Long noncoding RNA PAHAL modulates locust behavioural plasticity through the feedback regulation of dopamine biosynthesis.

Some long noncoding RNAs (lncRNAs) are specifically expressed in brain cells, implying their neural and behavioural functions. However, how lncRNAs contribute to neural regulatory networks governing the precise behaviour of animals is less explored. Here, we report the regulatory mechanism of the nuclear-enriched lncRNA PAHAL for dopamine biosynthesis and behavioural adjustment in migratory locusts (Locusta migratoria), a species with extreme behavioral plasticity. PAHAL is transcribed from the sense (coding) strand of the gene encoding phenylalanine hydroxylase (PAH), which is responsible for the synthesis of dopamine from phenylalanine. PAHAL positively regulates PAH expression resulting in dopamine production in the brain. In addition, PAHAL modulates locust behavioral aggregation in a population density-dependent manner. Mechanistically, PAHAL mediates PAH transcriptional activation by recruiting serine/arginine-rich splicing factor 2 (SRSF2), a transcription/splicing factor, to the PAH proximal promoter. The co-activation effect of PAHAL requires the interaction of the PAHAL/SRSF2 complex with the promoter-associated nascent RNA of PAH. Thus, the data support a model of feedback modulation of animal behavioural plasticity by an lncRNA. In this model, the lncRNA mediates neurotransmitter metabolism through orchestrating a local transcriptional loop. Author summary The neurotransmitter dopamine is crucial for the neuronal and behavioral response in animals. Phenylalanine hydroxylase (PAH) is involved in dopamine biosynthesis and behavioral regulation in the migratory locust. However, the molecular mechanism for the fine tuning of PAH expression in behavioral response remains ambiguous. Here we discovered a nuclear-enriched lncRNA PAHAL that is transcribed from the coding strand of the PAH gene in the locust (i.e., sense lncRNA). PAHAL positively regulated PAH expression and dopamine production in the brain. In addition, PAHAL modulated behavioral aggregation of the locust. Mechanistically, PAHAL mediated the transcriptional activation of PAH by recruiting SRSF2, a transcription/splicing factor, to the promoter-associated nascent RNA of PAH. These data support a model of feedback modulation of dopamine biosynthesis and behavioral plasticity via a sense lncRNA in the catecholamine metabolic pathway.