Role of toll-like receptor 7 (TLR7) in voluntary alcohol consumption.
Ontology highlight
ABSTRACT:
SUBMITTER: Grantham EK
PROVIDER: S-EPMC7572874 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Alcohol is part of the usual diet of millions of individuals worldwide. However, not all individuals who drink alcohol experience the same effects, nor will everyone develop an alcohol use disorder. Here we propose that the intestinal microbiota (IMB) helps explain the different consumption patterns of alcohol among individuals. 507 humans participated in this study and alcohol consumption and IMB composition were analyzed. On the other hand, in 80 adult male Wistar rats, behavioral tests, alcohol intoxication, fecal transplantation, administration of antibiotics and collection of fecal samples were performed. For identification and relative quantification of bacterial taxa was used the bacterial 16 S ribosomal RNA gene. In humans, we found that heavy episodic drinking is associated with a specific stool type phenotype (type 1, according to Bristol Stool Scale; p < 0.05) and with an increase in the abundance of Actinobacteria (p < 0.05). Next, using rats, we demonstrate that the transfer of IMB from alcohol-intoxicated animals causes an increase in voluntary alcohol consumption in transplant-recipient animals (p < 0.001). The relative quantification data indicate that the genus Porphyromonas could be associated with the effect on voluntary alcohol consumption. We also show that gut microbiota depletion by antibiotics administration causes a reduction in alcohol consumption (p < 0.001) and altered the relative abundance of relevant phyla such as Firmicutes, Bacteroidetes or Cyanobacteria (p < 0.05), among others. Benjamini-Hochberg false discovery rate (FDR) correction was performed for multiple comparisons. These studies reveal some of the consequences of alcohol on the IMB and provide evidence that manipulation of IMB may alter voluntary alcohol consumption.
| S-EPMC8990010 | biostudies-literature
Project description:Many genes differentially expressed in brain tissue from human alcoholics and animals that have consumed large amounts of alcohol are components of the innate immune toll-like receptor (TLR) pathway. TLRs initiate inflammatory responses via two branches: (1) MyD88-dependent or (2) TRIF-dependent. All TLRs signal through MyD88 except TLR3. Prior work demonstrated a direct role for MyD88-dependent signaling in regulation of alcohol consumption. However, the role of TLR3 as a potential regulator of excessive alcohol drinking has not previously been investigated. To test the possibility TLR3 activation regulates alcohol consumption, we injected mice with the TLR3 agonist polyinosinic:polycytidylic acid (poly(I:C)) and tested alcohol consumption in an every-other-day two-bottle choice test. Poly(I:C) produced a persistent increase in alcohol intake that developed over several days. Repeated poly(I:C) and ethanol exposure altered innate immune transcript abundance; increased levels of TRIF-dependent pathway components correlated with increased alcohol consumption. Administration of poly(I:C) before exposure to alcohol did not alter alcohol intake, suggesting that poly(I:C) and ethanol must be present together to change drinking behavior. To determine which branch of TLR signaling mediates poly(I:C)-induced changes in drinking behavior, we tested either mice lacking MyD88 or mice administered a TLR3/dsRNA complex inhibitor. MyD88 null mutants showed poly(I:C)-induced increases in alcohol intake. In contrast, mice pretreated with a TLR3/dsRNA complex inhibitor reduced their alcohol intake, suggesting poly(I:C)-induced escalations in alcohol intake are, at least partially, dependent on TLR3. Together, these results strongly suggest that TLR3-dependent signaling drives excessive alcohol drinking behavior.
