Article

Wohleb ES, Hanke ML, Corona AW, Powell ND, Stiner LM, Bailey MT et al. β-Adrenergic receptor antagonism prevents anxiety-like behavior and microglial reactivity induced by repeated social defeat. J Neurosci 31: 6277-6288

Division of Oral Biology, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio 43210, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 04/2011; 31(17):6277-88. DOI: 10.1523/JNEUROSCI.0450-11.2011
Source: PubMed

ABSTRACT

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, innate immune cells of the brain, produce proinflammatory cytokines interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α when activated, and these cytokines stimulate the induction of the kynurenine pathway. Chronic or severe stress results in increased production of proinflammatory cytokines by activated microglia (Wohleb et al., 2011;Patki et al., 2013). Thus, central inflammation and kynurenine metabolism may be one of the factors linking stress with depression. "
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    • "Anxiety-like behavior was determined using the OF and L&D preference tests as previously described (Kinsey et al., 2007; Bailey et al., 2009; Wohleb et al., 2011). For the OF test, mice were placed in the corner of the test apparatus (45L × 45W × 25H cm Plexiglas box) and activity was recorded for 5 min. "
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    • "More recently, research has focused on stress-evoked priming of brain myeloid cells, i.e., microglia. This area of inquiry has rapidly increased with evidence of stress-evoked microglia arousal occurring following a vast array of stressors including experimental stressors (e.g., tailshock (Frank et al., 2012), social defeat (Wohleb et al., 2011), prenatal stress (Diz-Chaves et al., 2012)), physiological stressors (e.g., aging (Morgan et al., 1999; Wynne et al., 2009), high fat diet (Grayson et al., 2010), radiation (Schnegg et al., 2012)), and alcohol (Cooper et al., 2012; Ehrlich et al., 2012; McClain et al., 2011). Fig. 1B depicts the results of a PubMed search of the literature using the key words microglia and stress. "

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