TLR4 signaling in VTA dopaminergic neurons regulates impulsivity through tyrosine hydroxylase modulation.
TLR4 signaling in VTA dopaminergic neurons regulates impulsivity through tyrosine hydroxylase modulation.
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DOI：
10.1038/tp.2016.72
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发表时间：
2016-05-17
影响因子：
6.8
通讯作者：
June H
中科院分区：
文献类型：
--
作者：
Aurelian L;Warnock KT;Balan I;Puche A;June H
酒精依赖是一种复杂的疾病，由过度饮酒（称为酗酒）引起，遗传易感基因的风险贡献为50-60%。认知冲动是一种可遗传的特征，可能为向酒精依赖的过渡奠定基础，但其在乙醇寻求行为中的作用及其相关基因仍然知之甚少。我们以前已经表明，酒精偏好的P大鼠有先天性升高的神经元Toll样受体4（TLR 4）信号在腹侧被盖区（VTA），控制过量饮酒的开始。在这里，我们报告，TLR 4是本地化的多巴胺（TH+）神经元，它上调酪氨酸羟化酶（TH）的表达，通过cAMP依赖性蛋白激酶（PKA）/环AMP反应元件结合蛋白（CREB）信号。P大鼠比野生型（WT）大鼠具有更高的冲动性，并且用于TLR 4特异性小干扰RNA（siRNA; pHSVsiTLR 4）的非复制型单纯疱疹病毒（HSV）载体的VTA输注抑制冲动性和TLR 4/TH表达。乱序siRNA载体不影响基因表达或冲动。这些数据表明，腹侧被盖区多巴胺能神经元中的TLR 4信号传导控制与TH表达调节相关的冲动性，可能有助于饮酒的起始及其向酒精依赖的过渡。
Alcohol dependence is a complex disorder that initiates with episodes of excessive alcohol drinking known as binge drinking, and has a 50–60% risk contribution from inherited susceptibility genes. Cognitive impulsivity is a heritable trait that may set the stage for transition to alcohol dependence but its role in the ethanol-seeking behavior and the involved genes are still poorly understood. We have previously shown that alcohol-preferring P rats have innately elevated levels of a neuronal Toll-like receptor 4 (TLR4) signal in the ventral tegmental area (VTA) that controls the initiation of excessive alcohol drinking. Here we report that TLR4 is localized in dopaminergic (TH+) neurons and it upregulates the expression of tyrosine hydroxylase (TH) through a cAMP-dependent protein kinase (PKA)/cyclic AMP response element binding protein (CREB) signal. P rats have higher impulsivity than wild-type (WT) rats and VTA infusion of a non-replicating Herpes simplex virus (HSV) vector for TLR4-specific small interfering RNA (siRNA; pHSVsiTLR4) inhibits both impulsivity and TLR4/TH expression. A scrambled siRNA vector does not affect gene expression or impulsivity. The data suggest that TLR4 signaling in VTA dopaminergic neurons controls impulsivity related to the regulation of TH expression, likely contributing to the initiation of alcohol drinking and its transition to alcohol dependence.