0000000001188874
AUTHOR
Jorge Montesinos
TLR4 elimination prevents synaptic and myelin alterations and long-term cognitive dysfunctions in adolescent mice with intermittent ethanol treatment.
The adolescent brain undergoes important dynamic and plastic cell changes, including overproduction of axons and synapses, followed by rapid pruning along with ongoing axon myelination. These developmental changes make the adolescent brain particularly vulnerable to neurotoxic and behavioral effects of alcohol. Although the mechanisms of these effects are largely unknown, we demonstrated that ethanol by activating innate immune receptors toll-like receptor 4 (TLR4), induces neuroinflammation and brain damage in adult mice. The present study aims to evaluate whether intermittent ethanol treatment in adolescence promotes TLR4-dependent pro-inflammatory processes, leading to myelin and synapti…
Additional file 2: of TLR4 response mediates ethanol-induced neurodevelopment alterations in a model of fetal alcohol spectrum disorders
Table S2. Summary table of the two-way ANOVA of biochemical data (only statistically significant data is shown). Table S3. Summary table of the three-way ANOVA to study gender differences in ethanol-treated and non-treated WT and TLR4-KO pups at PND 0 and 20 (only statistically significant data is shown). Table S4. Summary table of the two-way ANOVA of western blot, immunohistochemistry, and electron microscopy data (only statistically significant data is shown). (DOC 74 kb)
'Up-regulation of histone acetylation induced by social defeat mediates the conditioned rewarding effects of cocaine
Social defeat (SD) induces a long-lasting increase in the rewarding effects of psychostimulants measured using the self-administration and conditioned place procedures (CPP). However, little is known about the epigenetic changes induced by social stress and about their role in the increased response to the rewarding effects of psychostimulants. Considering that histone acetylation regulates transcriptional activity and contributes to drug-induced behavioral changes, we addressed the hypothesis that SD induces transcriptional changes by histone modifications associated with the acquisition of place conditioning. After a fourth defeat, H3(K9) acetylation was decreased in the hippocampus, whil…
TLR4 participates in the transmission of ethanol-induced neuroinflammation via astrocyte-derived extracellular vesicles
Background Current evidence indicates that extracellular vesicles (EVs) participate in intercellular signaling, and in the regulation and amplification of neuroinflammation. We have previously shown that ethanol activates glial cells through Toll-like receptor 4 (TLR4) by triggering neuroinflammation. Here, we evaluate if ethanol and the TLR4 response change the release and inflammatory content of astrocyte-derived EVs, and whether these vesicles are capable of communicating with neurons by spreading neuroinflammation. Methods Cortical neurons and astrocytes in culture were used. EVs were isolated from the extracellular medium of the primary culture of the WT and TLR4-KO astrocytes treated …
Involvement of TLR4 in the long-term epigenetic changes, rewarding and anxiety effects induced by intermittent ethanol treatment in adolescence
Studies in humans and experimental animals have demonstrated the vulnerability of the adolescent brain to actions of ethanol and the long-term consequences of binge drinking, including the behavioral and cognitive deficits that result from alcohol neurotoxicity, and increased risk to alcohol abuse and dependence. Although the mechanisms that participate in these effects are largely unknown, we have shown that ethanol by activating innate immune receptors, toll-like receptor 4 (TLR4), induces neuroinflammation, impairs myelin proteins and causes cognitive dysfunctions in adolescent mice. Since neuroimmune signaling is also involved in alcohol abuse, the aim of this study was to assess whethe…
Social defeat-induced increase in the conditioned rewarding effects of cocaine: Role of CX3CL1
Abstract Social stress is associated with higher vulnerability to drug use, as it enhances the reinforcing effects of psychostimulants in rodents. Furthermore, continued or severe stress induces a proinflammatory state of microglial activation and augmented cytokine production. The aim of the present work was to evaluate the role of fractalkine [C-X3-C motif ligand 1 (CX3CL1)], an inflammatory chemokine, in the increased conditioned rewarding effects of cocaine in animals exposed to social defeat stress. In addition, we measured the signaling cascade pathway of CX3CL1 in the hippocampus (HPC) (including p-ERK/ERK, p-p38/p38 MAPK, p-p65/p65 NFκB and p-CREB/CREB ratios). The glutamate recepto…
TLR4 response mediates ethanol-induced neurodevelopment alterations in a model of fetal alcohol spectrum disorders
Background Inflammation during brain development participates in the pathogenesis of early brain injury and cognitive dysfunctions. Prenatal ethanol exposure affects the developing brain and causes neural impairment, cognitive and behavioral effects, collectively known as fetal alcohol spectrum disorders (FASD). Our previous studies demonstrate that ethanol activates the innate immune response and TLR4 receptor and causes neuroinflammation, brain damage, and cognitive defects in the developmental brain stage of adolescents. We hypothesize that by activating the TLR4 response, maternal alcohol consumption during pregnancy triggers the release of cytokines and chemokines in both the maternal …
Binge-like ethanol treatment in adolescence impairs autophagy and hinders synaptic maturation: Role of TLR4.
