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 (J2))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
United States
Zip Code
Havekes, Robbert; Park, Alan J; Tolentino, Rosa E et al. (2016) Compartmentalized PDE4A5 Signaling Impairs Hippocampal Synaptic Plasticity and Long-Term Memory. J Neurosci 36:8936-46
Tudor, Jennifer C; Davis, Emily J; Peixoto, Lucia et al. (2016) Sleep deprivation impairs memory by attenuating mTORC1-dependent protein synthesis. Sci Signal 9:ra41
Gerstner, Jason R; Lenz, Olivia; Vanderheyden, William M et al. (2016) Amyloid-β induces sleep fragmentation that is rescued by fatty acid binding proteins in Drosophila. J Neurosci Res :
Gardner, Benjamin; Strus, Ewa; Meng, Qing Cheng et al. (2016) Sleep Homeostasis and General Anesthesia: Are Fruit Flies Well Rested after Emergence from Propofol? Anesthesiology 124:404-16
Perron, Isaac J; Pack, Allan I; Veasey, Sigrid (2015) Diet/Energy Balance Affect Sleep and Wakefulness Independent of Body Weight. Sleep 38:1893-903
Vecsey, Christopher G; Park, Alan J; Khatib, Nora et al. (2015) Effects of sleep deprivation and aging on long-term and remote memory in mice. Learn Mem 22:197-202
Stern, Anna L; Naidoo, Nirinjini (2015) Wake-active neurons across aging and neurodegeneration: a potential role for sleep disturbances in promoting disease. Springerplus 4:25
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
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

Showing the most recent 10 out of 74 publications