Ocular dominance plasticity is a canonical form of synaptic plasticity in vivo triggered by changes in binocular vision. It has provided crucial insights into how cortical circuits develop and remodel in early life. We have shown that ocular dominance plasticity is consolidated via cellular mechanisms similar to those mediating long-term synaptic potentiation (LTP). Our goal is to more completely identify these mechanisms and the brain states in which they occur. To achieve this goal we will use our established methods of eliciting ocular dominance plasticity combined with behavioral state monitoring, inactivation of intracortical enzymes, optical imaging of intrinsic cortical signals, acute single-neuron electrophysiology in vivo, chronic tetrode recording of single-neurons in freely-behaving animals, and Western blot measurements of cortical proteins. These techniques are combined in a simple experimental design that allows us to determine how different brain states and intracellular signaling pathways promote long-lasting modifications of cortical circuitry. More specifically, we will test the following hypotheses a) rapid-eye-movement (REM) sleep is necessary for the consolidation of ocular dominance plasticity b) this is mediated by protein kinases (Ca2+/calmodulin- dependent protein kinase [CaMKII] and extracellular regulated kinase [ERK]) activated in REM sleep. We propose the following Specific Aims: 1. Determine the role of REM sleep in the consolidation of ocular dominance plasticity. In this Aim, we will examine the effects of different amounts of REM sleep on two different types of cortical plasticity that require strengthening of visual circuits. This will be accomplished by quantitatively measuring and manipulating vigilance states and binocular visual input to primary visual cortex in the freely-behaving animal. This is followed by three independent and objective measures of cortical plasticity in vivo (acute and chronic single-neuron electrophysiology and optical imaging of intrinsic cortical signals). 2. Determine the role of CaMKII and ERK in the consolidation of ocular dominance plasticity. In this Aim, we will examine the role of CaMKII and ERK signaling in the strengthening of cortical circuits that occurs during sleep. This will be achieved by a) measuring total and phosphorylated CaMKII and ERK proteins in the primary visual cortices of animals that are sacrificed after different amounts of visual experience and rapid- eye-movement sleep b) determining the effects of intracortical pan-CaMK, selective CaMKII and ERK inhibition on the consolidation of ocular dominance plasticity c) mimicry and occlusion experiments are then used to determine if the effects of REM sleep are mediated by CaMK, CaMKII or ERK kinase activity. The results of our investigations will provide new insights into how experience and endogenous brain activity guide cortical circuit development and plasticity. They will also provide new information about how normal and abnormal sleep impacts mammalian brain development.

Public Health Relevance

The research in this proposal will provide important new insights into how rapid-eye-movement (REM) sleep promotes critical developmental processes in the cerebral cortex. This will improve our understanding of normal and pathological brain development and the function of sleep in early life.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (SPC)
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Laposky, Aaron D
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University of Pennsylvania
Schools of Medicine
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Frank, Marcos G (2017) Sleep and plasticity in the visual cortex: more than meets the eye. Curr Opin Neurobiol 44:8-12
Krueger, James M; Frank, Marcos G; Wisor, Jonathan P et al. (2016) Sleep function: Toward elucidating an enigma. Sleep Med Rev 28:46-54
Frank, Marcos G (2016) Circadian Regulation of Synaptic Plasticity. Biology (Basel) 5:
Frank, Marcos G (2015) Sleep and synaptic plasticity in the developing and adult brain. Curr Top Behav Neurosci 25:123-49
Dumoulin, Michelle C; Aton, Sara J; Watson, Adam J et al. (2015) Extracellular signal-regulated kinase (ERK) activity during sleep consolidates cortical plasticity in vivo. Cereb Cortex 25:507-15
Dumoulin Bridi, Michelle C; Aton, Sara J; Seibt, Julie et al. (2015) Rapid eye movement sleep promotes cortical plasticity in the developing brain. Sci Adv 1:e1500105
Frank, Marcos G; Cantera, Rafael (2014) Sleep, clocks, and synaptic plasticity. Trends Neurosci 37:491-501
Aton, Sara J; Suresh, Aneesha; Broussard, Christopher et al. (2014) Sleep promotes cortical response potentiation following visual experience. Sleep 37:1163-70
Frank, Marcos Gabriel (2013) Why I am not shy: a reply to Tononi and Cirelli. Neural Plast 2013:394946
Aton, Sara J; Broussard, Christopher; Dumoulin, Michelle et al. (2013) Visual experience and subsequent sleep induce sequential plastic changes in putative inhibitory and excitatory cortical neurons. Proc Natl Acad Sci U S A 110:3101-6

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