Minocycline Modulates Human Social Decision-Making: Possible Impact of Microglia on Personality-Oriented Social Behaviors

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Abstract

Background

Microglia, one of the glial cells, play important roles in various brain pathologies including psychiatric disorders. In addition, microglia have recently been proved to monitor synaptic reactions via direct-touching even in normal brain. Human microglia may modulate various social/mental functions, while microglial social/mental roles remain unresolved especially in healthy humans. There is no known drug with the specific effect of modulating microglia. Therefore, using minocycline, a tetracycline antibiotic and the most famous microglial inhibitor, is one of the best alternative approaches to clarify microglial functions on human social/mental activities.

Methodology/Principal Findings

We conducted a double-blind randomized trial of trust game, a monetary decision-making experiment, with ninety-nine human adult males who decided how much to trust an anonymous partner after a four-day administration of minocycline. Our previous pilot trial indicated a positive effect of minocycline, while the underlying mechanisms were not clarified. Therefore, in this trial with larger samples, we additionally measured the effects of anxiety and personality. The monetary score in trust game was significantly lower in the minocycline group. Interestingly, participants’ ways of decision-making were significantly shifted; cooperativeness, one component of personality, proved to be the main modulating factor of decision-making in the placebo group, on the other hand, the minocycline group was mainly modulated by state anxiety and trustworthiness.

Conclusions/Significance

Our results suggest that minocycline led to more situation-oriented decision-making, possibly by suppressing the effects of personality traits, and furthermore that personality and social behaviors might be modulated by microglia. Early-life events may activate human microglia, establish a certain neuro-synaptic connection, and this formation may determine each human’s personality and personality- oriented social behaviors in later life. To explore these mechanisms, further translational research is needed.

Trial Registration

UMIN clinical trial center UMIN000004803

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Most cited references 40

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Microglial activation and increased microglial density observed in the dorsolateral prefrontal cortex in autism.

John T. Morgan, Gursharan Chana, Carlos A Pardo … (2010)

In the neurodevelopmental disorder autism, several neuroimmune abnormalities have been reported. However, it is unknown whether microglial somal volume or density are altered in the cortex and whether any alteration is associated with age or other potential covariates. Microglia in sections from the dorsolateral prefrontal cortex of nonmacrencephalic male cases with autism (n = 13) and control cases (n = 9) were visualized via ionized calcium binding adapter molecule 1 immunohistochemistry. In addition to a neuropathological assessment, microglial cell density was stereologically estimated via optical fractionator and average somal volume was quantified via isotropic nucleator. Microglia appeared markedly activated in 5 of 13 cases with autism, including 2 of 3 under age 6, and marginally activated in an additional 4 of 13 cases. Morphological alterations included somal enlargement, process retraction and thickening, and extension of filopodia from processes. Average microglial somal volume was significantly increased in white matter (p = .013), with a trend in gray matter (p = .098). Microglial cell density was increased in gray matter (p = .002). Seizure history did not influence any activation measure. The activation profile described represents a neuropathological alteration in a sizeable fraction of cases with autism. Given its early presence, microglial activation may play a central role in the pathogenesis of autism in a substantial proportion of patients. Alternatively, activation may represent a response of the innate neuroimmune system to synaptic, neuronal, or neuronal network disturbances, or reflect genetic and/or environmental abnormalities impacting multiple cellular populations. Copyright 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

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β-Adrenergic receptor antagonism prevents anxiety-like behavior and microglial reactivity induced by repeated social defeat.

