Hippocampal GABAB(1a) Receptors Constrain Generalized Contextual Fear
Hippocampal GABAB(1a) Receptors Constrain Generalized Contextual Fear
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DOI：
10.1038/npp.2016.255
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发表时间：
2017-03
影响因子：
7.6
通讯作者：
J. Lynch;P. Winiecki;T. L. Gilman;Jordan M. Adkins;A. Jasnow
中科院分区：
文献类型：
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作者：
J. Lynch;P. Winiecki;T. L. Gilman;Jordan M. Adkins;A. Jasnow
许多焦虑障碍的特征是对中性或模糊刺激的恐惧反应的泛化。因此，全面了解导致广泛性恐惧的机制对于制定成功的焦虑症治疗方法至关重要。先前的研究表明，GABA介导的突触前抑制在线索恐惧泛化中起着关键作用，因为遗传缺失突触前GABA B （1a）受体的动物不能区分CS+和CS -音调。我们实验室的工作进一步确定了GABA B （1a）受体对于维持情境记忆的准确性是必要的，从而限制了广义情境恐惧。我们之前发现，GABA B (1a) KO小鼠在训练后24小时对中性环境表现出广泛性恐惧，但在训练后2小时则没有。在物体定位和识别方面也观察到类似的模式，这表明这种受体亚型影响精确的上下文和空间记忆的巩固和/或检索。在这里，我们试图专门研究GABA B （1a）受体在巩固或检索精确恐惧记忆中的作用。为此，我们在情境恐惧训练的巩固和检索过程中，将选择性GABA B （1a）受体拮抗剂CGP 36216注入脑室内（ICV），或局部注入背侧海马、腹侧海马或前扣带皮层（ACC）。在训练后（巩固）通过ICV、海马背侧或海马腹侧输注阻断GABA B （1a）受体可导致小鼠对中性环境的恐惧泛化，但在训练后24小时，而不是6小时。然而，训练后将CGP注入ACC并没有促进广泛性恐惧。此外，ICV、海马背侧、海马腹侧或ACC在测试（检索）前立即注射不会导致情境恐惧泛化。这些数据表明，gaba介导的突触前抑制对精确情境记忆的检索并不重要，而是在精确情境记忆的长期巩固和限制广义恐惧反应中起重要作用。
Many anxiety disorders are characterized by generalization of fear responses to neutral or ambiguous stimuli. Therefore, a comprehensive understanding of the mechanisms contributing to generalized fear is essential for formulating successful treatments for anxiety disorders. Previous research shows that GABA-mediated presynaptic inhibition has a critical role in cued fear generalization, as animals with genetically deleted presynaptic GABA B (1a) receptors cannot discriminate between CS+ and CS− tones. Work from our laboratory has further identified that GABA B (1a) receptors are necessary for maintaining contextual memory precision, thereby constraining generalized contextual fear. We previously found that GABA B (1a) KO mice show generalized fear to a neutral context 24 h after training, but not 2 h after training. A similar pattern was observed with object location and recognition, suggesting that this receptor subtype affects consolidation and/or retrieval of precise contextual and spatial memories. Here we sought to specifically examine the involvement of GABA B (1a) receptors in consolidation or retrieval of a precise fear memory. To do so, we infused a selective GABA B (1a) receptor antagonist, CGP 36216, intracerebroventricularly (ICV), or locally into the dorsal hippocampus, ventral hippocampus, or anterior cingulate cortex (ACC), during consolidation and retrieval of context fear training. Blockade of GABA B (1a) receptors through ICV, dorsal hippocampal, or ventral hippocampal infusions ‘after’training (consolidation) resulted in fear generalization to the neutral context when mice were tested 24, but not 6 h after training. Post-training infusions of CGP into the ACC, however, did not promote generalized fear. In addition, ICV, dorsal hippocampal, ventral hippocampal, or ACC infusions immediately ‘before’testing (retrieval) did not result in context fear generalization. These data suggest that GABA-mediated presynaptic inhibition is not critical for retrieval of precise contextual memory, but rather has an important role in the long-term consolidation of precise contextual memories and constrains generalized fear responses.