James M. Krueger
Room: SPBS 247
EducationPh.D. in physiology, University of Pennsylvania, Philadelphia
Bachelor of Science, University of Wisconsin, Madison
Doctorem Medicinae Honoris Causa, University of Szeged, Hungary
FellowshipsNIH Fellowship, the Institute of Neurological Sciences, University of Pennsylvania
BiographyKrueger received his Bachelor of Science from the University of Wisconsin, his doctorate in physiology from the University of Pennsylvania, and his Doctorem Medicinae Honoris Causa from the University of Szeged. From 1974-78 he served as a research fellow and then an instructor in the Harvard Medical School Department of Physiology, and from 1978-81 he was a research associate in the same department. In 1981, he joined the Chicago Medical School Department of Physiology and Biophysics. He worked as an associate and full professor from 1985-97 at the Department of Physiology and Biophysics at the University of Tennessee. He joined WSU in 1997, and in 2007 was named a WSU Regents Professor. In 2010, Krueger received designation as Eminent Professor, the highest award given to WSU faculty. In 2012, he was named the WSU Honors College Faculty Thesis Advisor of the Year, and elected to the Washington State Academy of Sciences.
Dr. Krueger’s research is focused on the biochemical regulation of sleep. He has described how many hormones and immune regulators are involved in physiological sleep regulation. These substances, and their corresponding mRNAs and protein levels, vary in brain with the sleep-wake cycle and are affected by sleep deprivation. If injected into animals, these substances increase sleep. Conversely, if they are inhibited, sleep is inhibited, and the sleep rebound after sleep deprivation is also blocked. These substances include cytokines such as interleukin-1 (IL1) and tumor necrosis factor (TNF). Cytokines are a group of small proteins involved in immune response regulation as well as brain functions such as brain plasticity and sleep. In brain, they are synthesized in neurons in response to neuronal activity. Collectively, his work led to a description of a molecular sleep homeostat.
Dr. Krueger’s research also is concerned with sleep and infectious diseases. Although known for millennia, e.g. Hippocrates proposed that sleep benefits recovery from illness, Dr. Krueger provided the first measures of sleep over the course of infections. Dr. Krueger went on to show that bacterial, protozoan, fungal and viral infectious agents greatly alter sleep. His work determined how the presence of microbes is translated into sleep responses. Thus, bacterial cell wall-peptidoglycan is digested by macrophages, releasing somnogenic muramyl peptides (these are the monomeric building blocks of bacterial cell walls). Muramyl peptides in turn induce enhanced production of cytokines which in turn promote sleep. With virus infections, viral double-stranded RNA enhances cytokine release and thereby sleep.
Another interest of Dr. Krueger’s laboratory is with sleep function and brain organization of sleep. In short, he hypothesized that small neuronal/glial networks are the organizational level at which sleep is initiated and that local sleep is dependent upon prior activity within the local network. Thus, active glia and neurons increase expression of TNF and IL1 that in turn drive increases in sleep locally. Individual cortical columns (these are the functional units of the cerebral cortex) alternate between functional states. The cortical column sleep-like state correlates with organism sleep and it is induced by TNF. In vitro mature co-cultures of neurons/glia have a default sleep-like state. If electrically stimulated, the cultures wake up. If treated with TNF the cultures, go into a deeper sleep-like state. Finally, if cells from mice lacking a key molecule involved in IL1 signaling are cultured, they fail to rapidly develop a sleep-like state and electrical stimulation fails to wake them up. These data clearly demonstrate that sleep is an emergent property of any viable network of neurons and glia whether found with a living animal or in a culture dish. The concept of sleep as a fundamental process of small networks driven by cell activity has provided a paradigm shift within the sleep research community.
