A drosophila model of sleep restriction therapy for insomnia and neurodegenerative disease / Samuel J. Belfer.

Format:

Book

Thesis/Dissertation

Author/Creator:

Belfer, Samuel J., author.

Contributor:

University of Pennsylvania. Department of Neuroscience, degree granting institution.

Kayser, Matthew S., degree supervisor.

Language:

English

Subjects (All):

Neurosciences.

Neuroscience--Penn dissertations.

Penn dissertations--Neuroscience.

Local Subjects:

Neurosciences.

Neuroscience--Penn dissertations.

Penn dissertations--Neuroscience.

Genre:

Academic theses.

Physical Description:

1 online resource (193 pages)

Contained In:

Dissertations Abstracts International 81-09B.

Place of Publication:

[Philadelphia, Pennsylvania] : University of Pennsylvania ; Ann Arbor : ProQuest Dissertations & Theses, 2019.

Language Note:

English

System Details:

Mode of access: World Wide Web.

text file

Summary:

Insomnia is the most common sleep disorder among adults, especially affecting individuals of advanced age or with neurodegenerative disease. Humans with insomnia often expand the amount of time they spend in bed in an attempt to compensate for inability to sleep. However, this mismatch of time in bed (high) with sleep ability (low) perpetuates insomnia symptoms. Cognitive Behavioral Therapy for Insomnia (CBT-I) is the first-line insomnia treatment. Sleep restriction - a key component of CBT-I - addresses mismatch between sleep opportunity and ability by restricting time in bed to an amount equal to average sleep ability, leading to enhanced sleep drive and consolidation. Though effective, limited accessibility of practitioners and long duration of therapy are barriers to broad implementation of CBT-I. Deciphering a molecular basis for this behavioral therapy has potential to open new treatment avenues. In Chapter 1, I discuss the utility of modeling insomnia, behavioral therapy, and neurodegenerative disease in Drosophila. In Chapter 2, we develop a Drosophila model for sleep restriction therapy (SRT). We find that restriction of sleep opportunity through manipulation of environmental cues improves sleep efficiency and continuity in multiple short-sleeping Drosophila mutants. We apply SRT to a Drosophila model of Alzheimer's disease, in which Aβ accumulation causes decreased and fragmented sleep, and demonstrated that sleep restriction reverses these sleep deficits, with associated extension in lifespan. In Chapter 3, we expand our search for fly models of human neurodegenerative disease associated with short-sleeping phenotypes. We find that overexpression of human TDP-43, the protein deposited in intracellular inclusions in ALS and FTD, cause profound sleep disturbances that can be rescued by SRT. TDP-43 flies also exhibit increased arousal threshold and extended longevity with SRT, suggesting deeper sleep with sleep opportunity restriction confers health benefits. In Chapter 4, I discuss ongoing work investigating the intracellular localization of TDP-43, and how improved sleep might mediate toxicity of this protein. Finally, I discuss use of this model to identify molecular signals mediating the response to sleep restriction therapy. These findings have important implications for our understanding of behavioral sleep therapy and its potential as a therapeutic intervention for neurodegenerative disease.

Notes:

Source: Dissertations Abstracts International, Volume: 81-09, Section: B.

Advisors: Kayser, Matthew S.; Committee members: David Raizen; Philip Gehrman; F. Bradley Johnson; Kyunghee Koh.

Department: Neuroscience.

Ph.D. University of Pennsylvania 2019.

Local Notes:

School code: 0175

ISBN:

9781392469903

Access Restriction:

Restricted for use by site license.

This item is not available from ProQuest Dissertations & Theses.

This item must not be sold to any third party vendors.