A Hypomorphic Vasopressin Allele Prevents Anxiety-Related Behavior
A Hypomorphic Vasopressin Allele Prevents Anxiety-Related Behavior
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DOI：
10.1371/journal.pone.0005129
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发表时间：
2009-04-09
期刊：
影响因子：
3.7
通讯作者：
Landgraf, Rainer
中科院分区：
文献类型：
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作者：
Bunck, Mirjam;Czibere, Ludwig;Landgraf, Rainer
背景：为了研究特质焦虑的神经生物学相关性，CD1小鼠被选择性地培育出极端的焦虑相关行为，高（HAB）和低（LAB）焦虑相关行为的小鼠在反映抑郁样行为的行为测试中也不同。方法/主要发现：在本研究中，微阵列分析、原位杂交、实时定量PCR和免疫组织化学显示，与HAB、NAB（正常焦虑相关行为）和HABxLAB F1交叉对照相比，成年LAB小鼠下丘脑室旁核（PVN）和视上核（SON）中的抗压素基因（Avp）表达降低，但未检测到受体表达或密度的差异。通过对Avp基因位点上下2.5 kbp区域的测序，我们可以鉴定出几个在HAB系和LAB系之间不同的多态性位点。在基因启动子中，12bp D（22180-2191）的缺失特别可能导致在基础条件下LAB动物中检测到的Avp表达降低。事实上，对F1动物的等位基因特异性转录分析显示，与hab特异性等位基因相比，一个低形态的实验室特异性Avp等位基因的转录率降低了75%，从而解释了系特异性Avp表达谱和表型特征。因此，发现pvn内Avp mRNA水平与焦虑相关和抑郁样行为相关。除了这些相关证据外，在自由分离的F2组的258只雄性小鼠中，还发现了显著的基因型/表型关联，这表明Avp启动子缺失与焦虑相关行为有因果关系。讨论：因此，Avp基因启动子多态性的鉴定解释了与观察到的表型相关的基因表达差异，从而进一步加强了集中释放Avp在特质焦虑中的关键参与的概念。
Background: To investigate neurobiological correlates of trait anxiety, CD1 mice were selectively bred for extremes in anxiety-related behavior, with high (HAB) and low (LAB) anxiety-related behavior mice additionally differing in behavioral tests reflecting depression-like behavior.Methodology/Principal Findings: In this study, microarray analysis, in situ hybridization, quantitative real-time PCR and immunohistochemistry revealed decreased expression of the vasopressin gene (Avp) in the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei of adult LAB mice compared to HAB, NAB (normal anxiety-related behavior) and HABxLAB F1 intercross controls, without detecting differences in receptor expression or density. By sequencing the regions 2.5 kbp up-and downstream of the Avp gene locus, we could identify several polymorphic loci, differing between the HAB and LAB lines. In the gene promoter, a deletion of twelve bp D(22180-2191) is particularly likely to contribute to the reduced Avp expression detected in LAB animals under basal conditions. Indeed, allele-specific transcription analysis of F1 animals revealed a hypomorphic LAB-specific Avp allele with a reduced transcription rate by 75% compared to the HAB-specific allele, thus explaining line-specific Avp expression profiles and phenotypic features. Accordingly, intra-PVN Avp mRNA levels were found to correlate with anxiety-related and depression-like behaviors. In addition to this correlative evidence, a significant, though moderate, genotype/phenotype association was demonstrated in 258 male mice of a freely-segregating F2 panel, suggesting a causal contribution of the Avp promoter deletion to anxiety-related behavior.Discussion: Thus, the identification of polymorphisms in the Avp gene promoter explains gene expression differences in association with the observed phenotype, thus further strengthening the concept of the critical involvement of centrally released AVP in trait anxiety.