Involvement of TLR4 in the long-term epigenetic changes, rewarding and anxiety effects induced by intermittent ethanol treatment in adolescence

Brain Behav Immun. 2016 Mar:53:159-171. doi: 10.1016/j.bbi.2015.12.006. Epub 2015 Dec 10.


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 whether ethanol treatment in adolescence promotes the long-term synaptic and molecular events associated with alcohol abuse and addiction. Using wild-type (WT) and TLR4-deficient (TLR4-KO) adolescent mice treated intermittently with ethanol (3g/kg) for 2 weeks, we showed that binge-like ethanol treatment in adolescent mice promotes short- and long-term alterations in synaptic plasticity and epigenetic changes in the promoter region of bdnf and fosb, which increased their expression in the mPFC of young adult animals. These molecular events were associated with long-term rewarding and anxiogenic-related behavioral effects, along with increased alcohol preference. Our results further showed the participation of neuroimmune system activation and the TLR4 signaling response since deficient mice in TLR4 (TLR4-KO) are protected against molecular and behavioral alterations of ethanol in the adolescent brain. Our results highlight a new role of the neuroimmune function and open up new avenues to develop pharmacological treatments that can normalize the immune signaling responsible for long-term effects in adolescence, including alcohol abuse and related disorders.

Keywords: Adolescence; Anxiety-like behavior; Binge ethanol treatment; Epigenetic changes; Ethanol preference; Prelimbic medial prefrontal cortex; Rewarding effects; TLR4.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Alcoholism / genetics*
  • Alcoholism / metabolism
  • Animals
  • Anxiety / chemically induced
  • Anxiety / genetics
  • Anxiety / metabolism
  • Binge Drinking / genetics*
  • Binge Drinking / metabolism
  • Brain / drug effects
  • Brain / metabolism
  • Cognition Disorders / chemically induced
  • Cognition Disorders / genetics
  • Cognition Disorders / metabolism
  • Epigenesis, Genetic
  • Ethanol / administration & dosage
  • Ethanol / toxicity*
  • Female
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myelin Proteins / metabolism
  • Reward
  • Toll-Like Receptor 4 / deficiency
  • Toll-Like Receptor 4 / genetics*
  • Toll-Like Receptor 4 / metabolism


  • Myelin Proteins
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Ethanol