Synaptic plasticity is a fundamental feature of the nervous system that underlies neural development, adaptation and learning. There is growing evidence that deficits in the mechanisms of synaptic plasticity are involved in the pathophysiology of many psychiatric disorders, from schizophrenia to mood disorders. For this reason, NIMH has established as one of his strategic research priorities the study of brain plasticity "at the cellular, synaptic, circuit, and behavioral level," with the final goal of "determining the neurobiological bases of these processes." This proposal will study humans and three animal models (flies, mice, rats) to test the novel and provocative idea that synaptic plasticity is adaptive up to a point, but beyond that point, or in vulnerable individuals, it can become maladaptive. The "cost" of synaptic plasticity is not often considered but may be crucial in the pathophysiology of psychiatric disorders, and will be assessed at the ultrastructural, cellular, circuit, and behavioral level. Our previous NIMH-funded work has established that the overall result of wake plasticity is a net increase in synaptic strength, which is renormalized by sleep. But what happens when plasticity is "excessive," for instance because it is extended beyond the physiological range without intervening sleep? Based on preliminary results obtained in both animals and humans, we hypothesize that extended plasticity can lead to negative consequences on neuronal activity (OFF periods, performance deficits) and on cellular function/integrity (cellular stress, ultrastructural abnormalities).
Aim 1 will use rats to test whether plasticity-dependent synaptic overload leads to the occurrence of neuronal OFF periods, local EEG slowing during wake, and performance impairment. It will also establish to what extent these effects are a region- specific consequence of plasticity, rather than a general effect of prolonged wake.
Aim 2 will use high density (hd) EEG in humans to ask whether the local increase in EEG theta waves, which occurs during wake as a result of extended plasticity in specific brain circuits, leads to local performance deficits, locally increased sleep need, and o sleep-dependent restoration of function.
Aim 3 will use flies and mice to test whether extending plasticity by prolonging wakefulness leads to cellular stress and subcellular damage, and whether doing so chronically under sleep restriction conditions leads to lasting cellular damage and cognitive deficits. Plasticity plays a central role in the life of every organism, but its coston neural structure and function may be substantial especially at vulnerable developmental times, such as adolescence, or in vulnerable populations, such as psychiatric patients. Demonstrating the cost of plasticity at the cellular and systems level will have clear practical implications forthe prevention and treatment of mental disorders.

Public Health Relevance

This proposal will study humans and three animal models (flies, mice, rats) to understand at the ultrastructural, cellular, circuit, and behavioral level te cost of synaptic plasticity, an aspect of plasticity that is not often considered but may be crucal in the pathophysiology of psychiatric disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH099231-02
Application #
8690156
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
Vicentic, Aleksandra
Project Start
2013-07-01
Project End
2018-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
$668,090
Indirect Cost
$221,761
Name
University of Wisconsin Madison
Department
Psychiatry
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Tononi, Giulio; Cirelli, Chiara (2014) Sleep and the price of plasticity: from synaptic and cellular homeostasis to memory consolidation and integration. Neuron 81:12-34
Vyazovskiy, Vladyslav V; Cui, Nanyi; Rodriguez, Alexander V et al. (2014) The dynamics of cortical neuronal activity in the first minutes after spontaneous awakening in rats and mice. Sleep 37:1337-47
Siclari, Francesca; Bernardi, Giulio; Riedner, Brady A et al. (2014) Two distinct synchronization processes in the transition to sleep: a high-density electroencephalographic study. Sleep 37:1621-37