Research in VCAPP

My laboratory is concerned with three areas of research.  First, we focus on the biochemical regulation of sleep.  We described the somnogenic actions of many cytokines.  We showed that interleukin-1 and tumor necrosis factor are involved in physiological sleep regulation.  Further we have an independent project demonstrating the involvement of growth hormone releasing hormone in sleep regulation.  For each of these substances we showed that their mRNA and protein levels vary in brain with the sleep-wake cycle and are affected by sleep deprivation.  We showed that these substances increase non-rapid eye movement sleep (NREMS).  Conversely, if they are inhibited sleep is inhibited and the sleep rebound after sleep deprivation is also blocked.  Mice lacking IL1 or TNF receptors and animals underexpressing GHRH or the GHRH receptor sleep less than normal.  We have also examined many substances related to these somnogens with the goal of developing our knowledge of the biochemical network regulating sleep.

Our second interest deals with sleep and infectious diseases.  Bacterial, protozoan, fungal and viral infectious agents greatly alter sleep.  In the case of bacteria we determined the molecular steps responsible.  For example, with gram-positive bacteria, bacterial peptidoglycan (from cell walls) 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 affect sleep.  Currently our efforts are focused on the mechanisms involved in influenza virus induced sleep.  In this case, viral double-stranded RNA, released from infected cells, seems responsible for initiating the sleep cascade.

A third interest of my laboratory is with sleep function and brain organization as it applies to sleep.  In short, we hypothesized that neuronal groups are the organizational level at which sleep is initiated.  Much recent experimental data support this idea.  For instance, individual cortical columns such as somatosensory barrels alternate between functional states, one of which is usually associated with organism sleep and which is induced by TNF.  We are currently testing the hypothesis that sleep serves a synaptic plasticity function by examination of molecular events associated with synaptic reorganization and whether sleep affects those events.  For example, rats given a whisker cut on one side of the face change several molecular markers of synaptic plasticity in the contralateral somatosensory cortex, e.g. GAD 67, and NGF.  The direction of the change was dependent upon the nature of the ongoing synaptic reorganization.

Obl F Jr, Garcia-Garcia F, Kacsh B, Taishi P, Bohnet S, Horseman ND, Krueger JM.  (2005)  REM sleep is reduced in prolactin deficient mice.  J Neurosci 25: 10282-10289.

Szentirmai , Hajdu I, Obl F Jr, Krueger JM.  (2006)  Ghrelin-induced sleep responses in ad libitum fed and food restricted rats.  Brain Res 1088: 131-140.

Szentirmai , Krueger JM.  (2006)  Central administration of neuropeptides Y induces wakefulness in rats.  Am J Physiol 291: R473-R480.

Peterfi Z, Obl F Jr, Taishi P, Gardi J, Kacsh B, Unterman T, Krueger JM.  (2006)  Sleep in spontaneous dwarf rats.  Brain Res 1108: 133-146.

Szentirmai , Krueger JM.  (2006)  Obestatin alters sleep in rats.  Neurosci Lett 404: 222-226.

Churchill L, Taishi P, Wang M, Brandt J, Cearley C, Krueger JM.  (2006)  Brain distribution of cytokine mRNA induced by systemic administration of interleukin-1 or tumor necrosis factor α.  Brain Res 1120: 64-73.

Traynor T, Majde JA, Bohnet S, Krueger JM.  (2007)  Interferon type I receptor-deficient mice have altered disease symptoms in response to influenza virus.  Brain Behav Immunity 21: 311-322.

Szentirmai , Kaps L, Krueger JM.  (2007)  Ghrelin microinjection into forebrain sites induces wakefulness and feeding in rats.  Am J Physiol 292: R575-R585.

Yasuda K, Churchill L, Yasuda T, Blindheim K, Falter M, Krueger JM (2007) Unilateral cortical application of interleukin-1b (IL1b) induces asymmetry in Fos- and IL1b-immunoreactivity: Implications for sleep regulation.  Brain Res 1131: 44-59.

Cambras T, Weller JR, Angles-Pujoras M, Lee M, Christopher H, Oiez-Noguera A, Krueger JM, de la Iglesia H.  (2007) Desynchronization of core body temperature and sleep stages is associated with uncoupling of oscillators within the master circadian clock.  Proc Natl Acad Sci.  104: 7634-7639.

