Revisiting the role of cAMP in Drosophila aversive olfactory memory formation

In the olfactory aversive conditioning of Drosophila melanogaster, an odor, the conditioned stimulus (CS), is associated with electric shock, the unconditioned stimulus (US). The Rutabaga adenylyl cyclase in Kenyon cells (KCs) of the fly brain synthesizes cAMP, which is believed to serve as the coincidence detector synergistically stimulated by calcium/calmodulin evoked by the odor reception and GS released in response to the dopamine signaling elicited by electric shock. However, live imaging analyses revealed that olfactory stimulation itself prompted the activation of dopaminergic neurons and resulted in the elevation of cAMP levels in KCs that received dopamine, regardless of calcium signaling. This finding raises questions about the longstanding and fundamental comprehension of conditioning mechanisms, as the cAMP levels in conditioned stimulus-positive (CS+) KCs could not be distinguished from those in the rest of the KCs. Our findings suggest that cAMP concentrations do not function as a mnemonic engram to CS+ neurons. Rather, the collective dynamics of cAMP are capable of integratively encoding the valence ascribed to odors being perceived at a given time. Furthermore, our investigation revealed that associative conditioning induces modifications in dopamine levels in response to both CS and US, resulting in alterations in cAMP levels. The increase in cAMP exerts a deleterious effect on the acetylcholine transmission from KCs. Accordingly, we postulate that, during conditioning, cAMP depresses KCs, thereby skewing the valence of the CS+ odor towards a more aversive state for the conditioned flies, and ultimately culminating in the formation of aversive memories.