Research in VCAPP/Neuroscience

My laboratory focuses 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 under-expressing 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.

 

Obal 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.

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.

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

Kapas 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. PMCID: PMC2576045

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. PMCID: PMC2586424

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. PMCID: PMC2698612

Rector DM, Schei JL, Van Dongen HPA, Belenky G, Krueger JM. (2009)  Physiological markers of localized sleep.  Europ. J. Neurosci. 29:1771-1778. PMCID: PMC2688439

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. PMCID: PMC2696569

May U, Schiffelholz T, Baier PC, Krueger JM, Rose-John S, Scheller J. (2009) IL-6 trans-signalling increases rapid eye-movement sleep in rats.  European. J. Pharmacology 613:141-145. PMID: 19383498

Szentirmai , Kaps 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.

Leyva-Grado V, Churchill L, Harding J, Krueger JM (2010) The olfactory nerve has a role in the body temperature and brain cytokine responses to influenza virus. Brain Beh. Immun. 24: 281-288. PMCID: PMC2729021

Majde JA, Kapas L, Bohnet SG, De A, Krueger JM. (2010) Attenuation of the influenza virus sickness behavior in mice deficient in Toll-like receptor 3. Brain Beh. Immun. 24: 306-315. PMCID: 2818367

Szentirmai E, Kapas L, Sun Y, Smith RG, Krueger JM (2010) Restricted feeding-induced sleep, activity and body temperature changes in normal and preproghrelin deficient mice. Am. J. Physiol. 298: R467-R477. PMCID: PMC2828180

Liao F, Taishi P, Churchill L, Urza JM, Krueger JM (2010) Localized suppression of cortical growth hormone releasing hormone receptors state-specifically attenuates EEG delta waves. J. Neurosci. 30:4151-4159. PMCID: PMC2846621

Hallett H, Churchill L, Taishi P, De A, Krueger JM (2010) Whisker stimulation increases expression of nerve growth factor and interleukin-1 beta immunoreactivity in the rat somatosensory cortex. Brain Res. 1333: 48-56. PMCID: PMC2879054

Hight K, Hallett H, Churchill L, De A, Boucher A, Krueger JM (2010) Time of day differences in the number of cytokine-, neurotrophin- and NeuN-immunoreactive cells in the rat somatosensory or visual cortex. Brain Res. 1337: 32-40. PMCID: PMC2892412

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. J Appl Physiol. 109:1318-1327. PMCID: PMC2980381

Krueger JM, Wisor JP. (2011) Local use-dependent sleep; an introduction. Current Topics in Medicinal Chemistry 11:2390-2391. PMCID: PMC3243827

Krueger JM, Tononi G. (2011) Local use-dependent sleep; synthesis of the new paradigm. Current Topics in Medicinal Chemistry 11:2490-2492.360. PMCID: PMC3248786

Gardi J, Nelson OL, Robbins CT, Szentirmai E, Kapas L, Krueger JM. (2011) Energy homeostasis regulatory peptides in hibernating grizzly bears. Gen. and Comp. Endocrinology 172:181-183. PMCID: PMC3263427

Davis, CJ, Clinton JM, Taishi P, Bohnet SG, Honn, KA, Krueger, JM. (2011) MicroRNA 132 alters sleep and varies with time in brain. J Appl. Physiol. 111:665-672. PMCID: PMC3174793

Hodgson NR, Bohnet SG, Majde JA, Krueger JM. Influenza virus pathophysiology and brain invasion in mice with functional and dysfunctional Mx1 genes. (2012) Brain, Behav. Immunity 26:83-89. PMCID: PMC3221813

Winters BD, Huang Y, Dong Y, Krueger JM. (2011) Sleep loss alters synaptic and intrinsic neuronal properties in mouse prefrontal cortex. Brain Res 1420:1-7. PMCID: PMC3205322

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. (In press).

Zielinski M, Taishi P, Clinton JM, Krueger JM. (2-12) 5’-ectonucleotidase knockout mice lack non-REM sleep responses to sleep deprivation. Europ. J. Neurosci. (in press).