Sample Peer Reviewed Research (in chronological order)
Krueger JM, Pappenheimer JR, Karnovsky ML. (1982) Sleep-promoting effects of muramyl peptides. Proc Natl Acad Sci (USA) 79: 6102-6106. This was the first demonstration of a microbial product inducing sleep. We also first showed that lipopolysaccharides and influenza viral double stranded RNA induce sleep responses. Excess sleep is now considered part of the acute phase response and sleep disorders are recognized as being associated with inflammation. We identified the microbial components responsible for sleep responses.
Krueger JM, Walter J, Dinarello CA, Wolff SM, Chedid L. (1984) Sleep-promoting effects of endogenous pyrogen (interleukin-1). Am J Physiol 246: R994-R999. This was the first report of any cytokine inducing sleep. We also first reported the somnogenic properties of TNF and other cytokines and neurotrophins. TNF is the best characterized SRS varying in pathological conditions associated with sleepiness or excess sleep. Many labs confirmed our work (Am J Physiol 275:R509, 1998) in this area, (Science 294;2511, 2001) (Nature Neurosci 10;1160, 2007).
Shoham S, Davenne D, Cady AB, Dinarello CA, Krueger JM. (1987) Recombinant tumor necrosis factor and interleukin 1 enhance slow-wave sleep. Am J Physiol 253: R142-R149. This was the first report linking TNF to sleep. TNF may be the best characterized sleep regulatory substance (SRS) varying in pathological conditions associated with sleepiness or excess sleep.
Toth LA, Krueger JM. (1988) Alteration of sleep in rabbits by Staphylococcus aureus infection. Infect Immun 56: 1785-1791. This was the first report quantifying changes in sleep over the course of an infectious disease. There was a gap of 2400 years from Hippocrates mentioning of sleep changes during illness and our measurements. There are now many reports relating sleep and some aspect of the immune response; e.g. sleep loss reduces antibody titers after inoculations.
Krueger JM, Obál F Jr. (1993) A neuronal group theory of sleep function. J Sleep Res 2: 63-69. This was the first statement of the hypothesis that sleep is a local use-dependent process.
Hansen MK, Taishi P, Chen Z, Krueger JM. (1998) Vagotomy blocks the induction of interleukin-1b mRNA in the brain of rats in response to systemic interleukin-1b. J Neurosci 18: 2247-2253. This was the first demonstration that systemic IL1-induction of brain IL1 mRNA was mediated by the vagus nerve.
Kushikata T, Fang J, Krueger JM. (1999) Brain-derived neurotrophic factor enhances spontaneous sleep in rats and rabbits. Am J Physiol 276: R1334-1338. This was the first demonstration that BDNF induced sleep. We went on to show that several other neurotrophins also are somnogenic.
Brandt J, Churchill L, Guan Z, Fang J, Chen L, Krueger JM. (2001) Sleep deprivation, but not a whisker trim, increases nerve growth factor within barrel cortical neurons. Brain Res 898: 105-112. We showed that afferent activity and sleep interact to alter neuronal NGF expression thereby linking cell activity to local sleep. Subsequently we also first showed that afferent activity enhances brain expression of other cytokines, such as IL1 and TNF, and that they induce local enhancements of EEG delta power if topically applied to the cortex.
Yoshida H, Peterfi Z, Garcia-Garcia F, Kirkpatrick R, Yasuda T, Krueger JM. (2004) State-specific asymmetries EEG in slow wave sleep induced by local application of TNFa. Brain Res 1009: 129-136. This was the first demonstration that local application of a sleep regulatory substance to the cortex could induce state-dependent enhancement in EEG delta wave activity unilaterally.
Churchill L, Rector DM, Yasuda K, Fix C, Rojas MJ, Yasuda T, Hall SJ, Guan X, Krueger JM. (2008) Tumor necrosis factor a: activity dependent expression and promotion of cortical column sleep in rats. Neuroscience 156:71-80. This was the first demonstration that a sleep regulatory substance can induce a sleep-like state within single cortical columns thereby showing SRS involvement in the local sleep process. In this article we also show that neuronal TNF immune-reactivity is enhanced by afferent activity suggesting that afferent activity enhances SRS expression that in turn induces local state oscillations.