| S-EPMC6399060 | biostudies-literature
Project description:Chronic alcohol consumption alters the levels of microRNAs and mRNAs in the brain, but the specific microRNAs and processes that target mRNAs to affect cellular function and behavior are not known. We examined the in vivo manipulation of previously identified alcohol-responsive microRNAs as potential targets to reduce alcohol consumption. Silencing of miR-411 by infusing antagomiR-411 into the prefrontal cortex of female C57BL/6J mice reduced alcohol consumption and preference, without altering total fluid consumption, saccharin consumption, or anxiety-related behaviors. AntagomiR-411 reduced alcohol consumption when given to mice exposed to a chronic alcohol drinking paradigm but did not affect the acquisition of consumption in mice without a history of alcohol exposure, suggesting that antagomiR-411 has a neuroadaptive, alcohol-dependent effect. AntagomiR-411 decreased the levels of miR-411, as well as the association of immunoprecipitated miR-411 with Argonaute2; and, it increased levels of Faah and Ppard mRNAs. Moreover, antagomiR-411 increased the neuronal expression of glutamate receptor AMPA-2 protein, a known alcohol target and a predicted target of miR-411. These results suggest that alcohol and miR-411 function in a homeostatic manner to regulate synaptic mRNA and protein, thus reversing alcohol-related neuroadaptations and reducing chronic alcohol consumption.
| S-EPMC6192878 | biostudies-literature
Project description:Alcohol-use-disorders are chronic relapsing illnesses, often co-morbid with anxiety. We have previously shown using the "drinking-in-the-dark" model in mice that the stimulation of the serotonin receptor 1A (5-HT1A) reduces ethanol binge-drinking behaviour and withdrawal-induced anxiety. The 5-HT1A receptor is located either on Raphe neurons as autoreceptors, or on target neurons as heteroreceptors. By combining a pharmacological approach with biased agonists targeting the 5-HT1A auto- or heteroreceptor and a chemogenetic approach (DREADDs), here we identified that ethanol-binge drinking behaviour is dependent on 5-HT1A autoreceptors and 5-HT neuronal function, with a transition from DRN-dependent regulation of short-term (6 weeks) ethanol intake, to MRN-dependent regulation after longer ethanol exposure (12 weeks). We further identified a serotonergic microcircuit (5-HTMRN→DG) originating from the MRN and projecting to the dentate gyrus (DG) of the hippocampus, that is specifically affected by, and modulates long-term ethanol consumption. The present study indicates that targeting Raphe nuclei 5-HT1A autoreceptors with agonists might represent an innovative pharmacotherapeutic strategy to combat alcohol abuse.
| S-EPMC9531213 | biostudies-literature
Project description:In the accompanying article, we showed that activation of peroxisome proliferator-activated receptor alpha (PPAR?) signaling by fenofibrate and tesaglitazar decreases ethanol (EtOH) consumption in mice. In this study, we determined the role of these PPAR agonists in EtOH-related behaviors and other actions that may be important in regulating EtOH consumption.The effects of fenofibrate (150 mg/kg) and tesaglitazar (1.5 mg/kg) were examined on the following responses in male and female C57BL/6J (B6) and B6 × 129S4 mice: preference for saccharin, EtOH-induced conditioned place preference (CPP), conditioned taste aversion (CTA), loss of righting reflex, and withdrawal, acoustic startle reflex, response to novelty, and EtOH clearance. Because the B6 inbred strain usually displays weak EtOH-induced CPP and weak EtOH-induced acute withdrawal, B6 × 129S4 mice were also studied.Fenofibrate and tesaglitazar decreased the novelty response and increased acute EtOH withdrawal severity, and fenofibrate increased EtOH-induced CTA. Two important factors for EtOH consumption (saccharin preference and EtOH-induced CPP) were not altered by fenofibrate or tesaglitazar. EtOH clearance was increased by both fenofibrate and tesaglitazar. Response to novelty, acute withdrawal, and EtOH clearance show sex differences and could contribute to the reduced EtOH consumption following fenofibrate administration.These studies indicate the complexity of EtOH-dependent and EtOH-independent behaviors that are altered by PPAR agonists and provide evidence for novel behavioral actions of these drugs that may contribute to PPAR-mediated effects on alcohol drinking.
