Ph.D. Johns Hopkins Univ., 1988
Sleep Circadian Rhythms
My research addresses questions related to sleep and circadian rhythms. The research ranges from molecular and genetic approaches to behavioral studies in mice and humans. Great progress has been made recently in understanding fundamental aspects of circadian rhythms, but many aspects of sleep are poorly understood. Although sleep occupies approximately one third of our lives, we still cannot answer the basic question of why we sleep. It now appears that most animals have some form of sleep, and birds and mammals generally have two very different kinds of sleep – Rapid-Eye-Movement (REM) sleep and non-REM sleep that may serve different or complementary functions. In addition to fundamental questions about sleep function and sleep regulation, sleep is also of great medical and societal importance. Sleep disturbances afflict approximately 75 million people in the United States alone, and even normal sleepers often get insufficient sleep due to lifestyle factors that can result in serious accidents, poor performance, lowered quality of life, and even grouchiness. Clearly, something about the brain requires sleep and, in our view, genetic approaches in mice provide one of the best opportunities for a better understanding of sleep.
Mice are an excellent model organism for genetic studies because there is a wide diversity of inbred strains. Members of each individual inbred strain are genetically identical, like identical twins in humans, but among different strains there are many different alleles of each gene that contribute to physiological and behavioral differences. We are currently investigating differences in gene expression among these strains for genes that we believe are critical for sleep regulation or sleep function. We also monitor different strains for behavioral differences ranging from total sleep time, to their daily activity patterns. For example, we have one mouse strain called CAST/EiJ that is similar to humans with the clinical condition called Advanced Sleep Phase Syndrome, and wake up much earlier than normal. We have recently identified at least one chromosomal region (or Quantitative Trait Locus) that contributes to this trait, and are now trying to find which of the approximately one hundred genes in this region is the critical one.
A major limitation in all studies of sleep in mice, or any mammal, is the difficulty of performing EEG/EMG analyses. In mice, this requires extensive surgery, recovery, cabling of animals, and considerable time for signal analyses. Therefore, we developed a non-invasive, high-throughput alternative using a piezoelectric film attached to the floor of a mouse cage, and then developed signal processing algorithms to score sleep and wake in real time. This work is being done in collaboration with Prof. Kevin Donohue in Engineering. We currently have our system screening mice at Oak Ridge National Laboratory and other locations to take advantage of the extensive diversity of mice available at these locations, including a large cross that may revolutionize complex genetic studies, called the Collaborative Cross.
In addition to our studies in mice, we are also studying various aspects of sleep, meditation and performance in people, such as whether meditation might provide some of the restoration we normally associate with sleep. We are using a well-validated psychomotor vigilance test that accurately reflects underlying sleepiness. Our data thus far suggest meditation can indeed boost performance, and in a way that appears to compensate or pay-off sleep debt.
Kaul P, J Passafiume, RC Sargent, BF O’Hara. Meditation acutely improves psychomotor vigilance and may decrease sleep need. Behav Brain Functions. 6:47 (pp. 1-9) (2010).
- "Increased fragmentation of sleep-wake cycles in the 5XFAD mouse model of Alzheimer's disease." Neuroscience 290, (2015): 80-9. Details. Full text
- "Resolvins AT-D1 and E1 differentially impact functional outcome, post-traumatic sleep, and microglial activation following diffuse brain injury in the mouse." Brain, behavior, and immunity 47, (2015): 131-40. Details. Full text
- "Acute over-the-counter pharmacological intervention does not adversely affect behavioral outcome following diffuse traumatic brain injury in the mouse." Experimental brain research 232, 9 (2014): 2709-19. Details. Full text
- "Recovery of neurological function despite immediate sleep disruption following diffuse brain injury in the mouse: clinical relevance to medically untreated concussion." Sleep 37, 4 (2014): 743-52. Details.
- "Evaluation of a piezoelectric system as an alternative to electroencephalogram/ electromyogram recordings in mouse sleep studies." Sleep 37, 8 (2014): 1383-92. Details.
- "Clock genes and sleep homeostasis: a fundamental link within the two-process model?" Sleep 36, 3 (2013): 301-2. Details.
- "Distinct phase relationships between suprachiasmatic molecular rhythms, cerebral cortex molecular rhythms, and behavioral rhythms in early runner (CAST/EiJ) and nocturnal (C57BL/6J) mice." Sleep 35, 10 (2012): 1385-94. Details.
- "Effects of aging and genotype on circadian rhythms, sleep, and clock gene expression in APPxPS1 knock-in mice, a model for Alzheimer's disease." Experimental neurology 236, 2 (2012): 249-58. Details. Full text
- "Behavioral and genetic dissection of a mouse model for advanced sleep phase syndrome." Sleep 34, 1 (2011): 39-48. Details.
