注意力不足/過動症為臨床上具高度異質性之神經疾病，通常表現衝動、過動與注意力缺失等症狀。基於果蠅發展完備之基因工具與自動化行為監測技術，我們使用群體社交行為分析系統以量化果蠅的注意力不足/過動症行為。透過此系統，我們首先大量篩選經由跨基因體關聯性研究分析所預測之具有致病潛力的125株突變果蠅。接著2個候選基因突變株(dDAT, radish)的行為參數被集中分析以建立三個與注意力不足/過動症相關的疾病指數。這些指數能夠使我們以更加簡化的方式描述疾病行為。當果蠅失去特定的候選基因時，疾病指數會產生顯著差異而此變化可被臨床用藥(methylphenidate)所緩解。我們接著研究dDAT在不同腦部區域的充分與必要角色，結果顯示只有在特定GAL4表達區域下操控dDAT表現才能誘導或緩解注意力不足/過動症行為。最後我們分析所有經過測試之突變株果蠅的疾病指數並把這些蟲株區分為數個近似於臨床分類的表現型。這些結果顯示我們成功建立果蠅的注意力不足/過動症行為模式參數以研究注意力不足/過動症之分子與神經迴路致病機制。

Attention-deficit/hyperactivity disorder (ADHD) is a clinically heterogeneous disorder presenting as various combinations of impulsivity, hyperactivity and inattention symptoms. Taking the advantage of sophisticated Drosophila genetic tools and automatic monitoring technique, we applied Analytic Social Conduct Observatory (ASCO), a multi-fly social behaviour analysis system to quantitatively measure fly ADHD behaviour. We first performed large scale genetic screening to test 125 candidate mutant genes predicted by genome-wide association study (GWAS). Next we focused on the behavioural parameters of candidate mutant flies including dDATMB07315, dDATZ2-1744 and radish1 to define three ADHD-related indexes which were capable of simply describing the disease phenotype. The loss of candidate mutant gene caused significant difference in these indexes and such phenotype could be relieved by clinical ADHD drug methylphenidate (MPH). We next investigate the necessary and sufficient role of dDAT in different DA neuron subsets and found out that genetic inducing and rescuing could only be achieved by manipulating dDAT in specific drivers. Finally we categorized all the tested candidate mutants into several types based on the disease index analyzation. With all these results, we established fly ADHD indexes which provided great opportunities for figuring out the detailed molecular and circuit mechanism of ADHD.

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