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 o 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 produc """"""""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)
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Araj, Houmam H
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Johns Hopkins University
Schools of Arts and Sciences
United States
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He, Kaiwen; Huertas, Marco; Hong, Su Z et al. (2015) Distinct Eligibility Traces for LTP and LTD in Cortical Synapses. Neuron 88:528-38
Huang, Shiyong; Hokenson, Kristen; Bandyopadhyay, Sabita et al. (2015) Brief Dark Exposure Reduces Tonic Inhibition in Visual Cortex. J Neurosci 35:15916-20
Huang, Shiyong; Rozas, Carlos; Treviño, Mario et al. (2014) Associative Hebbian synaptic plasticity in primate visual cortex. J Neurosci 34:7575-9
Yang, Sungchil; Yang, Sunggu; Park, Jae-Sung et al. (2014) Failed stabilization for long-term potentiation in the auditory cortex of FMR1 knockout mice. PLoS One 9:e104691
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
Guo, Yatu; Huang, Shiyong; de Pasquale, Roberto et al. (2012) Dark exposure extends the integration window for spike-timing-dependent plasticity. J Neurosci 32:15027-35
Huang, ShiYong; Treviño, Mario; He, Kaiwen et al. (2012) Pull-push neuromodulation of LTP and LTD enables bidirectional experience-induced synaptic scaling in visual cortex. Neuron 73:497-510
Lee, Hey-Kyoung; Kirkwood, Alfredo (2011) AMPA receptor regulation during synaptic plasticity in hippocampus and neocortex. Semin Cell Dev Biol 22:514-20
Kulkarni, Mauktik; Zhang, Kechen; Kirkwood, Alfredo (2011) Single-cell persistent activity in anterodorsal thalamus. Neurosci Lett 498:179-84

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