70 million Americans suffer from some sort of sleep disorder. How the brain switches between states of consciousness is not known, but researchers have now determined that a distributed network of neurons are responsible for wake, non-REM and REM sleep. First-order circuit models have emerged, and these have been tested using traditional lesion and gene deletion methods. We now propose to repair the network using the gene transfer method. This approach has proven to be an effective neurobiological tool in a number of neurodegenerative diseases but surprisingly no one has used it to correct a sleep disorder. In this project recombinant adeno-associated viral vector (rAAV-serotype 8) will be used to transfer the gene for the arousal peptide hypocretin (also known as orexin) into a specific neuronal phenotype. An integrated series of four aims will test specific hypotheses in two murine models with targeted deletions of the hypocretin gene or of the hypocretin neurons. Experiments with appropriate controls are proposed to strengthen the conclusions.
These aims are supported by our very strong preliminary data that shows robust expression of the hypocretin gene product in specific neurons along with unambiguous decline of narcoleptic behavior in the two murine models. These studies will demonstrate that genetic pharmacology can serve as a valuable neurobiological tool to repair the network.

Public Health Relevance

At least two sleep disorders are now linked to specific genes. The significance of this project is that it will develop a gene transfer approach that will serve as a neurobiological tool to repair a defective network in disorders characterized by a significant sleep disturbance.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
1I01BX000798-01
Application #
7929293
Study Section
Neurobiology C (NURC)
Project Start
2010-10-01
Project End
2014-09-30
Budget Start
2010-10-01
Budget End
2011-09-30
Support Year
1
Fiscal Year
2011
Total Cost
Indirect Cost
Name
VA Boston Health Care System
Department
Type
DUNS #
034432265
City
Boston
State
MA
Country
United States
Zip Code
02130
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Shiromani, Priyattam J; Peever, John H (2017) New Neuroscience Tools That Are Identifying the Sleep-Wake Circuit. Sleep 40:
Blanco-Centurion, Carlos; Liu, Meng; Konadhode, Roda P et al. (2016) Optogenetic activation of melanin-concentrating hormone neurons increases non-rapid eye movement and rapid eye movement sleep during the night in rats. Eur J Neurosci 44:2846-2857
Liu, Meng; Blanco-Centurion, Carlos; Konadhode, Roda Rani et al. (2016) Orexin gene transfer into the amygdala suppresses both spontaneous and emotion-induced cataplexy in orexin-knockout mice. Eur J Neurosci 43:681-8
Pelluru, Dheeraj; Konadhode, Roda Rani; Bhat, Narayan R et al. (2016) Optogenetic stimulation of astrocytes in the posterior hypothalamus increases sleep at night in C57BL/6J mice. Eur J Neurosci 43:1298-306
Konadhode, Roda Rani; Pelluru, Dheeraj; Shiromani, Priyattam J (2016) Unihemispheric Sleep: An Enigma for Current Models of Sleep-Wake Regulation. Sleep 39:491-4
Konadhode, Roda Rani; Pelluru, Dheeraj; Shiromani, Priyattam J (2014) Neurons containing orexin or melanin concentrating hormone reciprocally regulate wake and sleep. Front Syst Neurosci 8:244