Source Paper
β-Adrenergic Receptor Antagonism Prevents Anxiety-Like Behavior and Microglial Reactivity Induced by Repeated Social Defeat
Eric S. Wohleb, Mark L. Hanke, Angela W. Corona, Nicole D. Powell, La'Tonia M. Stiner et al.
Source Paper
Eric S. Wohleb, Mark L. Hanke, Angela W. Corona, Nicole D. Powell, La'Tonia M. Stiner et al.
Journal of Neuroscience • 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.
Objective: To determine if β-adrenergic receptor antagonism with propranolol prevents anxiety-like behavior and microglial reactivity induced by repeated social defeat stress
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Mice were subjected to repeated social defeat stress to induce anxiety-like behavior and immune activation
Note: This stress paradigm increased c-Fos staining in brain regions associated with fear and threat appraisal
“repeated social defeat in mice increased c-Fos staining in brain regions associated with fear and threat appraisal and promoted anxiety-like behavior”
Propranolol was administered to block β-adrenergic receptors during or after social defeat stress
Note: Propranolol prevented stress-dependent changes in microglia and macrophages
“The stress-dependent changes in microglia and macrophages were prevented by propranolol, a β-adrenergic receptor antagonist”
Behavioral testing was conducted to measure anxiety-like responses following social defeat with or without propranolol treatment
Note: Anxiety-like behavior was dependent on β-adrenergic receptor activation
“promoted anxiety-like behavior in a β-adrenergic receptor-dependent manner”
Brain tissue was collected and processed for c-Fos immunostaining to assess neuronal activation in fear and threat appraisal regions
Note: c-Fos staining was increased in brain regions associated with fear and threat appraisal after social defeat
“repeated social defeat in mice increased c-Fos staining in brain regions associated with fear and threat appraisal”
Brain tissue was analyzed by flow cytometry to quantify CD11b+/CD45high/Ly6Chigh macrophages and assess inflammatory markers on microglia and macrophages
Note: Markers assessed included CD14, CD86, and TLR4 on microglia and macrophages
“Repeated social defeat also significantly increased the number of CD11b+/CD45high/Ly6Chigh 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)”
Brain tissue sections from medial amygdala, prefrontal cortex, and hippocampus were examined for microglial morphology
Note: Deramified (activated) microglia were increased in these brain regions after social defeat
“Repeated social defeat also increased the presence of deramified microglia in the medial amygdala, prefrontal cortex, and hippocampus”
mRNA was extracted from microglia and analyzed for expression of inflammatory cytokines and glucocorticoid-responsive genes
Note: Interleukin-1β levels were increased while GILZ and FKBP51 levels were reduced after social defeat
“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)]”
Microglia were isolated from socially defeated and control mice, cultured ex vivo, and stimulated with lipopolysaccharide
Note: Microglia from defeated mice produced higher levels of IL-6, TNF-α, and MCP-1 compared to controls
“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”
IL-1 receptor type-1-deficient mice were subjected to repeated social defeat to assess the role of IL-1 signaling
Note: Social defeat increased c-Fos activation but did not promote anxiety-like behavior or microglia activation in IL-1R1-deficient mice
“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”
IL-1 receptor type-1-deficient mice were used in some experiments