Imaging and Optically Manipulating Neuronal Ensembles. Annu Rev Biophys 46:271-293
Fang, Wei-Qun; Yuste, Rafael (2017) Overproduction of Neurons Is Correlated with Enhanced Cortical Ensembles and Increased Perceptual Discrimination. Cell Rep 21:381-392
Dupre, Christophe; Yuste, Rafael (2017) Non-overlapping Neural Networks in Hydra vulgaris. Curr Biol 27:1085-1097
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
Hamm, Jordan P; Peterka, Darcy S; Gogos, Joseph A et al. (2017) Altered Cortical Ensembles in Mouse Models of Schizophrenia. Neuron 94:153-167.e8
Bosch, Thomas C G; Klimovich, Alexander; Domazet-Lošo, Tomislav et al. (2017) Back to the Basics: Cnidarians Start to Fire. Trends Neurosci 40:92-105
Yang, Weijian; Yuste, Rafael (2017) In vivo imaging of neural activity. Nat Methods 14:349-359
Wei, Lu; Chen, Zhixing; Shi, Lixue et al. (2017) Super-multiplex vibrational imaging. Nature 544:465-470
Yang, Weijian; Miller, Jae-Eun Kang; Carrillo-Reid, Luis et al. (2016) Simultaneous Multi-plane Imaging of Neural Circuits. Neuron 89:269-84
Ayzenshtat, Inbal; Karnani, Mahesh Miikael; Jackson, Jesse et al. (2016) Cortical Control of Spatial Resolution by VIP+ Interneurons. J Neurosci 36:11498-11509

Showing the most recent 10 out of 31 publications