Institute of Neuroscience and State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
J Neurosci. 2012 Aug 22;32(34):11524-38. doi: 10.1523/JNEUROSCI.0827-12.2012.
Inflexible cognition and behavior are prominent features of prefrontal cortex damage and several neuropsychiatric disorders. The ability to flexibly adapt cognitive processing and behavior to dynamically changing environmental contingencies has been studied using the reversal learning paradigm in mammals, but the complexity of the brain circuits precludes a detailed analysis of the underlying neural mechanism. Here we study the neural circuitry mechanism supporting flexible behavior in a genetically tractable model organism, Drosophila melanogaster. Combining quantitative behavior analysis and genetic manipulation, we found that inhibition from a single pair of giant GABAergic neurons, the anterior paired lateral (APL) neurons, onto the mushroom bodies (MBs) selectively facilitates behavioral flexibility during visual reversal learning. This effect was mediated by ionotropic GABA(A) receptors in the MB. Moreover, flies with perturbed MB output recapitulated the poor reversal performance of flies with dysfunctional APL neurons. Importantly, we observed that flies with dysfunctional APL-MB circuit performed normally in simple forms of visual learning, including initial learning, extinction, and differential conditioning. Finally, we showed that acute disruption of the APL-MB circuit is sufficient to impair visual reversal learning. Together, these data suggest that the APL-MB circuit plays an essential role in the resolution of conflicting reinforcement contingencies and reveals an inhibitory neural mechanism underlying flexible behavior in Drosophila.
刻板的认知和行为是前额叶皮层损伤和几种神经精神疾病的突出特征。使用哺乳动物的反转学习范式研究了灵活适应认知处理和行为以适应动态变化的环境关联的能力，但大脑回路的复杂性排除了对潜在神经机制的详细分析。在这里，我们研究了在遗传上易于处理的模式生物果蝇中支持灵活行为的神经回路机制。通过定量行为分析和遗传操作相结合，我们发现来自一对单一的巨大 GABA 能神经元（前配对侧（APL）神经元）到蘑菇体（MB）的抑制作用选择性地促进了视觉反转学习期间的行为灵活性。这种效应是由 MB 中的离子型 GABA(A)受体介导的。此外，MB 输出受到干扰的苍蝇重现了 APL 神经元功能障碍的苍蝇的不良反转性能。重要的是，我们观察到，APL-MB 回路功能障碍的苍蝇在简单形式的视觉学习中表现正常，包括初始学习、消退和差异条件作用。最后，我们表明，APL-MB 回路的急性破坏足以损害视觉反转学习。总之，这些数据表明 APL-MB 回路在解决冲突的强化关联中起着至关重要的作用，并揭示了果蝇灵活行为的抑制性神经机制。
