Department of Molecular Physiology & Biophysics, Neuroscience Program in Substance Abuse, Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0615.
Department of Molecular Physiology & Biophysics, John F. Kennedy Center for Research on Human Development, and Neuroscience Program in Substance Abuse, Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0615.
J Neurosci. 2014 Jul 9;34(28):9319-31. doi: 10.1523/JNEUROSCI.0822-14.2014.
α2-adrenergic receptors (AR) within the bed nucleus of the stria terminalis (BNST) reduce stress-reward interactions in rodent models. In addition to their roles as autoreceptors, BNST α(2A)-ARs suppress glutamatergic transmission. One prominent glutamatergic input to the BNST originates from the parabrachial nucleus (PBN) and consists of asymmetric axosomatic synapses containing calcitonin gene-related peptide (CGRP) and vGluT2. Here we provide immunoelectron microscopic data showing that many asymmetric axosomatic synapses in the BNST contain α(2A)-ARs. Further, we examined optically evoked glutamate release ex vivo in BNST from mice with virally delivered channelrhodopsin2 (ChR2) expression in PBN. In BNST from these animals, ChR2 partially colocalized with CGRP, and activation generated EPSCs in dorsal anterolateral BNST neurons that elicited two cell-type-specific outcomes: (1) feedforward inhibition or (2) an EPSP that elicited firing. We found that the α(2A)-AR agonist guanfacine selectively inhibited this PBN input to the BNST, preferentially reducing the excitatory response in ex vivo mouse brain slices. To begin to assess the overall impact of α(2A)-AR control of this PBN input on BNST excitatory transmission, we used a Thy1-COP4 mouse line with little postsynaptic ChR2 expression nor colocalization of ChR2 with CGRP in the BNST. In slices from these mice, we found that guanfacine enhanced, rather than suppressed, optogenetically initiated excitatory drive in BNST. Thus, our study reveals distinct actions of PBN afferents within the BNST and suggests that α(2A)-AR agonists may filter excitatory transmission in the BNST by inhibiting a component of the PBN input while enhancing the actions of other inputs.
终纹床核（BNST）内的α2-肾上腺素能受体（AR）减少了啮齿动物模型中的应激-奖励相互作用。除了作为自身受体的作用外，BNST α(2A)-AR 还抑制谷氨酸能传递。BNST 的一个主要谷氨酸能传入来自臂旁核（PBN），并包含含有降钙素基因相关肽（CGRP）和 vGluT2 的不对称轴突-体突触。在这里，我们提供免疫电子显微镜数据，显示 BNST 中的许多不对称轴突-体突触包含 α(2A)-AR。此外，我们在 BNST 中检查了病毒传递的通道型视紫红质 2 (ChR2)在 PBN 中的表达的小鼠的体外光诱发谷氨酸释放。在这些动物的 BNST 中，ChR2 与 CGRP 部分共定位，激活在 BNST 背侧前外侧神经元中产生 EPSC，引发两种细胞类型特异性结果：(1) 前馈抑制或 (2) 引发放电的 EPSP。我们发现 α(2A)-AR 激动剂胍法辛选择性地抑制了 PBN 对 BNST 的这种输入，优先减少了离体小鼠脑片上的兴奋性反应。为了开始评估 α(2A)-AR 对这种 PBN 输入对 BNST 兴奋性传递的整体影响，我们使用了一种 Thy1-COP4 小鼠系，该系在 BNST 中几乎没有突触后 ChR2 表达，也没有 ChR2 与 CGRP 的共定位。在这些小鼠的切片中，我们发现胍法辛增强了而不是抑制了 BNST 中光遗传学引发的兴奋驱动。因此，我们的研究揭示了 BNST 内 PBN 传入的不同作用，并表明 α(2A)-AR 激动剂可能通过抑制 PBN 输入的一部分同时增强其他输入的作用来过滤 BNST 中的兴奋性传递。
