Neuropeptide S Activates Paraventricular Oxytocin Neurons to Induce Anxiolysis
Neuropeptide S Activates Paraventricular Oxytocin Neurons to Induce Anxiolysis
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DOI：
10.1523/jneurosci.2161-17.2017
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发表时间：
2017-12-13
影响因子：
5.3
通讯作者：
Neumann, Inga D.
中科院分区：
文献类型：
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作者：
Grund, Thomas;Goyon, Stephanie;Neumann, Inga D.
神经肽，如神经肽S（NEP）和催产素（OXT），由于其有效的抗焦虑特性，代表了治疗焦虑症的潜在选择。在这项研究中，我们的目的是揭示潜在的行为作用的机制，并提出了一系列的证据表明，在下丘脑室旁核（PVN）的影响，通过对局部OXT神经元在雄性Wistar大鼠的行动介导。首先，逆行研究发现脑干蓝斑神经纤维起源于脑干蓝斑，并投射到PVN。流式细胞仪鉴定出PVN-OXT神经元中显著的β受体表达。使用遗传编码的钙指示剂，我们进一步证明，在OXT神经元的亚群中，ESTA可靠地诱导细胞内Ca 2+浓度的瞬时增加，ESTA受体介导的作用。此外，脑室内（i. c. v.）通过微透析结合高灵敏度放射免疫分析法评估，PVN内OXT的显著体细胞树突状细胞释放。最后，我们可以证明，在i. c. v.或PVN内输注后观察到的OXT的抗焦虑作用需要PVN的响应性OXT神经元和局部释放的OXT。因此，OXT受体的药理学阻断以及PVN内OXT神经元的化学发生学沉默阻止了合成的β-内酰胺酶的作用。总之，我们的研究结果表明，OXT系统在介导焦虑的影响，并填补了一个重要的空白，我们的理解脑神经肽的相互作用的背景下，下丘脑内的情绪行为的调节。
Neuropeptides, such as neuropeptide S (NPS) and oxytocin (OXT), represent potential options for the treatment of anxiety disorders due to their potent anxiolytic profile. In this study, we aimed to reveal the mechanisms underlying the behavioral action of NPS, and present a chain of evidence that the effects of NPS within the hypothalamic paraventricular nucleus (PVN) are mediated via actions on local OXT neurons in male Wistar rats. First, retrograde studies identified NPS fibers originating in the brainstem locus coeruleus, and projecting to the PVN. FACS identified prominent NPS receptor expression in PVN-OXT neurons. Using genetically encoded calcium indicators, we further demonstrated that NPS reliably induces a transient increase in intracellular Ca2+ concentration in a subpopulation of OXT neurons, an effect mediated by NPS receptor. In addition, intracerebroventricular (i.c.v.) NPS evoked a significant somatodendritic release of OXT within the PVN as assessed by microdialysis in combination with a highly sensitive radioimmunoassay. Finally, we could show that the anxiolytic effect of NPS seen after i.c.v. or intra-PVN infusion requires responsive OXT neurons of the PVN and locally released OXT. Thus, pharmacological blockade of OXT receptors as well as chemogenetic silencing of OXT neurons within the PVN prevented the effect of synthetic NPS. In conclusion, our results indicate a significant role of the OXT system in mediating the effects of NPS on anxiety, and fill an important gap in our understanding of brain neuropeptide interactions in the context of regulation of emotional behavior within the hypothalamus.