Vanderbilt Center for Addiction Research.
Vanderbilt Brain Institute.
J Neurosci. 2019 Jan 16;39(3):472-484. doi: 10.1523/JNEUROSCI.1035-18.2018. Epub 2018 Nov 26.
Stress contributes to numerous psychiatric disorders. Corticotropin releasing factor (CRF) signaling and CRF neurons in the bed nucleus of the stria terminalis (BNST) drive negative affective behaviors, thus agents that decrease activity of these cells may be of therapeutic interest. Here, we show that acute restraint stress increases cFos expression in CRF neurons in the mouse dorsal BNST, consistent with a role for these neurons in stress-related behaviors. We find that activation of α-adrenergic receptors (ARs) by the agonist guanfacine reduced cFos expression in these neurons both in stressed and unstressed conditions. Further, we find that α- and β-ARs differentially regulate excitatory drive onto these neurons. Pharmacological and channelrhodopsin-assisted mapping experiments suggest that α-ARs specifically reduce excitatory drive from parabrachial nucleus (PBN) afferents onto CRF neurons. Given that the α-AR is a G-linked GPCR, we assessed the impact of activating the G-coupled DREADD hM4Di in the PBN on restraint stress regulation of BNST CRF neurons. CNO activation of PBN hM4Di reduced stress-induced in BNST neurons. Further, using as an additional marker of BNST neuronal identity, we uncovered a female-specific upregulation of the coexpression of in BNST neurons following stress, which was prevented by ovariectomy. These findings show that stress activates BNST CRF neurons, and that α-AR activation suppresses the activity of these cells, at least in part by suppressing excitatory drive from PBN inputs onto CRF neurons. Stress is a major variable contributing to mood disorders. Here, we show that stress increases activation of BNST CRF neurons that drive negative affective behavior. We find that the clinically well tolerated α-AR agonist guanfacine reduces activity of these cells , and reduces excitatory PBN inputs onto these cells Additionally, we uncover a novel sex-dependent coexpression of with in female BNST neurons after stress, an effect abolished by ovariectomy. These results demonstrate input-specific interactions between norepinephrine and CRF, and point to an action by which guanfacine may reduce negative affective responses.
压力会导致许多精神疾病。促肾上腺皮质释放因子 (CRF) 信号和终纹床核 (BNST) 中的 CRF 神经元驱动负面情感行为，因此，减少这些细胞活性的药物可能具有治疗意义。在这里，我们表明急性束缚应激会增加小鼠背侧 BNST 中 CRF 神经元的 cFos 表达，这与这些神经元在应激相关行为中的作用一致。我们发现，激动剂胍法辛激活α-肾上腺素能受体 (AR) 可减少应激和非应激条件下这些神经元中的 cFos 表达。此外，我们发现 α-和 β-AR 以不同的方式调节这些神经元的兴奋性驱动。药理学和通道视紫红质辅助映射实验表明，α-AR 特异性减少了来自臂旁核 (PBN) 传入的兴奋性驱动到 CRF 神经元上。鉴于 α-AR 是一种 G 链接的 GPCR，我们评估了激活 PBN 中的 G 偶联 DREADD hM4Di 对 BNST CRF 神经元的束缚应激调节的影响。PBN hM4Di 的 CNO 激活可减少应激诱导的 BNST 神经元。进一步，我们将 作为 BNST 神经元身份的另一个标记，我们发现应激后 BNST 神经元中 的共表达出现了女性特异性上调，而卵巢切除术则阻止了这种上调。这些发现表明，应激会激活 BNST CRF 神经元，而 α-AR 激活会抑制这些细胞的 活性，至少部分原因是抑制了 PBN 传入对 CRF 神经元的兴奋性驱动。压力是导致情绪障碍的主要因素。在这里，我们表明压力会增加驱动负面情感行为的 BNST CRF 神经元的激活。我们发现临床上耐受良好的 α-AR 激动剂胍法辛可降低这些细胞的活性，减少 PBN 传入对这些细胞的兴奋性输入。此外，我们在应激后发现 BNST 神经元中出现了一种新的性别依赖性的 与 共表达，这种效应被卵巢切除术所消除。这些结果表明去甲肾上腺素和 CRF 之间存在输入特异性相互作用，并指出胍法辛可能通过降低负面情感反应来发挥作用。
