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 neuromodulary inputs that convey information on the behavioral state of the animals, and on the strength of intracortical inhibition. The long-term goal of this project is to elucidate the cellular mechanisms by which age, 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 have found that neuromodulators control the polarity (increase or decrease) of synaptic changes induced by patterned neural activity in vitro, in slices of rat visual cortex. Therefore we will investigate the mechanisms of the neuromodulation of plasticity, and will examine whether these mechanism also operate in vivo and in primates. Second, prompted by the recent observation that exposure to complete darkness for a week reactivates juvenile-like plasticity in adults rats, the regulation of two forms of synaptic modification are believed to be involved in natural occurring plasticity: long-term potentiation (LTP) and long-term depression (LTD). The studies are aimed to test two hypotheses concerning how neuromodulators and synaptic inhibition might regulate the induction of these forms of plasticity. The first hypothesis states that neuromodulators control the polarity and magnitude of activity- dependent synaptic modification. The second hypothesis states that developmental increases in the strength of synaptic inhibition reduces or prevents the induction of LTP and LTD. The experiments will be performed in slices made from the visual cortex of rats and mice of different ages and raised in different environments. Changes in LTP and LTD will be compared with reported changes in naturally-occurring synaptic modifications. Understanding how LTP and LTD are regulated will yield insights into the mechanisms underlying the critical period and will provide a cellular understanding of the integrative aspects of cortical plasticity. Besides the obvious relevance of this neural plasticity to the development of visual capabilities, it seems 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. This 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-A (04))
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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
Lee, Hey-Kyoung; Kirkwood, Alfredo (2011) AMPA receptor regulation during synaptic plasticity in hippocampus and neocortex. Semin Cell Dev Biol 22:514-20
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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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