| S-EPMC4775356 | biostudies-literature
Project description:AimsAlcohol exposure during adolescence is associated with both increased risk for alcohol use disorders and anxiety in adulthood. Our present experiments examined this association using alcohol-preferring AA (Alko Alcohol) rats selected for high voluntary alcohol drinking.MethodsTwo groups of female AA rats acquired alcohol drinking at different ages. We gave the adolescent-onset group free choice to 10% alcohol and water for seven weeks, starting on post-natal day 42 (PND 42), whereas the adult-onset group started drinking alcohol on PND 112. After the 7-week drinking, we withdrew the adolescent group from alcohol for two weeks, followed by another voluntary 7-week drinking period, started at the same age as the adult-onset group. We assessed anxiety-like behaviour repeatedly during alcohol drinking with open field and elevated plus maze tests. At the end of alcohol drinking, we also tested the rats using the light/dark box, stress-induced body temperature test and social dominance test.ResultsDuring the first 7-week alcohol drinking, adolescent rats exhibited significantly slower acquisition of alcohol drinking and lower alcohol preference than the adult-onset group. However, when tested at the same age as the adult-onset rats, they displayed identical alcohol intake and preference. We found no alcohol-induced effects on anxiety- or stress-related behaviour in the experimental groups at any time points.ConclusionsThese data show that the genetically determined phenotype of high alcohol drinking of the female alcohol-preferring AA rats is not associated with a predisposition to develop anxiety-like behaviour following voluntary alcohol exposure, even when initiated during adolescence.
| S-EPMC9086760 | biostudies-literature
Project description:There is considerable evidence for the existence of comorbidity between alcohol-use disorders and depression in humans. One strategy to elucidate hereditary factors affecting the comorbidity of these disorders is to use genetic animal models, such as mouse lines selectively bred for voluntary ethanol consumption. We hypothesized that mice from lines that were bred for high-alcohol preference would manifest increased depression-like phenotypes compared to low-alcohol preferring mice. Mice that were bi-directionally selected and bred on the basis of their High- (HAP) or Low-Alcohol Preference (LAP) were tested in the open-field (OFT), dark-light box (DLB), forced swim (FST), and learned helplessness tests (LH). The study was conducted in two independently derived replicates. In the OFT, both HAP2 and HAP3 mice showed higher levels of general locomotion compared to LAP mice. However, only HAP2 mice spent more time in the center compared to LAP2 mice. In the DLB, there was a slightly higher anxiety-like phenotype in HAP mice. In both FST and LH, we observed higher depression-like behaviors in HAP mice compared to LAP mice, but this was limited to the Replicate 2 mice. Overall, we identified affect-related behavioral changes in mouse lines bred for high-alcohol preference. Notably, the Replicate 3 lines that showed fewer depression-like behaviors also manifest smaller differences in alcohol intake. These data suggest that there may be overlap between genes that predispose to excessive alcohol intake and those underlying affect-related behaviors in the mouse.
| S-EPMC5096405 | biostudies-literature
Project description:RNA-specific adenosine deaminase (ADAR)-mediated adenosine-to-inosine (A-to-I) editing is a critical arm of the antiviral response. However, mechanistic insights into how A-to-I RNA editing affects viral infection are lacking. We posited that inosine incorporation into RNA facilitates sensing of nonself RNA by innate immune sensors and accordingly investigated the impact of inosine-modified RNA on Toll-like receptor 7 and 8 (TLR7/8) sensing. Inosine incorporation into synthetic single-stranded RNA (ssRNA) potentiated tumor necrosis factor alpha (TNF-?) or alpha interferon (IFN-?) production in human peripheral blood mononuclear cells (PBMCs) in a sequence-dependent manner, indicative of TLR7/8 recruitment. The effect of inosine incorporation on TLR7/8 sensing was restricted to immunostimulatory ssRNAs and was not seen with inosine-containing short double-stranded RNAs or with a deoxy-inosine-modified ssRNA. Inosine-mediated increase of self-secondary structure of an ssRNA resulted in potentiated IFN-? production in human PBMCs through TLR7 recruitment, as established through the use of a TLR7 antagonist and Tlr7-deficient cells. There was a correlation between hyperediting of influenza A viral ssRNA and its ability to stimulate TNF-?, independent of 5'-triphosphate residues, and involving Adar-1. Furthermore, A-to-I editing of viral ssRNA directly enhanced mouse Tlr7 sensing, when present in proportions reproducing biologically relevant levels of RNA editing. Thus, we demonstrate for the first time that inosine incorporation into immunostimulatory ssRNA can potentiate TLR7/8 activation. Our results suggest a novel function of A-to-I RNA editing, which is to facilitate TLR7/8 sensing of phagocytosed viral RNA.
