Modulation of anxiety and fear via distinct intrahippocampal circuits.
Modulation of anxiety and fear via distinct intrahippocampal circuits.
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DOI：
10.7554/elife.14120
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发表时间：
2016-03-14
期刊：
影响因子：
7.7
通讯作者：
Rudolph U
中科院分区：
文献类型：
--
作者：
Engin E;Smith KS;Gao Y;Nagy D;Foster RA;Tsvetkov E;Keist R;Crestani F;Fritschy JM;Bolshakov VY;Hajos M;Heldt SA;Rudolph U
最近的研究结果表明，在控制恐惧和焦虑方面，大脑结构中的微电路和细胞群水平具有高度的专业化。然而，尽管越来越多的证据表明不同的海马子区域在其他认知领域中具有专门的作用，但海马在焦虑和恐惧研究中一直被视为一个单一的结构。使用新的细胞类型和区域特异性GABAA受体α2亚基的条件性敲除，我们证明，抑制齿状回和CA 3的主要神经元通过α2-含有GABAA受体（α2GABAARs）是抑制焦虑所必需的，而抑制CA 1锥体神经元是抑制恐惧反应所必需的。我们进一步表明，海马theta活动的地西泮调制与我们的行为研究结果显示出一定的相似之处，这表明所观察到的行为效应的可能机制。因此，我们的研究结果表明，海马微电路在焦虑与恐惧的调节中存在双重分离。http://dx.doi.org/10.7554/eLife.14120.001恐惧和焦虑可以被认为是不同但相关的情绪状态。恐惧是由特定的有害情况引发的，例如捕食者的直接存在。相反，焦虑是由一个模糊的威胁的可能性引起的，比如在一个暴露的环境中，这增加了被捕食者发现的机会。有证据表明，大脑中控制恐惧和焦虑的区域略有不同，但对于帮助调节这两种情绪状态的特定大脑区域仍有很多未知之处。海马体是一个与焦虑和恐惧以及学习和记忆有关的大脑区域。海马体因其形状而得名，它由三个子区域组成：CA 1，CA 3和齿状回。这些次区域中的每一个在学习和记忆中都有不同的作用。然而，他们对控制恐惧和焦虑的个人贡献尚不清楚。在一些海马神经元表面发现的一种抑制性受体蛋白先前已被证明与控制恐惧和焦虑有关。现在，Engin等人研究了三组不同的转基因小鼠，每组小鼠在海马体的不同亚区缺乏受体蛋白。这些老鼠完成了刺激焦虑或恐惧的测试，其中一些是在焦虑和恐惧减轻药物安定的影响下完成的。值得注意的是，地西泮未能减少海马CA 1亚区缺乏抑制性受体蛋白的动物的恐惧，这表明该亚区参与了恐惧反应。然而，在齿状回或CA 3中缺乏受体的小鼠对药物的反应正常（当给予地西泮时，它们表现出减少的恐惧）。在焦虑测试中，情况正好相反。在齿状回或CA 3中缺乏抑制性受体的动物中，地西泮未能减轻焦虑，这表明这些亚区域参与了焦虑的调节。然而，这种药物仍然减少了在CA 1亚区缺乏受体蛋白的小鼠的焦虑。现在需要进一步的研究来阐明操纵海马体的特定子区域如何改变它与其他大脑结构的通信方式，以产生焦虑或恐惧相关行为的变化。DOI：http://dx.doi.org/10.7554/eLife.14120.002网站
Recent findings indicate a high level of specialization at the level of microcircuits and cell populations within brain structures with regards to the control of fear and anxiety. The hippocampus, however, has been treated as a unitary structure in anxiety and fear research despite mounting evidence that different hippocampal subregions have specialized roles in other cognitive domains. Using novel cell-type- and region-specific conditional knockouts of the GABAA receptor α2 subunit, we demonstrate that inhibition of the principal neurons of the dentate gyrus and CA3 via α2-containing GABAA receptors (α2GABAARs) is required to suppress anxiety, while the inhibition of CA1 pyramidal neurons is required to suppress fear responses. We further show that the diazepam-modulation of hippocampal theta activity shows certain parallels with our behavioral findings, suggesting a possible mechanism for the observed behavioral effects. Thus, our findings demonstrate a double dissociation in the regulation of anxiety versus fear by hippocampal microcircuitry. DOI: http://dx.doi.org/10.7554/eLife.14120.001 Fear and anxiety can be thought of as different but related emotional states. Fear is triggered by specific harmful situations, such as the immediate presence of a predator. Anxiety instead results from the possibility of an obscure threat, such as being in an exposed environment, which increases the chance of being detected by a predator. Evidence suggests that slightly different areas of the brain control fear and anxiety, but much remains unknown about the specific brain regions that help to regulate these two emotional states. One brain region that has been implicated in both anxiety and fear – as well as in learning and memory – is the hippocampus. Named after the Greek word for seahorse because of its shape, the hippocampus is made up of three subregions: CA1, CA3 and the dentate gyrus. Each of these subregions has a distinct role in learning and memory. However, their individual contributions to the control of fear and anxiety were not known. An inhibitory receptor protein found in the surface of some hippocampal neurons had previously been shown to be involved in controlling fear and anxiety. Now, Engin et al. have studied three different groups of genetically modified mice, each of which lacks the receptor protein in a different subregion of the hippocampus. The mice completed tests that stimulated anxiety or fear, some while under the influence of the anxiety and fear-reducing drug diazepam. Notably, diazepam failed to reduce fear in animals that lacked the inhibitory receptor protein in the CA1 subregion of the hippocampus, suggesting that this subregion participates in the fear response. However, mice that lacked the receptor in the dentate gyrus or CA3 responded normally to the drug (they showed reduced fear when given diazepam). In tests of anxiety, the picture was exactly the opposite. Diazepam failed to reduce anxiety in animals lacking the inhibitory receptor in the dentate gyrus or CA3, indicating that these subregions are involved in the regulation of anxiety. However, the drug still reduced anxiety in mice that lacked the receptor protein in the CA1 subregion. Further studies are now needed to clarify how manipulating specific subregions of the hippocampus alters how it communicates with other brain structures to generate changes in anxiety or fear-related behaviors. DOI: http://dx.doi.org/10.7554/eLife.14120.002