Innately activated TLR4 signal in the nucleus accumbens is sustained by CRF amplification loop and regulates impulsivity

Brain Behav Immun. 2018 Mar:69:139-153. doi: 10.1016/j.bbi.2017.11.008. Epub 2017 Nov 13.


Cognitive impulsivity is a heritable trait believed to represent the behavior that defines the volition to initiate alcohol drinking. We have previously shown that a neuronal Toll-like receptor 4 (TLR4) signal located in the central amygdala (CeA) and ventral tegmental area (VTA) controls the initiation of binge drinking in alcohol-preferring P rats, and TLR4 expression is upregulated by alcohol-induced corticotropin-releasing factor (CRF) at these sites. However, the function of the TLR4 signal in the nucleus accumbens shell (NAc-shell), a site implicated in the control of reward, drug-seeking behavior and impulsivity and the contribution of other signal-associated genes, are still poorly understood. Here we report that P rats have an innately activated TLR4 signal in NAc-shell neurons that co-express the α2 GABAA receptor subunit and CRF prior to alcohol exposure. This signal is not present in non-alcohol drinking NP rats. The TLR4 signal is sustained by a CRF amplification loop, which includes TLR4-mediated CRF upregulation through PKA/CREB activation and CRF-mediated TLR4 upregulation through the CRF type 1 receptor (CRFR1) and the MAPK/ERK pathway. NAc-shell Infusion of a neurotropic, non-replicating herpes simplex virus vector for TLR4-specific small interfering RNA (pHSVsiTLR4) inhibits TLR4 expression and cognitive impulsivity, implicating the CRF-amplified TLR4 signal in impulsivity regulation.

Keywords: Activated TLR4 signal; CRF; GABA(A) α2; HSV siRNA vectors; Impulsivity; PKA/CREB.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alcohol Drinking / metabolism
  • Animals
  • Behavior, Animal / physiology
  • Corticotropin-Releasing Hormone / metabolism*
  • Drug-Seeking Behavior
  • Impulsive Behavior / physiology*
  • Neurons / metabolism*
  • Nucleus Accumbens / metabolism*
  • Protein Subunits / metabolism
  • Rats
  • Receptors, Corticotropin-Releasing Hormone / metabolism*
  • Receptors, GABA-A / metabolism*
  • Signal Transduction / physiology
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism*


  • Protein Subunits
  • Receptors, Corticotropin-Releasing Hormone
  • Receptors, GABA-A
  • Tlr4 protein, rat
  • Toll-Like Receptor 4
  • CRF receptor type 1
  • Corticotropin-Releasing Hormone