The mammalian visual cortex is necessary for vision and has been used over the decades as a model system for the rest of the cerebral cortex. In spite of this, little is known about its microcircuits, and one could argue that to really understad what the visual cortex does one needs to open the black box and decipher them. Moreover, the visual cortex is composed of many different cell types, and, it is likely that each cell type hs a particular circuit function. In the last cycle of the award, using a novel two-photon uncaging technique, we studied the GABAergic interneurons and discovered that two of their major subtypes, PARV and SOM positive cells, are connected in a very dense pattern to cells in their vicinity, often making synaptic connections with every single neighboring neuron. This was surprising since it implies that interneurons connect promiscuously, as if their function was not specific. We now propose to test if this is the case, by examining the input and output connectivity of the four major subtypes of interneurons in V1 (PARV, SOM, VIP and chandeliers). Using two-photon photoactivation with a novel caged compound and a novel channelrhodopsin, and transgenic mouse strains that label subtypes of interneurons specifically, we will map connections to and from interneurons in a systematic fashion, in order to arrive at the inhibitory circuit blueprint of mouse V1. In the last aim, using a novel SLM two-photon microscope, we will image the responses of these four subtypes of interneurons in anesthetized and awake animals, under spontaneous activity and visual stimulation. These data will be computationally analyzed to search for spatiotemporal patterns of activity indicative of specific subcircuits. Our work will provide a systematic description of the anatomical and functional connectivity of cortical interneurons, one that will enable to examine whether their function is specific or not and to understand how they regulate the activity of the visual cortex. Given the key role that interneurons appear to play in developmental plasticity, the generated knowledge could also help to understand the pathophysiology of developmental deficits in vision and to design novel therapeutic strategies to treat amblyopia.

Public Health Relevance

The role of inhibitory neurons in the visual cortex is still poorly understood, yet appears to be essential for processing of visual information and visual plasticity. In the last cycle of the grant we discovered that some inhibitory neurons are very densely connected in mouse cortex, and we now propose to obtain the complete circuit blueprint of all major types of inhibitory neurons in the visual cortex and understand whether they form specific circuits in vivo. This work could help to understand how neural circuits in the visual cortex operate and change and also help to design novel strategies to ameliorate amblyopia.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
4R01EY011787-16
Application #
9134146
Study Section
Mechanisms of Sensory, Perceptual, and Cognitive Processes Study Section (SPC)
Program Officer
Flanders, Martha C
Project Start
1998-01-01
Project End
2017-08-31
Budget Start
2016-09-01
Budget End
2017-08-31
Support Year
16
Fiscal Year
2016
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
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
Wei, Lu; Chen, Zhixing; Shi, Lixue et al. (2017) Super-multiplex vibrational imaging. Nature 544:465-470
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

Showing the most recent 10 out of 76 publications