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Publication

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

Irina Balan | Kaitlin T Warnock | Adam Puche | Marjorie C Gondre-Lewis | Laure Aurelian

Brain, behavior, and immunity | 2018

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.

Pubmed ID: 29146239 RIS Download

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Associated grants

Agency: NIAAA NIH HHS, United States
Id: R01 AA021262
Agency: NIAAA NIH HHS, United States
Id: U24 AA015512
Agency: NICHD NIH HHS, United States
Id: U54 HD090257

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