During critical periods of early adolescence, the wiring of circuitry in visual cortex is strongly influenced by sensory experience. Degraded visual experience, as occurs from cataracts or strabismus, during this critical period impairs the development of steopsis and high sptial frequency vision, thereby contributing to the etiology of amblyopia. The long term objectives of this proposal are to understand how sensory experience exerts its influence on cortical circuitry during the critical period, with particular emphasis on the role of inhibitory neurons. To determine how sensory experience acts on inhibitory neurons to gate circuit plasticity we propose three specific aims that leverage state-of-the-art techniques that are already working in our laboratories. To test the hypothesis that altered vision induces a rapid loss of inhibitory responses, which then gates excitatory plasticity, we use 2-photon in vivo imaging to visualize specific types of excitatory and inhibitory neurons in visual cortex of alert mice and then target cell attached patch recordings to these neurons across cortical layers. This approach provides the highest temporal and spatial resolution available. By comparing responses over time, we will reveal the choreography of plasticity across layers. To determine the spatial and temporal kinetics of excitatory/inhibitory network plasticity, we use high-speed 2-photon in vivo microscopy to simultaneously image hundreds of neurons expressing a new, extremely sensitive genetically encoded calcium indicator (GCaMP6). We follow the same populations of neurons before and during ocular dominance plasticity in mice where specific populations of inhibitory neurons are double labeled with a genetically encoded red fluorophore. In the third aim we test the hypothesis that monocular deprivation first changes the synaptic connectivity to fast-spiking interneurons. To do so we use laser scanning glutamate uncaging and channelrhodopsin-assisted circuit mapping. This work will significantly advance our understanding of inhibitory plasticity and address objectives of the Strabismus, Amblyopia, and Visual Processing Program of the NEI to "increase understanding of the critical period in order to determine how experience alters connectivity in the developing visual system"

Public Health Relevance

Developing a mechanistic understanding of the role of specific classes of inhibitory neurons in sensory plasticity is critically important to the development of therapeutic measures designed to rewire neural circuitry gone awry in diseases of cortical development

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY023871-01
Application #
8594027
Study Section
Special Emphasis Panel (ZRG1-IFCN-Q (02))
Program Officer
Steinmetz, Michael A
Project Start
2013-09-01
Project End
2017-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
1
Fiscal Year
2013
Total Cost
$393,730
Indirect Cost
$127,530
Name
University of California Los Angeles
Department
Neurosciences
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095