Department of Psychiatry and Behavioral Sciences, Howard Hughes Medical Institute, Center for Behavioral Neuroscience, Emory University School of Medicine, Atlanta, GA 30322, USA.
Proc Natl Acad Sci U S A. 2010 Feb 9;107(6):2675-80. doi: 10.1073/pnas.0909359107. Epub 2010 Jan 25.
In the medial prefrontal cortex, the prelimbic area is emerging as a major modulator of fear behavior, but the mechanisms remain unclear. Using a selective neocortical knockout mouse, virally mediated prelimbic cortical-specific gene deletion, and pharmacological rescue with a TrkB agonist, we examined the role of a primary candidate mechanism, BDNF, in conditioned fear. We found consistently robust deficits in consolidation of cued fear but no effects on acquisition, expression of unlearned fear, sensorimotor function, and spatial learning. This deficit in learned fear in the BDNF knockout mice was rescued with systemic administration of a TrkB receptor agonist, 7,8-dihydroxyflavone. These data indicate that prelimbic BDNF is critical for consolidation of learned fear memories, but it is not required for innate fear or extinction of fear. Moreover, use of site-specific, inducible BDNF deletions shows a powerful mechanism that may further our understanding of the pathophysiology of fear-related disorders.
在内侧前额叶皮层中，额前皮质区域作为恐惧行为的主要调节者而出现，但其中的机制仍不清楚。我们使用选择性新皮层敲除小鼠、病毒介导的额前皮质特异性基因缺失，以及使用 TrkB 激动剂进行药理学挽救，研究了一个主要候选机制 BDNF 在条件性恐惧中的作用。我们发现，在线索恐惧的巩固中存在一致且显著的缺陷，但对获得、未学习恐惧的表达、感觉运动功能和空间学习没有影响。BDNF 敲除小鼠中的这种习得性恐惧缺陷可以通过系统给予 TrkB 受体激动剂 7,8-二羟基黄酮来挽救。这些数据表明，额前皮质 BDNF 对于习得性恐惧记忆的巩固至关重要，但对于先天恐惧或恐惧的消退则不是必需的。此外，使用特定部位、诱导性 BDNF 缺失显示出一种强大的机制，可能会进一步加深我们对与恐惧相关障碍的病理生理学的理解。
