There are major changes in sleep and wake that occur with age in all species studied. The major changes are in the ability to sustain state, in particular wakefulness, and reduced amounts of sleep. These physiological changes with age make older adults vulnerable to conditions that lead to difficulty sustaining sleep and wakefulness. This program of research investigates mechanisms for this at a fundamental molecular level. The projects focuses on two key groups of neurons: a) orexin cells in the lateral hypothalamus that stabilize behavioral state and promote wakefulness and b) galanin cells in the ventrolateral preoptic (VLPO) area that are active during sleep and promote sleep. We propose that there will first be decreased transcriptional response to neuronal activation in these neural populations with cell loss occurring at a later age. A major hypothesis being addressed is that changes in these neuronal populations with age are the result of age-related changes in the ER stress response pathway. To address these key hypotheses, we have three specific aims.
In Aim 1, we will assess the temporal association between 3 measures of neuronal function of orexin cells and a key behavioral variable that is affected by age, i.e., the ability for mice to sustain long bouts of wakefulness.
In Aim 2 we will have a similar approach but studying galanin VLPO cells with behavioral measures being reduction in NREM sleep across 24 hours and the amount of NREM in the first 24 hours of recovery sleep following 6 hours of sleep deprivation.
Aim 3 will focus on the ER stress response pathway. Changes in expression of key genes in this pathway with age in these neuronal populations will be assessed. Moreover, we will determine, using a transgenic approach, whether reductions in the master regulator of the ER stress response pathway in BiP leads to changes with age being accelerated both in terms of function and number of cells in these neuronal groups and also in sleep/wake behavior. Finally, a discovery aim is proposed to use the new technology, RNA sequencing, to assess changes with age in the transcriptome of these two neuronal populations.

Public Health Relevance

Fragmentation of sleep and wake occur with age. There is a reduction in the ability to sustain wakefulness and reductions in sleep. This has adverse consequences and reduces the quality of life. The mechanisms underiying these changes are unknown. This project takes a mechanistic approach focusing on specific brain neurons that control sleep and wake. This study will identify new molecular pathways to target to reduce this key effect of aging on an important behavior.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAG1-ZIJ-5)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
United States
Zip Code
Anafi, Ron C; Lee, Yool; Sato, Trey K et al. (2014) Machine learning helps identify CHRONO as a circadian clock component. PLoS Biol 12:e1001840
Prince, Toni-Moi; Wimmer, Mathieu; Choi, Jennifer et al. (2014) Sleep deprivation during a specific 3-hour time window post-training impairs hippocampal synaptic plasticity and memory. Neurobiol Learn Mem 109:122-30
Nall, Aleksandra H; Sehgal, Amita (2013) Small-molecule screen in adult Drosophila identifies VMAT as a regulator of sleep. J Neurosci 33:8534-40
Anafi, Ron C; Pellegrino, Renata; Shockley, Keith R et al. (2013) Sleep is not just for the brain: transcriptional responses to sleep in peripheral tissues. BMC Genomics 14:362
Vecsey, Christopher G; Wimmer, Mathieu E J; Havekes, Robbert et al. (2013) Daily acclimation handling does not affect hippocampal long-term potentiation or cause chronic sleep deprivation in mice. Sleep 36:601-7
Prince, Toni-Moi; Abel, Ted (2013) The impact of sleep loss on hippocampal function. Learn Mem 20:558-69
Naidoo, Nirinjini; Ferber, Megan; Galante, Raymond J et al. (2012) Role of Homer proteins in the maintenance of sleep-wake states. PLoS One 7:e35174
Zimmerman, John E; Chan, May T; Jackson, Nicholas et al. (2012) Genetic background has a major impact on differences in sleep resulting from environmental influences in Drosophila. Sleep 35:545-57
McShane, Blakeley B; Galante, Raymond J; Biber, Michael et al. (2012) Assessing REM sleep in mice using video data. Sleep 35:433-42
Sehgal, Amita; Mignot, Emmanuel (2011) Genetics of sleep and sleep disorders. Cell 146:194-207

Showing the most recent 10 out of 60 publications