Paul Joseph Shaw - US grants

DESCRIPTION (provided by applicant): While the function of sleep remains a mystery, many of the most successful theories on sleep function, including synaptic downscaling, memory consolidation, developmental maturation, and even many theories on sleep restoration require that sleep must substantially influence aspects of brain plasticity. We demonstrate that increasing sleep restores brain functions supporting short-term memory in each of 12 classic memory mutants without specifically rescuing the causal molecular lesion or structural defect. We also demonstrate that sleep can rescue brain functions supporting long-term memory as assessed by courtship conditioning. Elucidating the underlying molecular mechanisms may shed new light on processes related to sleep function and may ultimately provide a roadmap for using sleep as a therapeutic to slow or reverse cognitive decline associated with degenerative disease and perhaps developmental disorders. Thus, in this proposal we will: 1) identify the circuits that are required to support sleep-dependent changes in adaptive behavior, 2) manipulate specific genes to determine if they are required for sleep induced restoration of memory, and 3) Determine whether the therapeutic role of sleep extends to disorders in which species of toxic proteins can actively impair neuronal functions and/or kill neurons.

[unreadable] DESCRIPTION (provided by applicant): It is a common experience to sacrifice sleep to meet the demands of our 24-h society. Current estimates reveal that, as a society, we sleep on average 2 h less than we did 40 years ago. This level of sleep restriction results in negative health outcomes and is sufficient to produce cognitive deficits, reduced attention, and is associated with increased risk for traffic and occupational accidents. Unfortunately, there is no simple quantifiable marker that can detect an individual who is excessively sleepy before adverse outcomes become evident. To address this issue we have developed a simple and effective strategy for identifying biomarkers of sleepiness using genetic and pharmacological tools that dissociate sleep drive from wake time in the model organism Drosophila melanogaster. In this proposal we will choose select genes from our Drosophila Database of Biomarkers to develop a noninvasive tool that can be used for the molecular diagnosis of sleepiness in humans. We will identify genes that are responsive to acute sleep loss then determine if these biomarkers are altered in patients with obstructive sleep apnea syndrome.PROJECT NARRATIVE [unreadable] [unreadable] Sleep loss adversely effects metabolic processes, endocrine functions, and immunology and may increase the susceptibility of individuals to serious diseases, including obesity, type II diabetes and coronary heart disease to name a few. Developing tools for the molecular diagnosis of sleepiness will assist with the identification and treatment of sleepiness in the general population and in critical patient populations. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): We have identified a group of ~20 neurons that can be activated on-demand using Drosophila genetics. The sleep observed during activation of these neurons meets the historical definition for identifying sleep. Our data highlight the importance of these neurons for regulating sleep. In this proposal we will use live-cell imaging and in vivo electrophysiological recording from Drosophila brains to define the properties of these neurons in the intact brain. The ability to use Drosophila genetics to induce sleep provides a unique opportunity to examine whether sleep can be used as a therapeutic for slowing or attenuating cognitive impairments associated with degenerative diseases. Thus, we will determine whether inducing sleep in Drosophila models of Parkinson's and Alzheimer's disease can offset deficits in cognitive behavior.