Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana 70118.
Department of Cell Biology and Anatomy, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112.
J Neurosci. 2023 Nov 22;43(47):7902-7912. doi: 10.1523/JNEUROSCI.1744-22.2023.
Chronic alcohol exposure leads to a neuroinflammatory response involving activation of the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome and proinflammatory cytokine production. Acute ethanol (EtOH) exposure activates GABAergic synapses in the central and basolateral amygdala (BLA) , but whether this rapid modulation of synaptic inhibition is because of an acute inflammatory response and alters anxiety-like behavior in male and female animals is not known. Here, we tested the hypotheses that acute EtOH facilitates inhibitory synaptic transmission in the BLA by activating the NLRP3 inflammasome-dependent acute inflammatory response, that the alcohol-induced increase in inhibition is cell type and sex dependent, and that acute EtOH in the BLA reduces anxiety-like behavior. Acute EtOH application at a binge-like concentration (22-44 mm) stimulated synaptic GABA release from putative parvalbumin (PV) interneurons onto BLA principal neurons in brain slices from male, but not female, rats. The EtOH facilitation of synaptic inhibition was blocked by antagonists of the Toll-like receptor 4 (TLR4), the NLRP3 inflammasome, and interleukin-1 receptors, suggesting it was mediated by a rapid local neuroinflammatory response in the BLA. , bilateral injection of EtOH directly into the BLA produced an acute concentration-dependent reduction in anxiety-like behavior in male but not female rats. These findings demonstrate that acute EtOH in the BLA regulates anxiety-like behavior in a sex-dependent manner and suggest that this effect is associated with presynaptic facilitation of parvalbumin-expressing interneuron inputs to BLA principal neurons via a local NLRP3 inflammasome-dependent neuroimmune response. Chronic alcohol exposure produces a neuroinflammatory response, which contributes to alcohol-associated pathologies. Acute alcohol administration increases inhibitory synaptic signaling in the brain, but the mechanism for the rapid alcohol facilitation of inhibitory circuits is unknown. We found that acute ethanol at binge-like concentrations in the basolateral amygdala (BLA) facilitates GABA release from parvalbumin-expressing (PV) interneuron synapses onto principal neurons in brain slices from male rats and that intra-BLA ethanol reduces anxiety-like behavior in male rats, but not female rats. The ethanol (EtOH) facilitation of inhibition in the BLA is mediated by Toll-like receptor 4 (TLR4) and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome activation and proinflammatory IL-1β signaling, which suggests a rapid NLRP3 inflammasome-dependent neuroimmune cascade that plays a critical role in acute alcohol intoxication.
慢性酒精暴露会导致神经炎症反应，涉及核苷酸结合寡聚化结构域样受体蛋白 3（NLRP3）炎性小体的激活和促炎细胞因子的产生。急性乙醇（EtOH）暴露会激活中枢和基底外侧杏仁核（BLA）中的 GABA 能突触，但这种突触抑制的快速调节是否是由于急性炎症反应引起的，以及是否会改变雄性和雌性动物的焦虑样行为尚不清楚。在这里，我们通过测试以下假设来检验以下假设：急性 EtOH 通过激活 NLRP3 炎性小体依赖性急性炎症反应，促进 BLA 中的抑制性突触传递；酒精诱导的抑制增加与细胞类型和性别有关；BLA 中的急性 EtOH 可降低焦虑样行为。在来自雄性大鼠的脑切片中，以 binge-like 浓度（22-44 mM）应用急性 EtOH 刺激了 BLA 中假定的 PV 中间神经元到 BLA 主神经元的突触 GABA 释放。EtOH 对突触抑制的促进作用被 Toll 样受体 4（TLR4）、NLRP3 炎性小体和白细胞介素 1 受体的拮抗剂阻断，表明这是由 BLA 中快速的局部神经炎症反应介导的。双侧 BLA 注射 EtOH 可直接产生急性浓度依赖性的雄性大鼠而非雌性大鼠焦虑样行为减少。这些发现表明，BLA 中的急性 EtOH 以性别依赖的方式调节焦虑样行为，并且表明这种作用与局部 NLRP3 炎性小体依赖性神经免疫反应有关，该反应通过 PV 表达中间神经元输入到 BLA 主神经元的突触前易化有关。慢性酒精暴露会产生神经炎症反应，从而导致与酒精相关的病理。急性酒精给药会增加大脑中的抑制性突触信号，但快速酒精促进抑制性回路的机制尚不清楚。我们发现，在 BLA 中以 binge-like 浓度（BLA）存在的急性乙醇促进了来自雄性大鼠脑切片中表达 PV 的中间神经元突触的 GABA 释放，并且 BLA 内的乙醇减少了雄性大鼠的焦虑样行为，而不是雌性大鼠。BLA 中的乙醇（EtOH）抑制作用是由 Toll 样受体 4（TLR4）和核苷酸结合寡聚化结构域样受体蛋白 3（NLRP3）炎性小体的激活和促炎 IL-1β信号介导的，这表明急性酒精中毒中发挥关键作用的是快速的 NLRP3 炎性小体依赖性神经免疫级联反应。
