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Significance Most animals record only labile memories of single events, whereas the formation of persistent long-term memories (LTMs) usually requires recurrent experiences. Our study distinguishes these different memory types through a deconvolution of molecular/biochemical processes within specific neurons of an identified memory circuit. A training-responsive gene activator, CREBA, engages paired DAL neurons in this circuit by promoting protein synthesis–dependent LTMs, which can otherwise be antagonized by CREBB repressor proteins. Increased CREBA expression or elevated membrane excitability enhances LTMs even after only one training cycle. These findings exemplify a circuit gating mechanism via cellular changes in specific single neurons to distinguish one-time experiences from multiple sessions of learning for storage as persistent memory., Episodic events are frequently consolidated into labile memory but are not necessarily transferred to persistent long-term memory (LTM). Regulatory mechanisms leading to LTM formation are poorly understood, however, especially at the resolution of identified neurons. Here, we demonstrate enhanced LTM following aversive olfactory conditioning in Drosophila when the transcription factor cyclic AMP response element binding protein A (CREBA) is induced in just two dorsal-anterior-lateral (DAL) neurons. Our experiments show that this process is regulated by protein–gene interactions in DAL neurons: (1) crebA transcription is induced by training and repressed by crebB overexpression, (2) CREBA bidirectionally modulates LTM formation, (3) crebA overexpression enhances training-induced gene transcription, and (4) increasing membrane excitability enhances LTM formation and gene expression. These findings suggest that activity-dependent gene expression in DAL neurons during LTM formation is regulated by CREB proteins.

Challenging the Mushroom Bodies Early memory is labile and is gradually consolidated over time into long-lasting, stable memory. In several species, including mammals, memory consolidation depends on protein synthesis. In Drosophila , long-term memory is produced by spaced repetitive training, which induces cyclic adenosine monophosphate (cAMP)–response element–binding protein (CREB)–dependent gene transcription and de novo protein synthesis. Using a large number of genetic tools, Chen et al. (p. 678 ; see the Perspective by Dubnau ) localized this CREB-dependent induction of de novo protein synthesis to two dorsal-anterior-lateral neurons in the adult brain. Importantly, protein synthesis was not required within the mushroom bodies, which are usually considered to be the site of associative learning and memory in insects.