Signs of enhanced sleep and sleep-associated memory processing following the anti-inflammatory antibiotic minocycline in men

Pro-inflammatory cytokines can promote sleep and neuronal processes underlying memory formation. However, this has mainly been revealed in animal studies. In this double-blind, placebo-controlled within-subject designed study, we examined how changes in the balance between pro- and anti-inflammatory signalling affect sleep and sleep-associated memory consolidation in humans. After learning declarative memory tasks (word pairs, texts) and a procedural memory task (finger tapping) in the evening, 21 healthy young men orally received either 200 mg of the anti-inflammatory antibiotic minocycline or placebo shortly before nocturnal sleep. Sleep was allowed between 23:00 and 07:00 h and recorded polysomnographically. Retrieval of memories was tested two days later. Because of outliers or missing data, final sample size was reduced to n = 14–19. Our data suggest that rather than weakening sleep as expected based on animal studies, the anti-inflammatory agent promoted sleep and memory consolidation. Specifically, minocycline increased slow-wave activity (0.68–4.0 Hz) during non-rapid eye movement sleep stage 2 and selectively enhanced episodic aspects in memory (i.e. memory for the temporal order of events in the texts). In combination with previous results, our findings indicate that, in humans, reducing pro-inflammatory signalling can act towards deepening non-rapid eye movement sleep and enhancing its memory forming efficacy.

[1]  J. Born,et al.  Effects of an interleukin-1 receptor antagonist on human sleep, sleep-associated memory consolidation, and blood monocytes , 2015, Brain, Behavior, and Immunity.

[2]  D. Kelly,et al.  Adjunctive Minocycline in Clozapine-Treated Schizophrenia Patients With Persistent Symptoms , 2015, Journal of clinical psychopharmacology.

[3]  R. Pi,et al.  Minocycline enhances hippocampal memory, neuroplasticity and synapse-associated proteins in aged C57 BL/6 mice , 2015, Neurobiology of Learning and Memory.

[4]  Zili You,et al.  Phenotypic dysregulation of microglial activation in young offspring rats with maternal sleep deprivation-induced cognitive impairment , 2015, Scientific Reports.

[5]  M. Xiao,et al.  Minocycline upregulates cyclic AMP response element binding protein and brain-derived neurotrophic factor in the hippocampus of cerebral ischemia rats and improves behavioral deficits , 2015, Neuropsychiatric disease and treatment.

[6]  N. Tronson,et al.  Modulation of learning and memory by cytokines: Signaling mechanisms and long term consequences , 2014, Neurobiology of Learning and Memory.

[7]  H. Kettenmann,et al.  Minocycline rescues decrease in neurogenesis, increase in microglia cytokines and deficits in sensorimotor gating in an animal model of schizophrenia , 2014, Brain, Behavior, and Immunity.

[8]  B. Baune,et al.  TNF-α and its receptors modulate complex behaviours and neurotrophins in transgenic mice , 2013, Psychoneuroendocrinology.

[9]  I. Wilhelm,et al.  Differential contribution of mineralocorticoid and glucocorticoid receptors to memory formation during sleep , 2013, Psychoneuroendocrinology.

[10]  J. Kipnis,et al.  Learning and memory … and the immune system , 2013, Learning & memory.

[11]  D. Balschun,et al.  A cytokine network involving brain-borne IL-1β, IL-1ra, IL-18, IL-6, and TNFα operates during long-term potentiation and learning , 2013, Brain, Behavior, and Immunity.

[12]  A. Zarzuelo,et al.  Minocycline: far beyond an antibiotic , 2013, British journal of pharmacology.

[13]  S. Bilbo,et al.  Chemokines and the hippocampus: A new perspective on hippocampal plasticity and vulnerability , 2013, Brain, Behavior, and Immunity.

[14]  J. Sandkühler,et al.  Induction of Thermal Hyperalgesia and Synaptic Long-Term Potentiation in the Spinal Cord Lamina I by TNF-α and IL-1β is Mediated by Glial Cells , 2013, The Journal of Neuroscience.

[15]  J. Born,et al.  About sleep's role in memory. , 2013, Physiological reviews.

[16]  Jan Born,et al.  Opposite Effects of Cortisol on Consolidation of Temporal Sequence Memory during Waking and Sleep , 2011, Journal of Cognitive Neuroscience.

