8月23日，《神經(jīng)科學(xué)雜志》（Journal of Neuroscience）發(fā)表了中科院上海生科院神經(jīng)科學(xué)研究所郭愛(ài)克研究組題為“調(diào)節(jié)果蠅視覺(jué)逆轉(zhuǎn)學(xué)習(xí)的一個(gè)伽馬氨基丁酸能的抑制性神經(jīng)環(huán)路”的研究論文,。該論文報(bào)道了一對(duì)伽馬氨基丁酸能神經(jīng)元（Anterior Paired Lateral Neurons, APL神經(jīng)元）與蘑菇體（mushroom body）形成的抑制性神經(jīng)環(huán)路參與果蠅靈活學(xué)習(xí)行為的調(diào)制,。該工作是由神經(jīng)所博士生任慶仲等人在郭愛(ài)克院士的指導(dǎo)下完成的。
生物生活在一個(gè)持續(xù)變化的環(huán)境里,。行為的靈活性可使生物更好的適應(yīng)環(huán)境,，從而在殘酷的自然選擇中生存下來(lái)。人類的一個(gè)重要特色就是我們?nèi)粘Ｉ钪挟惓５男袨殪`活性,，特別是在社會(huì)活動(dòng)方面,。令人遺憾的是，前額葉受到損傷的病人和精神疾病病人的行為靈活性顯著下降,，表現(xiàn)出很多固執(zhí)的,、不恰當(dāng)?shù)纳鐣?huì)活動(dòng)。由于哺乳類大腦神經(jīng)環(huán)路巨大的復(fù)雜性,，行為靈活性的神經(jīng)機(jī)制還未得到充分闡明,。
在這項(xiàng)研究中，郭愛(ài)克組的研究人員首先在果蠅中建立了一個(gè)廣泛用于檢測(cè)學(xué)習(xí)靈活性的逆轉(zhuǎn)學(xué)習(xí)范式,。兩個(gè)視覺(jué)線索中,，一個(gè)與懲罰偶聯(lián)而另一個(gè)是安全的。在果蠅學(xué)會(huì)這一聯(lián)系后,，實(shí)驗(yàn)者轉(zhuǎn)換了懲罰與視覺(jué)線索的聯(lián)系,，在這一新的訓(xùn)練條件下，果蠅被要求靈活的反轉(zhuǎn)已經(jīng)建立的刺激與反應(yīng)的聯(lián)系,。利用轉(zhuǎn)基因果蠅,、免疫組織化學(xué)、定量PCR和精細(xì)的遺傳操作,，郭愛(ài)克研究組的研究人員發(fā)現(xiàn)從APL神經(jīng)元到蘑菇體的抑制性的信號(hào)特異的促進(jìn)果蠅的視覺(jué)逆轉(zhuǎn)學(xué)習(xí),。在蘑菇體中降低離子型伽馬氨基丁酸能受體，或者沉默蘑菇體的突觸傳遞,，導(dǎo)致了與APL神經(jīng)元缺陷同樣的行為效果,。這些神經(jīng)操作對(duì)簡(jiǎn)單的視覺(jué)學(xué)習(xí)，包括初始的學(xué)習(xí),、消退學(xué)習(xí),、或全新刺激的學(xué)習(xí)沒(méi)有顯著的影響。
這些發(fā)現(xiàn)使果蠅這一傳統(tǒng)遺傳模式生物成為研究行為靈活性的神經(jīng)環(huán)路機(jī)制的一個(gè)新的選擇,。果蠅相對(duì)簡(jiǎn)單的腦為詳細(xì)了解負(fù)責(zé)行為性的神經(jīng)環(huán)路（如APL神經(jīng)元-蘑菇體環(huán)路）的神經(jīng)計(jì)算原理提供了明顯的優(yōu)勢(shì),。鑒于果蠅豐富的研究基因的遺傳工具,，這項(xiàng)研究為在分子層面更為深刻的解析行為靈活性的機(jī)制提供了可能。
該課題得到了中科院,、科技部“973項(xiàng)目”以及中國(guó)國(guó)家自然科學(xué)基金的資助,。（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.
