The Role of the Vagus Nerve in Cytokine-to-Brain Communication

Department of Psychology, University of Colorado, Boulder 80309, USA.
Annals of the New York Academy of Sciences (Impact Factor: 4.38). 06/1998; 840(1):289-300. DOI: 10.1111/j.1749-6632.1998.tb09569.x
Source: PubMed


Peripheral interleukin-1 beta (IL-beta) and inflammatory stimuli that induce the synthesis and release of IL-1 beta produce a variety of central nervous system responses. Most proposals designed to explain how peripheral IL-1 beta influences the CNS have focused on blood-borne routes of communication. We will review data that indicate that at least some of the CNS response to peripheral IL-1 beta are instead mediated by a neural route of communication between the periphery and the CNS. IL-1 beta activates afferent vagal fibers that terminate in the nucleus tractus solitarius, and communication via the vagus is responsible for much of the hyperalgesia, fever, anorexia, taste aversions, increased levels of plasma corticosteroid, and brain norepinephrine changes produced by intraperitoneal injections of IL-1 beta and LPS. Data extending this analysis to TNF-alpha and intravenous routes will be described.

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    • "Similarly, peripheral vagus nerve stimulation has been shown to induce production of anti-inflammatory cytokines in the neurovasculature of animals treated with LPS injection, suggesting that the activity of vagal afferents is able to modulate the brain's protective immune response (Mihaylova et al. 2012). Even cytokines and inflammation in the peripheral circulation have been shown to activate vagal afferents and modulate anti-inflammatory effects in the central nervous system (CNS) (Maier et al. 1998). It is therefore plausible that the humoral communication of cytokines to the brain is potentiated or permitted in the face of altered vagal signaling from the gut due to microbial imbalance. "
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    ABSTRACT: Neuroimmune and inflammatory processes have been locally associated with the amygdala in alcohol exposure and withdrawal. We and others have suggested that this inflammation in the amygdala may cause disturbance of neural function observed as anxiety and autonomic distress in withdrawal. Despite the potential importance of the robust neuroinflammatory response, the mechanisms contributing to this response are not well understood. We review literature that suggests the effects of alcohol, and other substances of abuse, cause dysbiosis of the gut microbiome. This peripheral response may modulate neuroprotective vagal afferent signaling that permits and exacerbates a neuroinflammatory response in the amygdala. We will examine the mounting evidence that suggests that (1) gut dysbiosis contributes to neuroinflammation, especially in the context of alcohol exposure and withdrawal, (2) the neuroinflammation in the amygdala involves the microglia and astrocytes and their effect on neural cells, and (3) amygdala neuroinflammation itself contributes directly to withdrawal behavior and symptoms. The contribution of the gut to an anxiogenic response is a promising therapeutic target for patients suffering with withdrawal symptoms given the safe and well-established methods of modulating the gut microbiome. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Jul 2015 · Progress in Neuro-Psychopharmacology and Biological Psychiatry
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    • "cytokines cross the blood brain barrier via an endocrine - like mechanism and activate microglia ( Maier et al . , 1998 ; Lee et al . , 2010 ; Ousman and Kubes , 2012 ) . We sought to evaluate the microglial Ca 2+ response in the brains of mice that were subjected to peripheral inflammation . In agreement with previous observations ( Gyoneva et al . , 2014 ) , imaging 24 h after subcutaneous LPS administration to the lower lip revealed that all microglia"
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    ABSTRACT: Microglia, the resident immune cells of the brain parenchyma, are highly responsive to tissue injury. Following cell damage, microglial processes redirect their motility from randomly scouting the extracellular space to specifically reaching toward the compromised tissue. While the cell morphology aspects of this defense mechanism have been characterized, the intracellular events underlying these responses remain largely unknown. Specifically, the role of intracellular Ca(2+) dynamics has not been systematically investigated in acutely activated microglia due to technical difficulty. Here we used live two-photon imaging of the mouse cortex ubiquitously expressing the genetically encoded Ca(2+) indicator GCaMP5G and fluorescent marker tdTomato in central nervous system microglia. We found that spontaneous Ca(2+) transients in microglial somas and processes were generally low (only 4% of all microglia showing transients within 20 min), but baseline activity increased about 8-fold when the animals were treated with LPS 12 h before imaging. When challenged with focal laser injury, an additional surge in Ca(2+) activity was observed in the somas and protruding processes. Notably, coherent and simultaneous Ca(2+) rises in multiple microglial cells were occasionally detected in LPS-treated animals. We show that Ca(2+) transients were pre-dominantly mediated via purinergic receptors. This work demonstrates the usefulness of genetically encoded Ca(2+) indicators for investigation of microglial physiology.
    Full-text · Article · May 2015 · Frontiers in Molecular Neuroscience
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    • "Lipopolysaccharide (LPS) mimics Gram negative infection by activating Toll-like receptor 4, which in turn initiates intracellular signaling events that lead to the synthesis of a variety of pro-inflammatory molecules such as interleukin (IL)-1b, IL-6 and tumor necrosis factor (TNF)-a (Blatteis et al., 2004; Dinarello, 1999; Steiner et al., 2006). These molecules activate the central nervous system and de novo synthesis of cytokines within the brain that are responsible for the initiation of fever and its accompanying constellation of behavioral and cognitive disruptions (i.e., sleep changes, lethargy, performance disruptions on memory tasks, reduced food and water intake, etc.), known as sickness behaviors (Maier et al., 1998). In animal models of MIA, these behavioral and physiological markers can be used to verify the initiation of the sickness response (French et al., 2013), without stressing the mother by collecting serological samples to confirm inflammation. "
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    ABSTRACT: Modest environmental enrichment (EE) is well recognized to protect and rescue the brain from the consequences of a variety of insults. Although animal models of maternal immune activation (MIA) are associated with several neurodevelopmental impairments in both the behavioral and cognitive functioning of offspring, the impact of EE in protecting or reversing these effects has not been fully evaluated. In the present study, female Sprague-Dawley rats were randomized into EE (pair-housed in a large multi-level cage with toys, tubes and ramps) or animal care control (ACC; pair-housed in standard cages) conditions. Each pair was bred, following assignment to their housing condition, and administered 100 ug/kg of lipopolysaccharide (LPS) on gestational day 11. After birth, and until the end of the study, offspring were maintained in their respective housing conditions. EE protected against both the social and hypothalamic pituitary adrenal axis consequences of MIA in juvenile male rats, but surprisingly not against the spatial discrimination deficits or accompanying decrease in glutamate levels within the hippocampus (as measured via LCMS-MS). Based on these preliminary results, the mechanisms that underlie the sex-specific consequences that follow MIA appear to be dependent on environmental context. Together, this work highlights the importance of environmental complexity in the prevention of neurodevelopmental deficits following MIA.
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