Selective Breeding for High Anxiety Introduces a Synonymous SNP That Increases Neuropeptide S Receptor Activity
Selective Breeding for High Anxiety Introduces a Synonymous SNP That Increases Neuropeptide S Receptor Activity
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DOI：
10.1523/jneurosci.4764-13.2015
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发表时间：
2015-03-18
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：
Slattery, David A.;Naik, Roshan R.;Neumann, Inga D.
神经肽S(NPS)因其在啮齿动物中的抗焦虑和减轻恐惧作用而引起人们的极大兴趣，而与NPS受体(NPSR1)表面表达和疗效增加相关的相应受体基因多态性已被认为与人类惊恐障碍的风险增加有关。为了深入了解这一悖论，我们研究了为高焦虑相关行为(HAB)和低焦虑相关行为(HAB)培育的大鼠和小鼠的NPS系统，并随后确定了中央NPS对焦虑和恐惧相关行为的影响。HAB表型伴随着基础NPS受体(Npsr1)的低表达，这一点可以通过体外双荧光素酶启动子检测得到证实。对含有序列突变的较短Npsr1启动子结构的评估，通过寡核苷酸下拉分析证实，引入糖皮质激素受体转录因子结合位点，显示HAB启动子活性增加-地塞米松可以阻止这种作用。与人类NPSR1风险亚型类似，对HAB啮齿动物编码区同义单核苷酸多态的功能分析表明，它导致了对NPS刺激的更高的cAMP反应。对这些差异的行为后果的评估表明，脑室内NPS分别逆转了HAB啮齿动物的高度焦虑、HAB大鼠受损的线索-恐惧消退和HAB小鼠增强的恐惧表达。这些结果表明，NPS系统的变化，在啮齿动物和人类中都是保守的，有助于产生先天的焦虑和恐惧，HAB啮齿动物特别适合于解决迄今为止临床前和临床发现之间的明显差异。
Neuropeptide S (NPS) has generated substantial interest due to its anxiolytic and fear-attenuating effects in rodents, while a corresponding receptor polymorphism associated with increased NPS receptor (NPSR1) surface expression and efficacy has been implicated in an increased risk of panic disorder in humans. To gain insight into this paradox, we examined the NPS system in rats and mice bred for high anxiety-related behavior (HAB) versus low anxiety-related behavior, and, thereafter, determined the effect of central NPS administration on anxiety- and fear-related behavior. The HAB phenotype was accompanied by lower basal NPS receptor (Npsr1) expression, which we could confirm via in vitro dual luciferase promoter assays. Assessment of shorter Npsr1 promoter constructs containing a sequence mutation that introduces a glucocorticoid receptor transcription factor binding site, confirmed via oligonucleotide pull-down assays, revealed increased HAB promoter activity-an effect that was prevented by dexamethasone. Analogous to the human NPSR1 risk isoform, functional analysis of a synonymous single nucleotide polymorphism in the coding region of HAB rodents revealed that it caused a higher cAMP response to NPS stimulation. Assessment of the behavioral consequence of these differences revealed that intracerebroventricular NPS reversed the hyperanxiety of HAB rodents as well as the impaired cued-fear extinction in HAB rats and the enhanced fear expression in HAB mice, respectively. These results suggest that alterations in the NPS system, conserved across rodents and humans, contribute to innate anxiety and fear, and that HAB rodents are particularly suited to resolve the apparent discrepancy between the preclinical and clinical findings to date.