Alcohol consumption and stress increase brain levels of known innate immune signaling molecules. Microglia, the innate immune cells of the brain, and neurons respond to alcohol, signaling through Toll-like receptors (TLRs), high-mobility group box 1 (HMGB1), miRNAs, pro-inflammatory cytokines and their associated receptors involved in signaling between microglia, other glia and neurons. Repeated cycles of alcohol and stress cause a progressive, persistent induction of HMGB1, miRNA and TLR receptors in brain that appear to underlie the progressive and persistent loss of behavioral control, increased impulsivity and anxiety, as well as craving, coupled with increasing ventral striatal responses that promote reward seeking behavior and increase risk of developing alcohol use disorders. Studies employing anti-oxidant, anti-inflammatory, anti-depressant, and innate immune antagonists further link innate immune gene expression to addiction-like behaviors. Innate immune molecules are novel targets for addiction and affective disorders therapies.

Communications temperature and pressure. X is dependent on the distinction between regions with weak and strong cohesion. The system is nevertheless easy to memorize and it fulfils the basic requirement of being less complicated to describe than the group of objects that it is applicable to.More important than any classification is that this scheme offers the preparative researcher a systematic way of thinking about possible new materials. If we want to find new sorbents extending the range of pore sizes found in zeolitetype 3(Y) materials, the X(0) classes with closed pores are of no interest and this leaves 9 classes. Inspection of Figure 1 suggests that 2(Y) materials with truly two-dimensional SUs and O(Y) materials with Y = 2 to 0 are unlikely candidates for new microporous solids, because they involve structural units of complicated shape that in some cases must be arranged in a very precise fashion.The remaining types of solid, i.e. 1 (3), 1(2), 111) and O (3), are represented by three rod packings and a sphere packing in Figure 1, and these four types seem to be the most feasible alternatives, since voids are automatically produced when rounded 1-or 0-dimensional SUs are packed. In order to obtain a narrow pore size distribution, all SUs must have the same diameter and the packing must exhibit a high degree of order. The most easily achieved arrangement of SUs is probably some form of close-packing. A look at the geometry of close-packed arrangements of spheres or cylindrical rods reveals that a pore diameter of > 10 A requires an SU diameter of 2 65 8, for these two types of O(3) and l(1) materials. The void fractions of these two arrangements are 26 and 9 vol.-%, respectively, and do not depend on the diameter of the SUs. Supercrystals of close-packed, surfactant-covered nanospheres of iron oxide have been studied by electron microscopy. [ I h ] The less dense O(3) and l(1) packings depicted in Figure 1 have void fractions of 48 and 21 vol.-o/~, and require an SU diameter of 24 A, in order to exhibit 10 A pores. A number of more complicated rod packings, of which two are shown in Figure 1 in ordcr to illustrate the l(2) and l(3) classes of solid, have been described by O'Keeffe and Andersson."In conclusion, analysis of the possible combinations of connectivity exhibited by pores and structural units, according to the proposed scheme, suggests that regular arrangements of uniform nanocylinders or nanospheres could constitute a family of microporous solids, extending the range of pore dimensions observed in zeolite-type materials. The simple X(Y) scheme of classification used in this note can easily be extended to include more complicated cases, like XY(Z) or X(Y)(Z). For example, a hypothetical O2(2) material such as fullerene-intercalated graphite could be an interesting target for synthesis.

BackgroundAthina Markou and her colleagues discovered persistent changes in adult behavior following adolescent exposure to ethanol or nicotine consistent with increased risk for developing addiction. Building on Dr. Markou’s important work and that of others in the field, researchers at the Bowles Center for Alcohol Studies have found that persistent changes in behavior following adolescent stress or alcohol exposure may be linked to induction of immune signaling in brain.AimThis study aims to illuminate the critical interrelationship of the innate immune system (e.g., toll-like receptors [TLRs], high-mobility group box 1 [HMGB1]) in the neurobiology of addiction.MethodThis study reviews the relevant research regarding the relationship between the innate immune system and addiction.ConclusionEmerging evidence indicates that TLRs in brain, particularly those on microglia, respond to endogenous innate immune agonists such as HMGB1 and microRNAs (miRNAs). Multiple TLRs, HMGB1, and miRNAs are induced in the brain by stress, alcohol, and other drugs of abuse and are increased in the postmortem human alcoholic brain. Enhanced TLR-innate immune signaling in brain leads to epigenetic modifications, alterations in synaptic plasticity, and loss of neuronal cell populations, which contribute to cognitive and emotive dysfunctions. Addiction involves progressive stages of drug binges and intoxication, withdrawal-negative affect, and ultimately compulsive drug use and abuse. Toll-like receptor signaling within cortical-limbic circuits is modified by alcohol and stress in a manner consistent with promoting progression through the stages of addiction.

BackgroundRecent studies have implicated microglia—the resident immune cells of the brain—in the pathophysiology of alcoholism. Indeed, post-mortem alcoholic brains show increased microglial markers and increased immune gene expression; however, the effects of ethanol on microglial functioning and how this impacts the brain remain unclear. In this present study, we investigate the effects of acute binge ethanol on microglia and how microglial depletion changes the brain neuroimmune response to acute binge ethanol withdrawal.MethodsC57BL/6J mice were treated intragastrically with acute binge ethanol for time course and dose-response studies. Cultured mouse BV2 microglia-like cells were treated with ethanol in vitro for time course studies. Mice were also administered the colony stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 to deplete microglia from the brain. These mice were subsequently treated with acute binge ethanol and sacrificed during withdrawal. Brain and BV2 mRNA were isolated and assessed using RT-PCR to examine expression of microglial and neuroimmune genes.ResultsAcute binge ethanol biphasically changed microglial (e.g., Iba1, CD68) gene expression, with initial decreases during intoxication and subsequent increases during withdrawal. Acute ethanol withdrawal dose dependently increased neuroimmune gene (e.g., TNFα, Ccl2, IL-1ra, IL-4) expression beginning at high doses. BV2 cells showed biphasic changes in pro-inflammatory (e.g., TNFα, Ccl2) gene expression following ethanol treatment in vitro. Administration of PLX5622 depleted microglia from the brains of mice. Although some neuroimmune genes were reduced by microglial depletion, many others were unchanged. Microglial depletion blunted pro-inflammatory (e.g., TNFα, Ccl2) gene expression and enhanced anti-inflammatory (e.g., IL-1ra, IL-4) gene expression during acute binge ethanol withdrawal.ConclusionsThese studies find acute binge ethanol withdrawal increases microglial and neuroimmune gene expression. Ethanol exposure also increases microglial pro-inflammatory gene expression in vitro. Furthermore, microglial depletion decreases expression of microglia-specific genes but has little effect on expression of many other neuroimmune signaling genes. Microglial depletion blunted the acute binge ethanol withdrawal induction of pro-inflammatory genes and enhanced induction of anti-inflammatory genes. These findings indicate microglia impact the brain response to acute binge ethanol withdrawal.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0856-z) contains supplementary material, which is available to authorized users.

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