Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Thurston Bowles Building 104 Manning Drive, Chapel Hill, NC, 27599, USA.
Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, 2751, USA.
Neuropharmacology. 2020 May 15;168:107759. doi: 10.1016/j.neuropharm.2019.107759. Epub 2019 Sep 5.
Neuroadaptations in brain regions that regulate emotional and reward-seeking behaviors have been suggested to contribute to pathological behaviors associated with alcohol-use disorder. One such region is the bed nucleus of the stria terminalis (BNST), which has been linked to both alcohol consumption and alcohol withdrawal-induced anxiety and depression. Recently, we identified a GABAergic microcircuit in the BNST that regulates anxiety-like behavior. In the present study, we examined how chronic alcohol exposure alters this BNST GABAergic microcircuit in mice. We selectively targeted neurons expressing corticotropin releasing factor (CRF) using a CRF-reporter mouse line and combined retrograde labeling to identify BNST projections to the ventral tegmental area (VTA) and lateral hypothalamus (LH). Following 72 h of withdrawal from four weekly cycles of chronic intermittent ethanol (CIE) vapor exposure, the excitability of a sub-population of putative local CRF neurons that did not project to either VTA or LH (CRF neurons) was increased. Withdrawal from CIE also increased excitability of non-CRF BNST neurons that project to both LH and VTA (BNST neurons). Furthermore, both populations of neurons had a reduction in spontaneous EPSC amplitude while frequency was unaltered. Withdrawal from chronic alcohol was accompanied by a significant increase in spontaneous IPSC frequency selectively in the BNST neurons. Together, these data suggest that withdrawal from chronic ethanol dysregulates local CRF-GABAergic microcircuit to inhibit anxiolytic outputs of the BNST which may contribute to enhanced anxiety during alcohol withdrawal and drive alcohol-seeking behavior. This article is part of the special issue on 'Neuropeptides'.
大脑中调节情绪和寻求奖励行为的区域的神经适应性被认为有助于与酒精使用障碍相关的病理性行为。其中一个区域是终纹床核（BNST），它与酒精摄入和酒精戒断引起的焦虑和抑郁有关。最近，我们在 BNST 中确定了一个调节焦虑样行为的 GABA 能微电路。在本研究中，我们研究了慢性酒精暴露如何改变小鼠 BNST 的 GABA 能微电路。我们使用 CRF 报告小鼠系选择性地靶向表达促肾上腺皮质素释放因子（CRF）的神经元，并结合逆行标记来识别 BNST 投射到腹侧被盖区（VTA）和外侧下丘脑（LH）的投射。在经历了为期四周的慢性间歇性乙醇（CIE）蒸气暴露的四个周期的戒断 72 小时后，未投射到 VTA 或 LH 的假定局部 CRF 神经元（CRF 神经元）的亚群的兴奋性增加。CIE 戒断也增加了投射到 LH 和 VTA 的非 CRF BNST 神经元（BNST 神经元）的兴奋性。此外，这两种神经元群体的自发性 EPSC 幅度减小而频率不变。慢性酒精戒断后，BNST 神经元的自发性 IPSC 频率显著增加。总之，这些数据表明，慢性乙醇戒断会使局部的 CRF-GABA 能微电路失调，从而抑制 BNST 的抗焦虑输出，这可能导致酒精戒断期间焦虑加剧，并促使酒精寻求行为。本文是“神经肽”特刊的一部分。
