Various functional properties of visual cortical neurons, as usually measured by their output responses, undergo progressive developmental maturations, the process of which can be susceptible to experience-dependent modifications during a critical period (CP). The functional changes of neuronal responses during development or induced by specific sensory experience can be attributed to changes in cortical synaptic circuitry, the nature of which has remained largely unknown. This is mainly due to a lack of measurements of stimulus-evoked excitatory and inhibitory synaptic inputs to neurons in the developing visual cortex, techniques for which remain very challenging. In this project, we will explore the possibility of probing into the functional synaptic circuits of the developing cortex b applying the-state-of-the-art in vivo whole-cell voltage-clamp recording and two-photon imaging guided patch-recording in young mice at various developmental stages. We will focus on orientation selectivity (OS) and ocular dominance (OD) properties in layer 4 of the primary visual cortex (V1).
In Aim1, we will determine the progression of OS development by recording spike responses at different developmental stages. We will then carry out voltage-clamp recordings to determine excitatory and inhibitory inputs underlying OS during stages when significant sharpening of OS occurs. We will test the hypothesis that the developmental sharpening of OS can be mainly attributed to a broadening of inhibitory tuning, rather than a sharpening of excitatory tuning or a decrease in excitation/inhibition (E/I) ratio. We will also record from genetically labeled inhibitory neuron subtypes to test the hypothesis that the broadening of inhibitory tuning can be attributed to a weakening of OS of specific inhibitory neurons.
In Aim2, we will compare eye-specific excitatory and inhibitory inputs to excitatory neurons between mice experiencing monocular deprivation (MD) during the CP and age-matched control mice. We will determine whether the MD-induced OD shift away from the deprived eye is mainly attributed to a weakening of synaptic excitation or a strengthening of synaptic inhibition driven by that eye. Finally, we will examine how specific inhibitory neurons shift their OD in response to MD. This line of research will greatly enhance our understanding of synaptic circuitry mechanisms underlying the normal cortical functional development as well as the plasticity induced by visual deprivation.

Public Health Relevance

This project investigates the excitatory and inhibitory circuit mechanisms underlying normal development of visual cortical functions as well as cortical plasticity after abnormal visual experience such as monocular deprivation. Understanding how the organization of synaptic circuits changes during development is necessary to identify mechanisms that go awry in developmental diseases. The work proposed here bears directly on a key theme in research on amblyopia, the examination of how abnormal visual experience leads to changes in cortical circuits.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21EY022478-02
Application #
8462983
Study Section
Special Emphasis Panel (SPC)
Program Officer
Steinmetz, Michael A
Project Start
2012-05-01
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2013
Total Cost
$194,750
Indirect Cost
$76,000
Name
University of Southern California
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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Li, Ya-tang; Ibrahim, Leena A; Liu, Bao-hua et al. (2013) Linear transformation of thalamocortical input by intracortical excitation. Nat Neurosci 16:1324-30
Ma, Wen-pei; Li, Ya-tang; Tao, Huizhong Whit (2013) Downregulation of cortical inhibition mediates ocular dominance plasticity during the critical period. J Neurosci 33:11276-80
Sun, Yujiao J; Kim, Young-Joo; Ibrahim, Leena A et al. (2013) Synaptic mechanisms underlying functional dichotomy between intrinsic-bursting and regular-spiking neurons in auditory cortical layer 5. J Neurosci 33:5326-39