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. 2021 Sep 10;118(37):e2100624118. doi: 10.1073/pnas.2100624118

Fig. 5.

Fig. 5.

CREBA and CREBB interactions regulate transcription in DAL neurons and gate LTM formation. (A) In normal flies, 1× or 3×S training (Top) induces neural activity in the memory circuit, which includes DAL neurons. Increased neural activity elevates cAMP signaling and activates PKA, which then directly or indirectly leads to phosphorylation and activation of CREBA. However, basal levels of CREBB repressor inhibit activated CREBA from inducing effector gene expression, thereby blocking LTM formation. With 10×S training (Bottom) activated CREBA accumulates to levels sufficient to overcome basal CREBB repression and promotes transcription of downstream effector “memory genes.” One downstream gene is crebA itself, establishing a putative positive feedback loop and contributing to further CREBA accumulation. CREBA then induces (further) transcription of downstream effector genes, which yields long-lasting changes in intrinsic neuronal excitability and/or synaptic plasticity during memory consolidation. (B) Transgenic overexpression of crebA (+CREBA) or sodium channels (+NaChBac) (Top) provides sufficient CREBA or activity (respectively) to overcome basal CREBB antagonism, establish the CREBA-positive feedback loop, and induce effector gene expression, even with subthreshold 1× or 3×S training, hence the appearance of enhanced LTM (eLTM). Conversely, transgenic overexpression of crebB (+CREBB) (Bottom) yields enough CREBB to block activation of the CREBA feedback loop and transcription of downstream effector genes even after 10×S training, thereby preventing LTM formation. (C) DAL neurons contribute to a circuit-level feedback loop among neurons intrinsic and extrinsic to MBs during olfactory memory consolidation and retrieval. The association of odor (CS) via PNs and foot shock (US) via DANs first is registered as an increase in neural activity within MBs, which then promotes a persistent neural trace among intrinsic and extrinsic MB neurons. Persistent output from MBs then drives neural activity directly or indirectly between MB and DAL neurons via several MBONs. After CREBA-induced changes in gene expression within DAL neurons is complete, output from DAL neurons projecting back to the dendrites of pioneer α/β neurons of the MB is required for memory retrieval.