It has long been appreciated that visual experience during an early critical period is essential for the normal maturation of visual cortex. Studies on animals reared in different environments have established that during this critical period, visual cortical connections can be modified in an activity dependent manner. Those studies have also shown that visual cortical plasticity depends on neuromodulatory inputs that convey information on the behavioral state of the animals, and on the strength of intracortical inhibition. The goal of this project is to elucidate the cellular mechanisms by which neuromodulators and synaptic inhibition control synaptic modification in visual cortex. This proposal builds upon two recent findings on the regulation of synaptic plasticity in cortex. First, we recently showed that neuromodulators exert a pull-push control of the gain of mechanisms that increase or decrease synaptic strength. Therefore we will investigate whether neuromodulators gate visual cortical plasticity via the pull-push control of synaptic modification, and whether this general mechanism can be recruited to visually induce cortical modifications in the adult brain, after the closure of the critical period. The second avenue opened by our previous research is the realization of a simple mechanism by which neuromodulators can provide a reward signal to guide cortical modifications. Specifically we will test the idea that certain patterns of synaptic activity produce "eligibility traces" for synaptic modification that need to be subsequently consolidated by the action of neuromodulators. Understanding how synaptic plasticity is regulated can provide essential insight for translational developments. In particular, the possibility of inducing rapid cortical modification with the aid of neuromodulators can be relevant for restoring visual cortical functions in adults. Besides the obvious relevance of neural plasticity to the development of visual capabilities, it is likely that similar processes may form the basis for some forms of learning and memory in the adult brain.

Public Health Relevance

Abnormal or insufficient visual experience during early infancy can result in inappropriate wiring of the visual system, and in diminished visual capabilities. Thi proposal will investigate the mechanisms that control the wiring of the visual system. The conclusions will be relevant for preventing incorrect wiring, and for restoring normal vision.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IFCN-Q (02))
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Steinmetz, Michael A
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Johns Hopkins University
Schools of Arts and Sciences
United States
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Huang, Shiyong; Rozas, Carlos; TreviƱo, Mario et al. (2014) Associative Hebbian synaptic plasticity in primate visual cortex. J Neurosci 34:7575-9
Huang, Shiyong; Huganir, Richard L; Kirkwood, Alfredo (2013) Adrenergic gating of Hebbian spike-timing-dependent plasticity in cortical interneurons. J Neurosci 33:13171-8
Gu, Yu; Huang, Shiyong; Chang, Michael C et al. (2013) Obligatory role for the immediate early gene NARP in critical period plasticity. Neuron 79:335-46
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Dong, Yi; Mihalas, Stefan; Niebur, Ernst (2011) Improved integral equation solution for the first passage time of leaky integrate-and-fire neurons. Neural Comput 23:421-34
Jiang, Bin; Huang, Shiyong; de Pasquale, Roberto et al. (2010) The maturation of GABAergic transmission in visual cortex requires endocannabinoid-mediated LTD of inhibitory inputs during a critical period. Neuron 66:248-59
Huang, Shiyong; Gu, Yu; Quinlan, Elizabeth M et al. (2010) A refractory period for rejuvenating GABAergic synaptic transmission and ocular dominance plasticity with dark exposure. J Neurosci 30:16636-42
Seol, Geun Hee; Ziburkus, Jokubas; Huang, ShiYong et al. (2007) Neuromodulators control the polarity of spike-timing-dependent synaptic plasticity. Neuron 55:919-29
Jiang, Bin; Trevino, Mario; Kirkwood, Alfredo (2007) Sequential development of long-term potentiation and depression in different layers of the mouse visual cortex. J Neurosci 27:9648-52

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