Comparison of inbred mouse substrains reveals segregation of maladaptive fear phenotypes.
Comparison of inbred mouse substrains reveals segregation of maladaptive fear phenotypes.
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DOI：
10.3389/fnbeh.2014.00282
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发表时间：
2014
影响因子：
3
通讯作者：
Murphy GG
中科院分区：
文献类型：
--
作者：
Temme SJ;Bell RZ;Pahumi R;Murphy GG
适应不良的恐惧，如持续的或容易概括为非威胁性刺激的恐惧，与人类焦虑相关的疾病有关。在实验室中，适应不良的恐惧可以在啮齿动物中使用巴甫洛夫恐惧条件反射进行建模。最近，一种被称为129 S1/SvImJ或129 S1的近交系小鼠被报道为表现出恐惧消退和增强的恐惧泛化障碍。为了确定适应不良恐惧的分离遗传标记的长期目标，我们使用巴甫洛夫恐惧条件反射来表征一个密切相关的亚株，称为129 S6/SvEvTac或129 S6。在这里，我们报告说，像129 S1动物一样，129 S6小鼠在条件反射时表现出适当的恐惧水平，但一旦它们被巩固，就无法消除恐惧记忆。重要的是，适应不良的恐惧表型在这个近交系菌株可以分离的亚株时，探测使用条件反射协议，旨在评估广义的恐惧。我们发现，与129 S1亚株不同，129 S6亚株的小鼠不会将条件性恐惧泛化到以前的新环境中，并且在使用歧视协议进行训练时，可以学会区分两个类似的环境。这些结果表明，至少有两种形式的适应不良恐惧（恐惧消退和恐惧泛化的缺陷）可以在功能上分离，进一步表明潜在的神经生物学是可遗传的。鉴于观察到两个密切相关的亚株可以表现出不同的适应不良恐惧的星座表明，这些发现可以被用来促进焦虑相关疾病的候选基因的识别。
Maladaptive fear, such as fear that is persistent or easily generalized to a nonthreatening stimuli, is associated with anxiety-related disorders in humans. In the laboratory, maladaptive fear can be modeled in rodents using Pavlovian fear conditioning. Recently, an inbred mouse strain known as 129S1/SvImJ, or 129S1 has been reported as exhibiting impairments in fear extinction and enhanced fear generalization. With a long-term goal of identifying segregating genetic markers of maladaptive fear, we used Pavlovian fear conditioning to characterize a closely related substrain designated as 129S6/SvEvTac, or 129S6. Here we report that, like 129S1 animals, 129S6 mice exhibit appropriate levels of fear upon conditioning, but are unable to extinguish fear memories once they are consolidated. Importantly, the maladaptive fear phenotype in this inbred stain can be segregated by sub-strain when probed using conditioning protocols designed to assess generalized fear. We find that unlike the 129S1 substrain, mice from the 129S6 sub-strain do not generalize conditioned fear to previously novel contexts and can learn to discriminate between two similar contexts when trained using a discrimination protocol. These results suggest that at least two forms of maladaptive fear (deficits in fear extinction and fear generalization) can be can be functionally segregated, further suggesting that the underlying neurobiology is heritable. Given the observation that two closely related sub-strains can exhibit different constellations of maladaptive fear suggests that these findings could be exploited to facilitate the identification of candidate genes for anxiety-related disorders.
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DOI：
10.1523/jneurosci.4904-07.2008
发表时间：
2008-08-06
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Hefner K;Whittle N;Juhasz J;Norcross M;Karlsson RM;Saksida LM;Bussey TJ;Singewald N;Holmes A
通讯作者：
Holmes A
影响因子：
2.5
作者：
Bolivar, VJ;Pooler, O;Flaherty, L
通讯作者：
Flaherty, L
影响因子：
2.5
作者：
Bothe, GWM;Bolivar, VJ;Geistfeld, JG
通讯作者：
Geistfeld, JG
影响因子：
7.7
作者：
Qi, ZH;Fujita, H;Breyer, MD
通讯作者：
Breyer, MD
DOI：
10.1111/j.1601-183x.2009.00519.x
发表时间：
2009-11
期刊：
Genes, brain, and behavior
影响因子：
--
作者：
Camp M;Norcross M;Whittle N;Feyder M;D'Hanis W;Yilmazer-Hanke D;Singewald N;Holmes A
通讯作者：
Holmes A