The mammalian visual cortex is critical for vision and has been used as a model for the rest of the cerebral cortex. In spite of this, little is known about the detailed operations of its microcircuits. In fact, the cortex is composed of many different cell types, and, it is likely that each cell type has a particular circuit function. In the past cycle we focused on four major subtypes of cortical GABAergic interneurons (PV, SOM, VIP and chandeliers) in mouse visual cortex, using two- photon photoactivation and transgenic mice to map connections to and from interneurons in a systematic fashion. We found that interneurons often make synaptic connections with every single neighboring cell, and this promiscuity could be an important feature of the cortical inhibitory ?circuit blueprint?. In the course of these experiments we unexpectedly discovered that groups of coactive neurons, which we termed ?neuronal ensembles?, account for the majority of the cortical response to visual stimuli. Moreover, ensembles also dominate spontaneous activity and have distinct spatiotemporal characteristics. Further, using two-photon optogenetics we found by chance that ensembles can be artificially imprinted into the cortex and they can be recalled by stimulating individual neurons, showing pattern completion, even days after imprinting. These intriguing results suggest that ensembles could be multicellular building blocks of cortical function, implementing a population neural code. To pursue this discovery and test these ideas we now propose an experimental ?deep dive? into the properties of these ensembles, in order to characterize their basic phenomenology, understand their synaptic circuit mechanisms and test their role in the behavior of the animal in sensory discrimination. The project will be carried out in primary visual cortex of awake behaving mice and make use of a novel two-photon holographic microscopy method that enables us to image and optically manipulate neurons in different cortical layers simultaneously. Our work will provide a systematic anatomical and functional description of neuronal ensembles, how they regulate the activity of the cortex and how they can be manipulated and reconfigured. This could help in novel therapeutic strategies by reconfiguring pathological circuits and correct visual deficits.

Public Health Relevance

Imaging Functional Connectivity in Visual Cortex The role of coordinated neuronal activity by groups of neurons in the visual cortex is still poorly understood. In the last cycle of the grant we discovered that one can reconfigure cortical activity in mouse visual cortex using optogenetics, by imprinting and recalling artificial activity patterns, and we now propose to understand how these patterns are build and whether their manipulation can lead to changes in behavior. This work could help to understand how neural circuits in the visual cortex operate and can be altered and also help to design novel strategies to ameliorate amblyopia and cortical cerebral visual impairment by reconfiguring abnormal circuits.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY011787-19
Application #
9912748
Study Section
Mechanisms of Sensory, Perceptual, and Cognitive Processes Study Section (SPC)
Program Officer
Flanders, Martha C
Project Start
1998-01-01
Project End
2022-04-30
Budget Start
2020-05-01
Budget End
2021-04-30
Support Year
19
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Biology
Type
Graduate Schools
DUNS #
049179401
City
New York
State
NY
Country
United States
Zip Code
10027
Liou, Jyun-You; Ma, Hongtao; Wenzel, Michael et al. (2018) Role of inhibitory control in modulating focal seizure spread. Brain 141:2083-2097
Yang, Weijian; Carrillo-Reid, Luis; Bando, Yuki et al. (2018) Simultaneous two-photon imaging and two-photon optogenetics of cortical circuits in three dimensions. Elife 7:
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
Yang, Weijian; Yuste, Rafael (2018) Holographic imaging and photostimulation of neural activity. Curr Opin Neurobiol 50:211-221
Carrillo-Reid, Luis; Yang, Weijian; Kang Miller, Jae-Eun et al. (2017) Imaging and Optically Manipulating Neuronal Ensembles. Annu Rev Biophys 46:271-293
Yang, Weijian; Yuste, Rafael (2017) In vivo imaging of neural activity. Nat Methods 14:349-359
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

Showing the most recent 10 out of 76 publications