8月23日,《神经科学杂志》(Journal of Neuroscience)发表了中科院上海生科院神经科学研究所郭爱克研究组题为“调节果蝇视觉逆转学习的一个伽马氨基丁酸能的抑制性神经环路”的研究论文。该论文报道了一对伽马氨基丁酸能神经元(Anterior Paired Lateral Neurons, APL神经元)与蘑菇体(mushroom body)形成的抑制性神经环路参与果蝇灵活学习行为的调制。该工作是由神经所博士生任庆仲等人在郭爱克院士的指导下完成的。
生物生活在一个持续变化的环境里。行为的灵活性可使生物更好的适应环境,从而在残酷的自然选择中生存下来。人类的一个重要特色就是我们日常生活中异常的行为灵活性,特别是在社会活动方面。令人遗憾的是,前额叶受到损伤的病人和精神疾病病人的行为灵活性显著下降,表现出很多固执的、不恰当的社会活动。由于哺乳类大脑神经环路巨大的复杂性,行为灵活性的神经机制还未得到充分阐明。
在这项研究中,郭爱克组的研究人员首先在果蝇中建立了一个广泛用于检测学习灵活性的逆转学习范式。两个视觉线索中,一个与惩罚偶联而另一个是安全的。在果蝇学会这一联系后,实验者转换了惩罚与视觉线索的联系,在这一新的训练条件下,果蝇被要求灵活的反转已经建立的刺激与反应的联系。利用转基因果蝇、免疫组织化学、定量PCR和精细的遗传操作,郭爱克研究组的研究人员发现从APL神经元到蘑菇体的抑制性的信号特异的促进果蝇的视觉逆转学习。在蘑菇体中降低离子型伽马氨基丁酸能受体,或者沉默蘑菇体的突触传递,导致了与APL神经元缺陷同样的行为效果。这些神经操作对简单的视觉学习,包括初始的学习、消退学习、或全新刺激的学习没有显著的影响。
这些发现使果蝇这一传统遗传模式生物成为研究行为灵活性的神经环路机制的一个新的选择。果蝇相对简单的脑为详细了解负责行为性的神经环路(如APL神经元-蘑菇体环路)的神经计算原理提供了明显的优势。鉴于果蝇丰富的研究基因的遗传工具,这项研究为在分子层面更为深刻的解析行为灵活性的机制提供了可能。
该课题得到了中科院、科技部“973项目”以及中国国家自然科学基金的资助。(生物谷Bioon.com)
doi: 10.1523/JNEUROSCI.0827-12.2012
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A GABAergic inhibitory neural circuit regulates visual reversal learning in Drosophila
Qingzhong Ren, Hao Li, Yanying Wu, Jing Ren, and Aike Guo
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 GABAA 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.