| S-EPMC3911656 | biostudies-literature
Project description:Heavy alcohol consumption has detrimental neurologic effects, inducing widespread neuronal loss in both fetuses and adults. One proposed mechanism of ethanol-induced cell loss with sufficient exposure is an elevation in concentrations of bioactive lipids that mediate apoptosis, including the membrane sphingolipid metabolites ceramide and sphingosine. While these naturally-occurring lipids serve as important modulators of normal neuronal development, elevated levels resulting from various extracellular insults have been implicated in pathological apoptosis of neurons and oligodendrocytes in several neuroinflammatory and neurodegenerative disorders. Prior work has shown that acute administration of ethanol to developing mice increases levels of ceramide in multiple brain regions, hypothesized to be a mediator of fetal alcohol-induced neuronal loss. Elevated ceramide levels have also been implicated in ethanol-mediated neurodegeneration in adult animals and humans. Here, we determined the effect of chronic voluntary ethanol consumption on lipid profiles in brain and peripheral tissues from adult alcohol-preferring (P) rats to further examine alterations in lipid composition as a potential contributor to ethanol-induced cellular damage. P rats were exposed for 13 weeks to a 20% ethanol intermittent-access drinking paradigm (45 ethanol sessions total) or were given access only to water (control). Following the final session, tissues were collected for subsequent chromatographic analysis of lipid content and enzymatic gene expression. Contrary to expectations, ethanol-exposed rats displayed substantial reductions in concentrations of ceramides in forebrain and heart relative to non-exposed controls, and modest but significant decreases in liver cholesterol. qRT-PCR analysis showed a reduction in the expression of sphingolipid delta(4)-desaturase (Degs2), an enzyme involved in de novo ceramide synthesis. These findings indicate that ethanol intake levels achieved by alcohol-preferring P rats as a result of chronic voluntary exposure may have favorable vs. detrimental effects on lipid profiles in this genetic line, consistent with data supporting beneficial cardioprotective and neuroprotective effects of moderate ethanol consumption.
| S-EPMC4583526 | biostudies-literature
Project description:BackgroundSeveral peroxisome proliferator-activated receptor (PPAR) agonists reduce voluntary alcohol consumption in rodent models, and evidence suggests that PPARα and γ subunits play an important role in this effect. To define the subunit dependence of this action, we tested selective PPARα and α/γ agonists and antagonists in addition to null mutant mice lacking PPARα.MethodsThe effects of fenofibrate (PPARα agonist) and tesaglitazar (PPARα/γ agonist) on continuous and intermittent 2-bottle choice drinking tests were examined in male and female wild-type mice and in male mice lacking PPARα. We compared the ability of MK886 (PPARα antagonist) and GW9662 (PPARγ antagonist) to inhibit the effects of fenofibrate and tesaglitazar in wild-type mice. The estrogen receptor antagonist, tamoxifen, can inhibit PPARγ-dependent transcription and was also studied in male and female mice.ResultsFenofibrate and tesaglitazar reduced ethanol (EtOH) consumption and preference in wild-type mice, but these effects were not observed in mice lacking PPARα. MK886 inhibited the action of fenofibrate, but not tesaglitazer, while GW9662 did not inhibit either agonist. The PPAR agonists were more effective in male mice compared to females, and drinking in the continuous 2-bottle choice test was more sensitive to fenofibrate and tesaglitazar compared to drinking in the intermittent access test. Tamoxifen also reduced EtOH consumption in male mice and this action was inhibited by GW9662, but not MK886, suggesting that it acts by activation of PPARγ.ConclusionsOur study using selective PPAR agonists, antagonists, and null mutant mice indicates a key role for PPARα in mediating reduced EtOH consumption by fenofibrate and tesaglitazar.
| S-EPMC4775296 | biostudies-literature