Krueger JM, Rector DM, Roy S, Van Dongen HPA, Belenky G, Panksepp J. (2008) Sleep as a fundamental property of neuronal assemblies. Nature Reviews Neuroscience 9:910-919. This is a modern update of our 1993 theory on local use-dependent sleep. This article also presents the ATP-cytokine-adenosine hypothesis for the first time.
Szentirmai É, Kapás L, Sun Y, Smith RG, Krueger JM. (2009) The preproghrelin gene is required for normal integration of thermoregulation and sleep in mice. Proc. Natl. Acad. Sci. USA 106:14069-14074. This work extended our demonstration that growth hormone releasing hormone is a SRS and it links metabolism to sleep. It is particularly sensational in that we showed that the lack of one gene rendered mice hibernators; when challenged with cold and food deprivation they reversibly dropped their body temperatures to ambient temperature.
Krueger JM, Taishi P, De A, Davis C, Winters BD, Clinton J, Szentirmai E, Zielinski MR. (2010) ATP and the purine type 2 X7 receptor affect sleep. Jour. Appl. Physiol. 109:1318-1327. This is the first demonstration that extracellular ATP plays a crucial role in sleep regulation. ATP released from neurons and glia as a consequence of cell activity serves to translate cell activity into a sleep regulatory signal by its induction of cytokine release via a purine type 2 receptor, the P2X7 receptor.
Taishi P, Davis CJ, Bayomy O, Zielinski MR, Liao F, Clinton JM, Smith DE, Krueger JM. Brain –specific interleukin-1 receptor accessory protein in sleep regulation. (2012) J. Appl. Physiol. 112:1015-102. We show that this IL1 receptor accessory protein is involved in sleep regulation. It was previously shown to play a role in synaptogenesis.
Krueger JM, Huang Y, Rector DM, Buysee, DJ. (2013) Sleep: A synchrony of cell activity-driven small network states. European J. Neuroscience 38:2199-2209. We show that correct learned responses are dependent upon the sleep or wake state of a single somatosensory cortical column. If the cortical column is in the sleep-like state errors are made.
Davis CJ, Dunbrasky D, Oonk M, Taishi P, Opp MR, Krueger JM. (2014) The neuron-specific interleukin-1 receptor accessory protein is required for homeostatic sleep and sleep responses to influenza viral challenge in mice. Brain Behav. Immunity. (on line 4 Nov 2014; PMID:25449578). We show that mice lacking the brain-specific interleukin 1 receptor accessory protein (AcPb) sleep less, not more like wild type mice, after sleep deprivation. Further, in response to influenza virus challenge the mice lacking the brain-specific AcPb have higher morbidity and mortality rates, including a lack of non-rem sleep responses.
Jewett KA, Taishi P, Sengupta P, Roy S, Davis CJ, Krueger, JM. (2015) Tumor necrosis factor enhances the sleep-like state and electrical stimulation induces a wake-like state in co-cultures of neurons and glia. European J. Neurosci. 42:2078-2090. We show that small cultured neuronal/glial networks show sleep homeostasis if kept in a wake-like state for prolonged periods and that a deeper sleep-like state is induced in these small networks by TNF application.
Davis CJ, Taishi P, Honn KA, Koberstein JN, Krueger JM. (2016) P2X7 receptors in body temperature, locomotor activity, and brain mRNA and lncRNA responses to sleep loss. Am. J. Physiology. 311:R1004-R1012.
Davis CJ, Zielinski MR, Dunbrasky D, Taishi P, Dinarello CA, Krueger JM. (2017) Interleukin-37 expression in mice alters sleep responses to inflammatory agents and influenza virus infection. Neurobiology of Sleep and Circadian Rhythms 3:1-9.