Abstract Adolescence is a developmental period of brain maturation in which remodeling and changes in synaptic plasticity and neural connectivity take place in some brain regions. A different mechanism participates in adolescent brain maturation, including autophagy processes that play a role in synaptic development and plasticity. Alcohol is a neurotoxic compound whose abuse in adolescence causes TLR4 response activation by triggering neuroinflammation, neural damage and behavioral alterations. However, the potential participation of autophagy in long-term neurochemical and cognitive dysfunctions induced by binge ethanol drinking in adolescence is uncertain. We therefore evaluated whether …
Plasma profile of pro-inflammatory cytokines and chemokines in cocaine users under outpatient treatment: influence of cocaine symptom severity and psychiatric co-morbidity
The treatment for cocaine use constitutes a clinical challenge because of the lack of appropriate therapies and the high rate of relapse. Recent evidence indicates that the immune system might be involved in the pathogenesis of cocaine addiction and its co-morbid psychiatric disorders. This work examined the plasma pro-inflammatory cytokine and chemokine profile in abstinent cocaine users (n = 82) who sought outpatient cocaine treatment and age/sex/body mass-matched controls (n = 65). Participants were assessed with the diagnostic interview Psychiatric Research Interview for Substance and Mental Diseases according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,…
Cocaine-induced changes in CX3CL1 and inflammatory signaling pathways in the hippocampus: Association with IL1β
Cocaine induces neuroinflammatory response and interleukin-1 beta (IL1β) is suggested a final effector for many cocaine-induced inflammatory signals. Recently, the chemokine fractalkine (CX3CL1) has been reported to regulate hippocampus-dependent neuroinflammation and synaptic plasticity via CX3C-receptor 1 (CX3CR1), but little is known about the impact of cocaine. This study is mainly focused on the characterization of CX3CL1, IL1β and relevant inflammatory signal transduction pathways in the hippocampus in acute and repeated cocaine-treated male mice. Complementarily, the rewarding properties of cocaine were also assessed in Cx3cr1-knockout (KO) mice using a conditioned place preference (…
Additional file 4: of TLR4 participates in the transmission of ethanol-induced neuroinflammation via astrocyte-derived extracellular vesicles
Table S1. Nucleotide sequences of the primers used for the TaqMan RT-qPCR of miRNAs. Table S2. Nucleotide sequences of the primers used for the RT-PCR of genes. Table S3. Targets for mmu-mir-146a, mmu-mir-182 and mmu-mir-200b obtained by the mirnet.es webserver. Table S4. The KEGG pathways obtained by the DIANA tool webserver. Table S5. The KEGG pathways that derived from the String protein-protrin interaction analysis between the target genes modulated by mmu-miR-146a and mmu-mir-182. (DOCX 57 kb)
Additional file 3: of TLR4 participates in the transmission of ethanol-induced neuroinflammation via astrocyte-derived extracellular vesicles
Figure S3. Analysis of the RNA population isolated from the WT and TLR4-KO, ethanol-treated or not astrocyte-derived EVs by a 2100 Agilent Bioanalyzer. X axis shows the nucleotide length of the RNA population and the Y axis its fluorescence intensity. (TIF 366 kb)
Additional file 1: of TLR4 response mediates ethanol-induced neurodevelopment alterations in a model of fetal alcohol spectrum disorders
Figure S1. Role of TLR4 in the expression of cytokines (IL-1β, IL-17) and chemokines (fractalkine, MCP-1, MIP-1α) in the cerebral cortices of the WT and TLR4-KO male pups on PND 0 and 20 exposed, or not, to ethanol during the embryonic and postnatal periods. PPEE: prenatal and postnatal ethanol exposure. Data represent mean ± SEM, n = 4 mice/group. *p
Additional file 2: of TLR4 participates in the transmission of ethanol-induced neuroinflammation via astrocyte-derived extracellular vesicles
Figure S2. A) Flow cytometry graph of a mixture of FITC fluorescent beads with different diameters of 100 nm, 300 nm, 500 nm and 900 nm (Megamix-Plus FSC beads), which was used to detect the EVs obtained from the WT and TLR4-KO astrocytes. B) Example of the graph obtained in the nanoparticles tracking analysis using size distribution and the concentration of microvesicles. (TIF 924 kb)
Additional file 1: of TLR4 participates in the transmission of ethanol-induced neuroinflammation via astrocyte-derived extracellular vesicles
Figure S1. Immunoblot analysis of the calnexin levels present in the EVs from the untreated and ethanol-treated WT and TLR4-KO astrocytes. The absence of the calnexin expression in the exosome samples confirmed the absence of cytosolic protein contamination. A sample of astrocyte lysate was used as positive control of the calnexin expression. (TIF 489 kb)