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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY012124-14
Application #
8204927
Study Section
Special Emphasis Panel (ZRG1-IFCN-A (04))
Program Officer
Steinmetz, Michael A
Project Start
1998-03-01
Project End
2013-07-31
Budget Start
2011-12-01
Budget End
2013-07-31
Support Year
14
Fiscal Year
2012
Total Cost
$389,664
Indirect Cost
$152,064
Name
Johns Hopkins University
Department
Neurosciences
Type
Schools of Arts and Sciences
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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
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; Rozas, Carlos; Treviño, 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
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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