Rockstrom M, Chen L, Taishi P, Nguyen JT, Gibbons CM, Veasey SC, Krueger JM. Tumor necrosis factor alpha in sleep regulation. Sleep Medicine Reviews (2017 Nov 16. pii: S1087-0792(17)30147-8. doi: 10.1016/j.smrv.2017.10.005. [Epub ahead of print]).
Xue M, Taishi P, Sahabandu D, Roy S, Krueger J. Signal analysis and stochastic-switching models of evoked responses in brain circuits grown in culture. IEEE GlobalSIP 2017 (978-1-5090-5990-4/17, page 452-456).
Recent Brief Reviews
Krueger JM, Frank M, Wisor J, Roy, S. (2016). Sleep function: Toward elucidating an enigma. Sleep Medicine Reviews 28:42-50.
Krueger JM, Roy S (2016). Sleep’s kernal. The Scientist, March 1, 2016 issue, pp 36-41.
Krueger JM, Opp MR. (2016). Sleep and Microbes: in International Review of Neurobiology, Gut Microbiome and Behavior. R.A. Harris and P. Jenner, Editors, Elsevier Inc. pp. 207-225.
Krueger JM, Opp MR. (2016). Pro-inflammatory cytokines in sleep regulation: Animal models. In: Primer of PsychoNeuroImmunology Research. Los Angeles, CA: PsychoNeuroImmunology Research Society. Opp, MR, Editor. Pp 267-272.
Szentirmai, E., Krueger, J.M., Kapas L. Hormones and sleep. In: Encyclopedia of Animal Behavior, Second Edition, R.J. Nelson, editor, Elsevier, (in press).
In the NewsTripping on the Edge of Consciousness: A Life’s Work
Sleep’s Kernel, March 1, 2016, The Scientist
Researchers discover brain-specific protein that could help fight flu, January 20, 2015, Spokesman-Review
Sleep Switch Found in the Brain, Discover Magazine’s Top 100 Stories of 2010
The Secrets of Sweet Oblivion, Washington State Magazine
Honors and Awards2016 – Keynote Speaker, Australasian Sleep Research Society, Adelaide, Australia
2014 – Keynote Speaker, European Sleep Research Society, Tallinn, Estonia
2012 – Washington State Academy of Sciences (elected 2012)
2012 – Honors College Faculty Thesis Advisor of the Year, Washington State University
2010 – Eminent Faculty Award, Washington State University
2006 – Pfizer Lectureship in Sleep, University of Michigan
2006 – Distinguished Scientist Award, Sleep Research Society
2005 – Doctorem Medicinae Honoris Causa, University of Szeged, Hungary
2003 – Pfizer Award for Research Excellence, Washington State University College of Veterinary Medicine
2001 – Sahlin Faculty Excellence Award for Research, Washington State University
2000 – Neuroscience Grass Traveling Scientist, Jackson, Mississippi
1999 – Visiting Professor, Nanjing Medical University, Jiangsu Province, China
1997-2004 – NIH/NINDS: Javits Award
1995-1996 – President of Faculty Senate, University of Tennessee-Memphis
1990 – Honorary Award, Tokyo Medical and Dental University, Japan
1983 – Board of Trustees Research Award, Chicago Medical School
1978-1979 – American Heart Association Career Investigator Fellow
Sleep Promoting Factor: issued August 3, 1982 [#4,342,748]
Somnogenic Compositions and Method of Use: issued May 26, 1987 [#4,668,661]
Interleukin-1 Fragment – Method of Inducing Sleep: issued December 24, 1991 [#5075288]
Complementary Peptides – Method of Inducing Sleep With GHRH Complementary Peptide Compositions: issued October 6, 1992 [#5153175]
Administering Bacteria to Improve Sleep: issued September 23, 2002 (#6,444,203 B2)
Method for reduction in caloric intake; GHRELIN siRNA administration. Application No. 12/700,009; filed 02/04/2010; issued Oct 2012