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


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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    ABSTRACT: Brain-derived neurotrophic factor (BDNF) deficiency confers vulnerability to stress, but the mechanisms are unclear. BDNF(+/-) mice exhibit behavioral, physiological and neurochemical changes following low-level stress that are hallmarks of major depression. After immune challenge, neuroinflammation-induced changes in tryptophan metabolism along the kynurenine pathway mediate depressive-like behaviors. We hypothesized that BDNF(+/-) mice would be more susceptible to stress-induced neuroinflammation and kynurenine metabolism, so BDNF(+/-) or wild-type littermate mice were subject to repeated unpredictable mild stress (UMS). Proinflammatory cytokine expression and kynurenine metabolites were measured. UMS did not induce neuroinflammation. However, only wild-type mice produced the neuroprotective factors interleukin-10 and kynurenic acid in response to repeated UMS. In BDNF(+/-) mice, kynurenine was metabolized preferentially to the neurotoxic intermediate 3-hydroxykynurenine following repeated UMS. Our data suggest that BDNF may modulate kynurenine pathway metabolism during stress, and provide a novel molecular mechanism of vulnerability and resilience to the development of stress-precipitated psychiatric disorders. © The Author 2015. Published by Oxford University Press on behalf of CINP.
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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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    ABSTRACT: Environmental enrichment (EE) that combines voluntary physical exercise, sensory and social stimuli, causes profound changes in rodent brain at molecular, anatomical and behavioral levels. Here, we show that EE efficiently reduces anxiety and depression-like behaviors in a mouse model of depression induced by long-term administration of corticosterone. Mechanisms underlying EE-related beneficial effects remain largely unexplored; however, our results point toward adiponectin, an adipocyte-secreted protein, as a main contributor. Indeed, adiponectin-deficient (adipo(-/-)) mice did not benefit from all the EE-induced anxiolytic and antidepressant-like effects as evidenced by their differential responses in a series of behavioral tests. Conversely, a single intravenous injection of exogenous adiponectin restored the sensitivity of adipo(-/-) mice to EE-induced behavioral benefits. Interestingly, adiponectin depletion did not prevent the hippocampal neurogenesis induced by EE. Therefore, antidepressant properties of adiponectin are likely to be related to changes in signaling in the hypothalamus rather than through hippocampal-neurogenesis mechanisms. Additionally, EE did not modify the plasma levels of adiponectin but may favor the passage of adiponectin from the blood to the cerebrospinal fluid. Our findings provide advances in the understanding of the anxiolytic and antidepressant-like effects of EE and highlight adiponectin as a pivotal mediator. Copyright © 2015 Elsevier Ltd. All rights reserved.
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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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