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Alpha2-adrenergic dysregulation in congenic DxH recombinant inbred mice selectively bred for a high fear-sensitized (H-FSS) startle response.
Pharmacology Biochemistry and Behavior ( IF 3.3 ) Pub Date : 2019-12-02 , DOI: 10.1016/j.pbb.2019.172835
Rochelle N Wickramasekara 1 , Charles Bockman 2 , Joachim Hanke 3 , Herbert Schwegler 3 , JoAnn McGee 4 , Edward Walsh 4 , Deniz Yilmazer-Hanke 5
Affiliation  

Patients with anxiety disorders and posttraumatic stress disorder (PTSD) exhibit exaggerated fear responses and noradrenergic dysregulation. Fear-related responses to α2-adrenergic challenge were therefore studied in DxH C3H/HeJ-like recombinant inbred (C3HLRI) mice, which are a DBA/2J-congenic strain selectively bred for a high fear-sensitized startle (H-FSS). C3HLRI mice showed an enhanced acoustic startle response and immobility in the forced swim test compared to DBA/2J controls. The α2-adrenoceptor antagonist yohimbine (Yoh; 5.0 mg/kg) induced an anxiogenic and the α2-adrenoceptor agonist clonidine (Clon; 0.1 mg/kg) an anxiolytic effect in the open field (OF) in C3HLRI but not DBA/2J mice. In auditory fear-conditioning, Yoh (5.0 mg/kg)-treated C3HLRI mice showed higher freezing during fear recall and extinction learning than DBA/2J mice, and a higher ceiling for the Yoh-induced deficit in fear extinction. No strain differences were observed in exploration-related anxiety/spatial learning or the Clon-induced (0.1 mg/kg) corticosterone surge. A global analysis of the behavioral profile of the two mouse strains based on observed and expected numbers of significant behavioral outcomes indicated that C3HLRI mice showed significantly more often fear- and stress-related PTSD-like behaviors than DBA/2J controls. The analysis of the robustness of significant outcomes based on false discovery rate (FDR) thresholds confirmed significant differences for the strain-Yoh-interactions in the OF center and periphery, the Yoh-induced general extinction deficit, strain differences in conditioned fear levels, and at the dose of 5.0 mg/kg for the Yoh-induced ceiling in freezing levels among others. The current findings are consistent with previous observations showing alterations in the central noradrenergic system of C3HLRI mice (Browne et al., 2014, Stress 17:471–83). Based on their behavioral profile and response to α2-adrenergic stimulation, C3HLRI mice are a valuable genetic model for studying adrenergic mechanisms of anxiety disorders and potentially also of PTSD.



中文翻译:

选择性繁殖高危恐惧症(H-FSS)惊吓反应的同基因DxH重组近交小鼠中的α2-肾上腺素功能失调。

患有焦虑症和创伤后应激障碍(PTSD)的患者表现出夸张的恐惧反应和去甲肾上腺素能失调。恐惧相关的响应α 2因此肾上腺素能挑战进行了研究在DXH C3H / HeJ小鼠样重组自交系(C3HLRI)小鼠,它们是DBA / 2J-同类系选择性繁殖用于高恐惧致敏惊吓(H-FSS) 。与DBA / 2J对照相比,C3HLRI小鼠在强迫游泳试验中表现出增强的听觉惊吓反应和不动。的α 2 -肾上腺素能受体拮抗剂育亨宾(Yoh公司; 5.0毫克/千克)诱导的致焦虑和α 2-肾上腺素受体激动剂可乐定(Clon; 0.1 mg / kg)在C3HLRI而非DBA / 2J小鼠的开阔视野(OF)中具有抗焦虑作用。在听觉恐惧条件下,Yoh(5.0 mg / kg)处理的C3HLRI小鼠在恐惧回想和灭绝学习过程中的冰冻度高于DBA / 2J小鼠,而Yoh诱发的恐惧消退赤字的上限也更高。在探索相关的焦虑/空间学习或Clon诱导的(0.1 mg / kg)皮质酮激增中未观察到菌株差异。根据观察到的和预期的重大行为结果数量对这两种小鼠品系的行为进行了全面分析,结果表明,与DBA / 2J对照相比,C3HLRI小鼠表现出与恐惧和压力相关的PTSD样行为的频率明显更高。基于错误发现率(FDR)阈值的重要结果的稳健性分析,证实了OF中心和周围的应变-Yoh相互作用,Yoh引起的一般性灭绝缺陷,条件恐惧水平的应变差异以及剂量为5.0 mg / kg时,Yoh诱导的冻结水平上限。目前的发现与以前的观察结果一致,后者表明C3HLRI小鼠的中央去甲肾上腺素能系统发生了改变(Browne等,2014,应力17:471-83)。根据他们的行为特征和对α的反应 Yoh诱导的冻结上限为0 mg / kg。目前的发现与以前的观察结果一致,后者表明C3HLRI小鼠的中央去甲肾上腺素能系统发生了改变(Browne等,2014,应力17:471-83)。根据他们的行为特征和对α的反应 Yoh诱导的冻结上限为0 mg / kg。目前的发现与先前的观察结果一致,后者表明C3HLRI小鼠的中央去甲肾上腺素能系统发生了改变(Browne等,2014,应力17:471-83)。根据他们的行为特征和对α的反应2-肾上腺素能刺激,C3HLRI小鼠是研究焦虑症甚至PTSD的肾上腺素能机制的有价值的遗传模型。

更新日期:2019-12-02
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