- "Genetic analysis in the Collaborative Cross breeding population." Genome research 21, 8 (2011): 1223-38. Details. Full text
- "Meditation acutely improves psychomotor vigilance, and may decrease sleep need." Behavioral and brain functions : BBF 6, (2010): 47. Details. Full text
- "Effects of ramelteon and triazolam in a mouse genetic model of early morning awakenings." Brain research 1296, (2009): 46-55. Details. Full text
- "Assessment of a non-invasive high-throughput classifier for behaviours associated with sleep and wake in mice." Biomedical engineering online 7, (2008): 14. Details. Full text
- "Pattern recognition of sleep in rodents using piezoelectric signals generated by gross body movements." IEEE transactions on bio-medical engineering 54, 2 (2007): 225-33. Details. Full text
- "Homer1a is a core brain molecular correlate of sleep loss." Proceedings of the National Academy of Sciences of the United States of America 104, 50 (2007): 20090-5. Details. Full text
- "A non-circadian role for clock-genes in sleep homeostasis: a strain comparison." BMC neuroscience 8, (2007): 87. Details. Full text
- "Genomic and proteomic approaches towards an understanding of sleep." CNS & neurological disorders drug targets 6, 1 (2007): 71-81. Details. Full text
- "A novel quantitative trait locus on mouse chromosome 18, "era1," modifies the entrainment of circadian rhythms." Sleep 30, 10 (2007): 1255-63. Details.
- "NPAS2 as a transcriptional regulator of non-rapid eye movement sleep: genotype and sex interactions." Proceedings of the National Academy of Sciences of the United States of America 103, 18 (2006): 7118-23. Details. Full text
- "Lack of the alanine-serine-cysteine transporter 1 causes tremors, seizures, and early postnatal death in mice." Brain research 1052, 2 (2005): 212-21. Details. Full text
- "Light induces c-fos and per1 expression in the suprachiasmatic nucleus of arrhythmic hamsters." American journal of physiology. Regulatory, integrative and comparative physiology 289, 5 (2005): R1381-6. Details. Full text
- "Light pulses do not induce c-fos or per1 in the SCN of hamsters that fail to reentrain to the photocycle." Journal of biological rhythms 19, 4 (2004): 287-97. Details. Full text
- "The Collaborative Cross, a community resource for the genetic analysis of complex traits." Nature genetics 36, 11 (2004): 1133-7. Details. Full text
- "Sleep deprivation effects on growth factor expression in neonatal rats: a potential role for BDNF in the mediation of delta power." Journal of neurophysiology 91, 4 (2004): 1586-95. Details. Full text
- "The nature and identification of quantitative trait loci: a community's view." Nature reviews. Genetics 4, 11 (2003): 911-6. Details. Full text
- "Role of melanopsin in circadian responses to light." Science (New York, N.Y.) 298, 5601 (2002): 2211-3. Details. Full text
- "A role for cryptochromes in sleep regulation." BMC neuroscience 3, (2002): 20. Details. Full text
- "Acetylcholine becomes the major excitatory neurotransmitter in the hypothalamus in vitro in the absence of glutamate excitation." The Journal of neuroscience : the official journal of the Society for Neuroscience 21, 6 (2001): 2015-27. Details. Full text
- "Gene expression in the brain across the hibernation cycle." The Journal of neuroscience : the official journal of the Society for Neuroscience 19, 10 (1999): 3781-90. Details. Full text
- "HSP70 expression is increased during the day in a diurnal animal, the golden-mantled ground squirrel Spermophilus lateralis." Molecular and cellular biochemistry 199, 1-2 (1999): 25-34. Details.
- "Developmental changes in nicotinic receptor mRNAs and responses to nicotine in the suprachiasmatic nucleus and other brain regions." Brain research. Molecular brain research 66, 1-2 (1999): 71-82. Details.