[17]  Inbal Goshen,et al.  Astrocytes support hippocampal-dependent memory and long-term potentiation via interleukin-1 signaling , 2011, Brain, Behavior, and Immunity.

[18]  J. Wisor,et al.  Quantification of short-term slow wave sleep homeostasis and its disruption by minocycline in the laboratory mouse , 2011, Neuroscience Letters.

[19]  William C Clegern,et al.  Evidence for neuroinflammatory and microglial changes in the cerebral response to sleep loss. , 2011, Sleep.

[20]  J. Born,et al.  The memory function of sleep , 2010, Nature Reviews Neuroscience.

[21]  Y. Levkovitz,et al.  A double-blind, randomized study of minocycline for the treatment of negative and cognitive symptoms in early-phase schizophrenia. , 2010, The Journal of clinical psychiatry.

[22]  M. Irwin,et al.  Tumor Necrosis Factor Antagonism Normalizes Rapid Eye Movement Sleep in Alcohol Dependence , 2009, Biological Psychiatry.

[23]  T. Bártfai,et al.  IL-1/IL-1ra balance in the brain revisited – Evidence from transgenic mouse models , 2009, Brain, Behavior, and Immunity.

[24]  Björn Rasch,et al.  Pharmacological REM sleep suppression paradoxically improves rather than impairs skill memory , 2009, Nature Neuroscience.

[25]  M. Opp,et al.  How (and why) the immune system makes us sleep , 2009, Nature Reviews Neuroscience.

[26]  J. Panksepp,et al.  Sleep as a fundamental property of neuronal assemblies , 2008, Nature Reviews Neuroscience.

[27]  I. Goshen,et al.  A dual role for interleukin-1 in hippocampal-dependent memory processes , 2007, Psychoneuroendocrinology.

[28]  Fiona C Baker,et al.  Circadian rhythms, sleep, and the menstrual cycle. , 2007, Sleep medicine.

[29]  J. Krueger,et al.  Sleep and Cytokines. , 2007, Sleep medicine clinics.

[30]  A. Gottlieb,et al.  Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial , 2006, The Lancet.

[31]  R. Omdal,et al.  The effect of interleukin-1 blockade on fatigue in rheumatoid arthritis—a pilot study , 2005, Rheumatology International.

[32]  E. Bixler,et al.  Marked decrease in sleepiness in patients with sleep apnea by etanercept, a tumor necrosis factor-alpha antagonist. , 2004, The Journal of clinical endocrinology and metabolism.

[33]  J. Krueger,et al.  Biochemical regulation of non-rapid-eye-movement sleep. , 2003, Frontiers in bioscience : a journal and virtual library.

[34]  J. Carrier,et al.  Age‐related modifications of NREM sleep EEG: from childhood to middle age , 2001, Journal of sleep research.

[35]  J. Born,et al.  INTERFERON-α ACUTELY IMPAIRS SLEEP IN HEALTHY HUMANS , 2000 .

[36]  T. Pollmächer,et al.  Experimental Immunomodulation, Sleep, and Sleepiness in Humans , 2000, Annals of the New York Academy of Sciences.

[37]  F. Holsboer,et al.  Effects of granulocyte colony-stimulating factor on night sleep in humans. , 1999, American journal of physiology. Regulatory, integrative and comparative physiology.

[38]  Detlef Balschun,et al.  A neuromodulatory role of interleukin-1β in the hippocampus , 1998 .

[39]  J. Born,et al.  Acute effects of recombinant human interleukin-6 on endocrine and central nervous sleep functions in healthy men. , 1998, The Journal of clinical endocrinology and metabolism.

[40]  F. Holsboer,et al.  Influence of endotoxin on nocturnal sleep in humans. , 1993, The American journal of physiology.

[41]  Y. Nakazawa,et al.  Effects of antibiotics, minocycline and ampicillin, on human sleep , 1983, Brain Research.

[42]  W. Dement,et al.  Quantification of sleepiness: a new approach. , 1973, Psychophysiology.

[43]  A. Zarzuelo,et al.  What is behind the non-antibiotic properties of minocycline? , 2013, Pharmacological research.

[44]  I. Goshen,et al.  Impaired interleukin‐1 signaling is associated with deficits in hippocampal memory processes and neural plasticity , 2003, Hippocampus.

[45]  F. Pitossi,et al.  A neuromodulatory role of interleukin-1beta in the hippocampus. , 1998, Proceedings of the National Academy of Sciences of the United States of America.