Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA.
Neuropsychopharmacology Laboratory, Department of Psychiatry and Behavioral Sciences, Howard University College of Medicine, Washington, DC, USA.
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 GABA 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.
认知冲动性是一种可遗传的特征，被认为代表了启动饮酒行为的意志行为。我们之前已经表明，位于杏仁中央核（CeA）和腹侧被盖区（VTA）的神经元 Toll 样受体 4（TLR4）信号控制了酒精偏好 P 大鼠的 binge 饮酒的起始，并且 TLR4 表达在这些部位被酒精诱导的促肾上腺皮质释放因子（CRF）上调。然而，TLR4 信号在伏隔核壳（NAc-shell）中的功能，该部位与奖赏、觅药行为和冲动性的控制有关，以及其他信号相关基因的贡献，仍然知之甚少。在这里，我们报告 P 大鼠在暴露于酒精之前，在共表达α2 GABA 受体亚单位和 CRF 的 NAc-shell 神经元中具有先天激活的 TLR4 信号。这种信号不存在于不饮酒的 NP 大鼠中。TLR4 信号通过 CRF 放大环维持，该环包括 TLR4 通过 PKA/CREB 激活介导的 CRF 上调和 CRF 通过 CRF 型 1 受体（CRFR1）和 MAPK/ERK 途径介导的 TLR4 上调。NAc-shell 中 TLR4 特异性小干扰 RNA（pHSVsiTLR4）的神经营养、非复制单纯疱疹病毒载体的输注抑制 TLR4 表达和认知冲动性，暗示 CRF 放大的 TLR4 信号参与冲动性调节。
