Brain, behavior, and immunity
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Brain Behav. Immun. · Jul 2016
Spinal inhibition of p38 MAP kinase reduces inflammatory and neuropathic pain in male but not female mice: Sex-dependent microglial signaling in the spinal cord.
Previous studies have shown that activation of p38 mitogen-activating kinase (MAPK) in spinal microglia participates in the generation of inflammatory and neuropathic pain in various rodent models. However, these studies focused on male mice to avoid confounding effects of the estrous cycle of females. Recent studies have shown that some spinal pro-inflammatory signaling such as Toll-like receptor 4-mediated signaling contributes to pain hypersensitivity only in male mice. ⋯ Notably, intraperitoneal or local perineural administration of skepinone inhibited CCI-induced mechanical allodynia in both sexes of mice. Finally, skepinone only reduced the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in lamina IIo neurons of spinal cord slices of males 7days post CCI. Therefore, the sex-specific p38 activation and signaling is confined to the spinal cord in inflammatory and neuropathic pain conditions.
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Brain Behav. Immun. · Jul 2016
The redox state of the alarmin HMGB1 is a pivotal factor in neuroinflammatory and microglial priming: A role for the NLRP3 inflammasome.
The alarmin high mobility group box-1 (HMGB1) has been implicated as a key factor mediating neuroinflammatory processes. Recent findings suggest that the redox state of HMGB1 is a critical molecular feature of HMGB1 such that the reduced form (fr-HMGB1) is chemotactic, while the disulfide form (ds-HMGB1) is pro-inflammatory. The present study examined the neuroinflammatory effects of these molecular forms as well as the ability of these forms to prime the neuroinflammatory and microglial response to an immune challenge. ⋯ Moreover, the present findings demonstrate for the first time that ds-HMGB1 directly potentiates the microglia pro-inflammatory response to an immune challenge, a finding that parallels the effects of ds-HMGB1 in vivo. In addition, ds-HMGB1 induced expression of NLRP3 and NF-κBIα in vivo and in vitro suggesting that the NLRP3 inflammasome may play role in the priming effects of ds-HMGB1. Taken together, the present results suggest that the redox state of HMGB1 is a critical determinant of the priming properties of HMGB1 such that the disulfide form of HMGB1 induces a primed immunophenotype in the CNS, which may result in an exacerbated neuroinflammatory response upon exposure to a subsequent pro-inflammatory stimulus.
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Brain Behav. Immun. · Jul 2016
Maternal separation activates microglial cells and induces an inflammatory response in the hippocampus of male rat pups, independently of hypothalamic and peripheral cytokine levels.
Adult animals subjected to chronic stress show an inflammatory response in the hippocampus which has been related to cognitive dysfunction and psychopathology. However the immediate consequences of early life stress on hippocampal glial cells have not been studied. Here we analyzed the effects of maternal separation (MS) on astrocyte and microglial cell morphology in the hippocampal hilus, compared the expression of cytokines in the hippocampus and hypothalamus, and the peripheral response of cytokines, on postnatal day (PD) 15. ⋯ A differential cytokine expression is observed in the hippocampus and the hypothalamus after MS, and after SS. Also, MS triggers an independent response of peripheral cytokines. These specific responses together could contribute to decrease hippocampal neurogenesis and alter the neuroendocrine axis.
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Brain Behav. Immun. · May 2016
Randomized Controlled TrialAlterations in functional connectivity of resting state networks during experimental endotoxemia - An exploratory study in healthy men.
Systemic inflammation impairs mood and cognitive functions, and seems to be involved in the pathophysiology of psychiatric disorders. Functional magnetic resonance imaging (fMRI) studies revealed altered task-related blood-oxygen-level-dependent (BOLD) responses during experimental endotoxemia, but little is known about effects of systemic inflammation on resting-state activity of the brain. Thus, we conducted a randomized, placebo-controlled study in healthy men receiving an intravenous injection of either low-dose (0.4 ng/kg) lipopolysaccharide (LPS) (N=20) or placebo (N=25). ⋯ Seed based analysis revealed greater functional connectivity between the left thalamus and the cerebellum after LPS compared to placebo administration, while the functional coupling between seeds within the amygdala, insula, and cingulate cortex and various brain regions including parieto-frontal networks was significantly reduced. Within the LPS group, endotoxin-induced increases in Interleukin (IL)-6 were significantly associated with resting-state connectivity between the left thalamus and left precuneus as well as the right posterior cingulate cortex. In summary, this exploratory study provides first evidence that systemic inflammation affects the coupling and regulation of multiple networks within the human brain at rest.
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Brain Behav. Immun. · May 2016
Cognitive deficits develop 1month after diffuse brain injury and are exaggerated by microglia-associated reactivity to peripheral immune challenge.
Traumatic brain injury (TBI) elicits immediate neuroinflammatory events that contribute to acute cognitive, motor, and affective disturbance. Despite resolution of these acute complications, significant neuropsychiatric and cognitive issues can develop and progress after TBI. We and others have provided novel evidence that these complications are potentiated by repeated injuries, immune challenges and stressors. A key component to this may be increased sensitization or priming of glia after TBI. Therefore, our objectives were to determine the degree to which cognitive deterioration occurred after diffuse TBI (moderate midline fluid percussion injury) and ascertain if glial reactivity induced by an acute immune challenge potentiated cognitive decline 30 days post injury (dpi). In post-recovery assessments, hippocampal-dependent learning and memory recall were normal 7 dpi, but anterograde learning was impaired by 30 dpi. Examination of mRNA and morphological profiles of glia 30 dpi indicated a low but persistent level of inflammation with elevated expression of GFAP and IL-1β in astrocytes and MHCII and IL-1β in microglia. Moreover, an acute immune challenge 30 dpi robustly interrupted memory consolidation specifically in TBI mice. These deficits were associated with exaggerated microglia-mediated inflammation with amplified (IL-1β, CCL2, TNFα) and prolonged (TNFα) cytokine/chemokine expression, and a marked reactive morphological profile of microglia in the CA3 of the hippocampus. Collectively, these data indicate that microglia remain sensitized 30 dpi after moderate TBI and a secondary inflammatory challenge elicits robust microglial reactivity that augments cognitive decline. ⋯ Traumatic brain injury (TBI) is a major risk factor in development of neuropsychiatric problems long after injury, negatively affecting quality of life. Mounting evidence indicates that inflammatory processes worsen with time after a brain injury and are likely mediated by glia. Here, we show that primed microglia and astrocytes developed in mice 1 month following moderate diffuse TBI, coinciding with cognitive deficits that were not initially evident after injury. Additionally, TBI-induced glial priming may adversely affect the ability of glia to appropriately respond to immune challenges, which occur regularly across the lifespan. Indeed, we show that an acute immune challenge augmented microglial reactivity and cognitive deficits. This idea may provide new avenues of clinical assessments and treatments following TBI.