Majde JA, Bohnet SG, Ellis GA, Churchill L, Leyva-Grado V, Wu M, Szentirmai , Rehman A, Krueger JM.  (2007)  Detection of a mouse-adapted human influenza virus in the olfactory bulb of mice within hours after intranasal infection.  J NeuroVirol 13: 399-409.

Szentirmai , Kaps L, Sun Y, Smith RG, Krueger JM.  (2007)  Spontaneous sleep and homeostatic sleep regulation in ghrelin knockout mice.  Am J Physiol 293: R510-R517.

Manoranjan VS, Rajapakse I, Krueger JM.  (2006)  Oscillation in a neuronal assembly – A phenomenological model.  Int J Computa Appl Math 1:57-64.

Taishi P, Churchill L, Wang M, Kay D, Davis CJ, Guan X, De A, Yasuda T, Liao F, Krueger JM.  (2007)  TNFa siRNA reduces brain TNF and EEG delta wave activity in rats.  Brain Res 1156: 125-132.

Davis CJ, Bohnet SG, Meyerson JM, Krueger JM.  (2007)  Sleep loss changes microRNA levels in the brain: A possible mechanism for state-dependent translational regulation.  Neurosci Lett 422: 68-73.

Szentirmai , Yasuda T, Taishi P, Wang W, Churchill L, Bohnet S, Magrath P, Kacsh B, Jimenez L, Krueger JM.  (2007)  Growth hormone releasing hormone: Cerebral cortical sleep-related EEG actions and expression.  Am J Physiol 293: R922-R930.

Krueger JM.  What exactly is it that sleeps?  The evolution, regulation and organization of an emergent network property. (2009) In: The Evolution of Sleep: Phylogenetic and Functional Perspectives.  P McNamara, R Barton, C Nunn (eds); Cambridge University Press.  Pp 86-106.

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.

Roy S, Krueger JM, Rector DM, Wan Y. (2008)  Network models for activity-dependent sleep regulation.  J Theor Biol.  253:462-468.

Krueger JM.  The role of cytokines in sleep regulation.  (2008) Current Pharm Design 14:3408-3416. 

Kaps L, Bohnet S, Traynor T, Majde JA, Szentirmai , Magrath P, Taishi P, Krueger JM. (2008)  Spontaneous and influenza virus-induced sleep are altered in TNFα double receptor deficient mice.  J Appl Physiol 105:1187-1198.

Taishi P, Churchill L, De A, Obal Jr F, Krueger JM.  (2008) Cytokine mRNA induction by interleukin-1 beta or tumor necrosis factor alpha in vitro and in vivo.  Brain Res. 1226:89-98.

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.

Peterfi Z, Makara GB, Obal Jr F, Krueger JM (2009) The anterolateral projections of the medial basal hypothalamus affect sleep.  Am. J. Physiol. 296:R1228-R1238.

Rector DM, Schei JL, Van Dongen HPA, Belenky G, Krueger JM. (2009)  Physiological markers of localized sleep.  Europ. J. Neurosci. 29:1771-1778.

Krueger JM, Szentirmai E, Kapas L. (2009) The biochemistry of sleep function.  SRS Basics of Sleep Guide; Sleep Research Society CJ Amlaner, PM Fuller editors, pp 69-74.

Leyva-Grado V, Churchill L, Wu M, Williams, TJ, Taishi P, Majde JA, Krueger JM.  (2009) Influenza virus- and cytokine-immunoreactive cells in the murine olfactory pathway and hypothalamus before and after illness onset. J. Neuroimmunol. 211:73-83.

May U, Schiffelholz T, Baier PC, Krueger JM, Rose-John S, Scheller J. (2009) IL-6trans-signalling increases rapid eye-movement sleep in rats.  European. J. Pharmacology 613:141-145.

Szentirmai , Kaps L, Sun Y, Smith RG, Krueger JM.  The preproghrelin gene is required for normal integration of thermoregulation and sleep in mice.  Proc. Natl. Acad. Sci. USA (in press).