- "Characterization of the circadian system of NGFI-A and NGFI-A/NGFI-B deficient mice." Journal of biological rhythms 13, 4 (1998): 347-57. Details. Full text
- "Nicotine and nicotinic receptors in the circadian system." Psychoneuroendocrinology 23, 2 (1998): 161-73. Details. Full text
- "Daily variation of CNS gene expression in nocturnal vs. diurnal rodents and in the developing rat brain." Brain research. Molecular brain research 48, 1 (1997): 73-86. Details. Full text
- "Sequence and tissue distribution of a candidate G-coupled receptor cloned from rat hypothalamus." Biochemical and biophysical research communications 209, 2 (1995): 606-13. Details. Full text
- "Nicotine administration differentially affects gene expression in the maternal and fetal circadian clock." Brain research. Developmental brain research 84, 1 (1995): 46-54. Details. Full text
- "GABAA, GABAC, and NMDA receptor subunit expression in the suprachiasmatic nucleus and other brain regions." Brain research. Molecular brain research 28, 2 (1995): 239-50. Details. Full text
- "C-fos mRNA increases in the ground squirrel suprachiasmatic nucleus during arousal from hibernation." Neuroscience letters 165, 1-2 (1994): 117-21. Details.
- "Proenkephalin transgenic mice: a short promoter confers high testis expression and reduced fertility." Molecular reproduction and development 38, 3 (1994): 275-84. Details.
- "Immediate early gene expression in brain during sleep deprivation: preliminary observations." Sleep 16, 1 (1993): 1-7. Details.
- "Brain transcription factor expression: effects of acute and chronic amphetamine and injection stress." Brain research. Molecular brain research 20, 1-2 (1993): 91-100. Details.
- "Dopamine D2 receptor gene Taq I 'A' locus map including 'A4' variant: relevance for alcoholism and drug abuse." Drug and alcohol dependence 31, 3 (1993): 229-34. Details.
- "Expression and novel subunit isoforms of glutamate receptor genes GluR5 and GluR6." Neuroreport 4, 12 (1993): 1343-6. Details.
- "Chromosomal localization of glutamate receptor genes: relationship to familial amyotrophic lateral sclerosis and other neurological disorders of mice and humans." Proceedings of the National Academy of Sciences of the United States of America 90, 7 (1993): 3053-7. Details. Full text
- "Genetic vulnerability to drug abuse. The D2 dopamine receptor Taq I B1 restriction fragment length polymorphism appears more frequently in polysubstance abusers." Archives of general psychiatry 49, 9 (1992): 723-7. Details. Full text
- "Preproenkephalin promoter "cassette" confers brain expression and synaptic regulation in transgenic mice." Proceedings of the National Academy of Sciences of the United States of America 89, 6 (1992): 2345-9. Details. Full text
- "Cloning of the gamma-aminobutyric acid (GABA) rho 1 cDNA: a GABA receptor subunit highly expressed in the retina." Proceedings of the National Academy of Sciences of the United States of America 88, 7 (1991): 2673-7. Details. Full text
- "Sex, strain, and species differences affect recombination across an evolutionarily conserved segment of mouse chromosome 16." Genomics 8, 1 (1990): 141-8. Details. Full text
- "Developmental expression of the amyloid precursor protein, growth-associated protein 43, and somatostatin in normal and trisomy 16 mice." Brain research. Developmental brain research 49, 2 (1989): 300-4. Details.
- "Genetic mapping and analysis of somatostatin expression in Snell dwarf mice." Brain research 464, 4 (1988): 283-92. Details.
- "Neuroanatomical localization and quantification of amyloid precursor protein mRNA by in situ hybridization in the brains of normal, aneuploid, and lesioned mice." Proceedings of the National Academy of Sciences of the United States of America 85, 10 (1988): 3628-32. Details. Full text
- "Genetic mapping of the Mx influenza virus resistance gene within the region of mouse chromosome 16 that is homologous to human chromosome 21." Journal of virology 62, 11 (1988): 4372-5. Details. Full text
- "Somatostatin-gene expression in the postmortem adult and fetal human brain." Peptide research 5, 4 (1969): 201-5. Details.
- "Dopamine D2 receptor RFLPs, haplotypes and their association with substance use in black and Caucasian research volunteers." Human heredity 43, 4 (1969): 209-18. Details.
- "The effect of cortisone on nutrition." The Journal of pediatrics 39, 3 (1951): 267-86. Details.
- "Validation of a closed-loop sensory stimulation technique for selective sleep restriction in mice." Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference 2014, (0): 3771-4. Details. Full text
- "Diffuse brain injury induces acute post-traumatic sleep." PloS one 9, 1 (0): e82507. Details. Full text
- "Diffuse brain injury does not affect chronic sleep patterns in the mouse." Brain injury 28, 4 (0): 504-10. Details. Full text
- "Sleepy genes." Frontiers in neuroscience 4, (0): 183. Details. Full text
- "Genetic mapping of Prm-1, Igl-1, Smst, Mtv-6, Sod-1, and Ets-2 and localization of the Down syndrome region on mouse chromosome 16." Cytogenetics and cell genetics 44, 2-3 (0): 76-81. Details.