Eric Wohleb, Mark L. Hanke, Angela W Corona … (2011)

Psychosocial stress is associated with altered immune function and development of psychological disorders including anxiety and depression. Here we show that repeated social defeat in mice increased c-Fos staining in brain regions associated with fear and threat appraisal and promoted anxiety-like behavior in a β-adrenergic receptor-dependent manner. Repeated social defeat also significantly increased the number of CD11b(+)/CD45(high)/Ly6C(high) macrophages that trafficked to the brain. In addition, several inflammatory markers were increased on the surface of microglia (CD14, CD86, and TLR4) and macrophages (CD14 and CD86) after social defeat. Repeated social defeat also increased the presence of deramified microglia in the medial amygdala, prefrontal cortex, and hippocampus. Moreover, mRNA analysis of microglia indicated that repeated social defeat increased levels of interleukin (IL)-1β and reduced levels of glucocorticoid responsive genes [glucocorticoid-induced leucine zipper (GILZ) and FK506 binding protein-51 (FKBP51)]. The stress-dependent changes in microglia and macrophages were prevented by propranolol, a β-adrenergic receptor antagonist. Microglia isolated from socially defeated mice and cultured ex vivo produced markedly higher levels of IL-6, tumor necrosis factor-α, and monocyte chemoattractant protein-1 after stimulation with lipopolysaccharide compared with microglia from control mice. Last, repeated social defeat increased c-Fos activation in IL-1 receptor type-1-deficient mice, but did not promote anxiety-like behavior or microglia activation in the absence of functional IL-1 receptor type-1. These findings indicate that repeated social defeat-induced anxiety-like behavior and enhanced reactivity of microglia was dependent on activation of β-adrenergic and IL-1 receptors.

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Microglia: biology and pathology.

Manuel Graeber, Wolfgang J Streit (2010)

The past 20 years have seen a gain in knowledge on microglia biology and microglia functions in disease that exceeds the expectations formulated when the microglia "immune network" was introduced. More than 10,000 articles have been published during this time. Important new research avenues of clinical importance have opened up such as the role of microglia in pain and in brain tumors. New controversies have also emerged such as the question of whether microglia are active or reactive players in neurodegenerative disease conditions, or whether they may be victims themselves. Premature commercial interests may be responsible for some of the confusion that currently surrounds microglia in both the Alzheimer and Parkinson's disease research fields. A critical review of the literature shows that the concept of "(micro)glial inflammation" is still open to interpretation, despite a prevailing slant towards a negative meaning. Perhaps the most exciting foreseeable development concerns research on the role of microglia in synaptic plasticity, which is expected to yield an answer to the question whether microglia are the brain's electricians. This review provides an analysis of the latest developments in the microglia field.

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Author and article information

Contributors

: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2012

Publication date (Electronic): 13 July 2012

Volume: 7

Issue: 7

Electronic Location Identifier: e40461

Affiliations

[1 ]Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

[2 ]Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Japan

[3 ]Graduate School of Economics, Waseda University, Waseda, Japan

[4 ]Department of Psychology, Graduate School of Letters, Kyoto University, Kyoto, Japan

[5 ]Graduate School of Human-Environment Studies, Kyushu University, Fukuoka, Japan

George Mason University/Krasnow Institute for Advanced Study, United States of America

Author notes

* E-mail: takahiro@ 123456npsych.med.kyushu-u.ac.jp (TAK); motokiw@ 123456gmail.com (MW)

Conceived and designed the experiments: TAK MW. Performed the experiments: TAK MW ST KI. Analyzed the data: MW. Contributed reagents/materials/analysis tools: TAK MW KH AM HU SK. Wrote the paper: TAK MW.

Article

Publisher ID: PONE-D-12-09453

DOI: 10.1371/journal.pone.0040461

PMC ID: 3396661

PubMed ID: 22808165

SO-VID: 23cf689b-6808-4e37-9a19-72d3ee296596

Copyright © Kato et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 1 April 2012

Date accepted : 7 June 2012

Page count

Pages: 9

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Minocycline Modulates Human Social Decision-Making: Possible Impact of Microglia on Personality-Oriented Social Behaviors

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Abstract

Background

Methodology/Principal Findings

Conclusions/Significance

Trial Registration

Related collections

Thermal Imaging in Social Decision Making

Most cited references 40

Microglial activation and increased microglial density observed in the dorsolateral prefrontal cortex in autism.

β-Adrenergic receptor antagonism prevents anxiety-like behavior and microglial reactivity induced by repeated social defeat.

Microglia: biology and pathology.

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Cited by 18

Most referenced authors 479