HDAC I inhibition in the dorsal and ventral hippocampus differentially modulates predator-odor fear learning and generalization.
HDAC I inhibition in the dorsal and ventral hippocampus differentially modulates predator-odor fear learning and generalization.
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DOI：
10.3389/fnins.2015.00319
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发表时间：
2015
影响因子：
4.3
通讯作者：
Muzzio IA
中科院分区：
文献类型：
--
作者：
Yuan RK;Hebert JC;Thomas AS;Wann EG;Muzzio IA
虽然捕食者气味是啮齿动物行为学相关的刺激，分子通路和参与捕食者气味条件反射的一些大脑区域的贡献仍然难以捉摸。抑制背海马中的组蛋白脱乙酰酶（HDAC）已被证明可增强休克诱导的情境恐惧学习，但尚不清楚HDAC在捕食者气味恐惧学习过程中是否沿背腹海马轴具有沿着差异效应。我们在小鼠的背侧或腹侧海马体中双侧注射MS-275，一种I类HDAC抑制剂，发现它对两个区域的先天性焦虑没有影响。然后，我们评估了MS-275在不同阶段的恐惧学习沿着纵向海马轴的影响。在环境预暴露后（预处理注射），当首次形成环境表征时，或在暴露于土狼尿液后（后处理注射），当环境与捕食者气味相关时，向动物注射MS-275或溶剂。当MS-275在背景预暴露后给药时，背部注射的动物在训练背景下表现出增强的恐惧，但能够将其与中性环境区分开来。相反，腹侧注射的动物没有显示出增强学习的训练背景下，但一般化的恐惧反应，以一个中立的背景。然而，当MS-275在预处理后给药时，MS-275和溶剂对照组之间的背侧或腹侧海马体无差异。令人惊讶的是，所有的群体都表现出对中性环境的概括，这表明捕食者气味暴露，然后是温和的压力，如约束，导致恐惧的概括。这些结果可能阐明背侧和腹侧海马在捕食者气味诱导的恐惧条件反射中的不同功能以及恐惧泛化的分子机制。
Although predator odors are ethologically relevant stimuli for rodents, the molecular pathways and contribution of some brain regions involved in predator odor conditioning remain elusive. Inhibition of histone deacetylases (HDACs) in the dorsal hippocampus has been shown to enhance shock-induced contextual fear learning, but it is unknown if HDACs have differential effects along the dorso-ventral hippocampal axis during predator odor fear learning. We injected MS-275, a class I HDAC inhibitor, bilaterally in the dorsal or ventral hippocampus of mice and found that it had no effects on innate anxiety in either region. We then assessed the effects of MS-275 at different stages of fear learning along the longitudinal hippocampal axis. Animals were injected with MS-275 or vehicle after context pre-exposure (pre-conditioning injections), when a representation of the context is first formed, or after exposure to coyote urine (post-conditioning injections), when the context becomes associated with predator odor. When MS-275 was administered after context pre-exposure, dorsally injected animals showed enhanced fear in the training context but were able to discriminate it from a neutral environment. Conversely, ventrally injected animals did not display enhanced learning in the training context but generalized the fear response to a neutral context. However, when MS-275 was administered after conditioning, there were no differences between the MS-275 and vehicle control groups in either the dorsal or ventral hippocampus. Surprisingly, all groups displayed generalization to a neutral context, suggesting that predator odor exposure followed by a mild stressor such as restraint leads to fear generalization. These results may elucidate distinct functions of the dorsal and ventral hippocampus in predator odor-induced fear conditioning as well as some of the molecular mechanisms underlying fear generalization.