Crh receptor priming in the bed nucleus of the stria terminalis (BNST) induces tph2 gene expression in the dorsomedial dorsal raphe nucleus and chronic anxiety
Crh receptor priming in the bed nucleus of the stria terminalis (BNST) induces tph2 gene expression in the dorsomedial dorsal raphe nucleus and chronic anxiety
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DOI：
10.1016/j.pnpbp.2019.109730
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发表时间：
2020-01-10
影响因子：
5.6
通讯作者：
Lowry, Christopher A.
中科院分区：
文献类型：
--
作者：
Donner, Nina C.;Davies, Sofia M.;Lowry, Christopher A.
终纹床核（BNST）是控制焦虑相关防御行为反应的神经回路中的节点结构。它包含表达应激和焦虑相关神经肽促肾上腺皮质激素释放激素（Crh）以及Crh受体的神经元。已知BNST中Crh受体的每日重复阈下激活会诱导慢性焦虑样状态，但这如何影响BNST目标区域中神经递质相关基因的表达仍不清楚。由于BNST项目严重中缝背核（DR），脑5-羟色胺的主要来源，我们在这里测试的假设，这种重复的，焦虑诱导激活的Crh受体在BNST改变的DR，包括tph 2，基因编码的限速酶脑5-羟色胺合成，和slc 6a 4，基因编码的5-羟色胺转运蛋白（SERT）的肾上腺素能基因的表达。连续5天，成年雄性Wistar大鼠接受每日双侧BNST内微量注射溶媒（1%牛血清白蛋白溶于0.9%生理盐水，n = 11）或行为阈下剂量的尿皮质素1（Ucn 1，n = 11），一种强效Crh受体激动剂。引发与Ucn 1增加tph 2 mRNA的表达选择性的焦虑相关的背侧部分的DR（DRD）和减少社会互动（SI）的时间，在啮齿动物的焦虑相关的防御行为反应的措施。减少社会互动与增加tph 2 mRNA的表达在DRD密切相关。与以前的研究一起，我们的数据与以下假设一致：Crh介导的BNST/DRD-神经元能系统的控制在慢性焦虑状态的发展中起着关键作用，可能也有助于应激诱导的药物滥用和成瘾行为的复发。
The bed nucleus of the stria terminalis (BNST) is a nodal structure in neural circuits controlling anxiety-related defensive behavioral responses. It contains neurons expressing the stress- and anxiety-related neuropeptide corticotropin-releasing hormone (Crh) as well as Crh receptors. Repeated daily subthreshold activation of Crh receptors in the BNST is known to induce a chronic anxiety-like state, but how this affects neurotransmitter-relevant gene expression in target regions of the BNST is still unclear. Since the BNST projects heavily to the dorsal raphe nucleus (DR), the main source of brain serotonin, we here tested the hypothesis that such repeated, anxiety-inducing activation of Crh receptors in the BNST alters the expression of serotonergic genes in the DR, including tph2, the gene encoding the rate-limiting enzyme for brain serotonin synthesis, and slc6a4, the gene encoding the serotonin transporter (SERT). For 5 days, adult male Wistar rats received daily, bilateral, intra-BNST microinjections of vehicle (1% bovine serum albumin in 0.9% saline, n = 11) or behaviorally subthreshold doses of urocortin 1 (Ucn1, n = 11), a potent Crh receptor agonist. Priming with Ucn1 increased tph2 mRNA expression selectively within the anxiety-related dorsal part of the DR (DRD) and decreased social interaction (SI) time, a measure of anxiety-related defensive behavioral responses in rodents. Decreased social interaction was strongly correlated with increased tph2 mRNA expression in the DRD. Together with previous studies, our data are consistent with the hypothesis that Crh-mediated control of the BNST/DRD-serotonergic system plays a key role in the development of chronic anxiety states, possibly also contributing to stress-induced relapses in drug abuse and addiction behavior.