Cellular and genetic regulation of short and intermediate-term memory and the Gq alpha regulated transition to long-term memory in C. elegans

Abstract

Current evidence suggests that the molecular basis of short-term associative memory (STAM) arises from changes in protein dynamics that increase the strength of synaptic signaling; however, many of the fundamental molecular mechanisms underlying STAM, particularly in C. elegans, remain unknown. Our lab developed a short-term associative memory (STAM) assay in which worms learn to associate food with an odor and remember this association for over one hour. I have found that a single massed training produces short-term memory that is genetically consistent with short-term memory in other organisms. For example, C. elegans STAM requires cAMP signaling and does not depend on CREB, gene transcription, or translation for 30-minute memory. One-hour memory is translation-dependent indicating that this time-point may be a form of intermediate-term associative memory (ITAM). Interestingly, I also find that translation is required for forgetting after massed training. Additionally, we find that STAM can be distinguished from olfactory adaptation. Adaptation mutants show variable responses to STAM training, suggesting that they may differentially employ the same molecular machinery. By testing canonical short-term memory regulators, I have established that C. elegans STAM training can now confidently be used to uncover novel and conserved short and intermediate-term memory regulators.

A gain-of-function mutation in the C. elegans Gqá homolog egl-30, inhibits adaptation, increases CREB expression after starvation, and enhances excitatory neurotransmitter release causing among others a hyperactive, loopy phenotype. egl-30 gain-of-function mutants have strikingly extended STAM with memory after STAM training lasting longer than 24 hours vs. 1 hour for wild-type worms. This 24 hr. memory is dependent on CREB, suggesting that the memory has become long-term. We are currently identifying the neurons and downstream genetic regulators involved egl-30 overexpression memory. To our knowledge, this is the first indication that Gqá is directly involved in the consolidation of and transition between short and long-term memory.

These findings indicate that C. elegans STAM is a unique learning and memory paradigm that we can use to elucidate conserved mechanisms of associative memory including molecular determinants and cellular dynamics. Indeed I have identified several novel regulators of memory and forgetting, including Gqá, that will contribute to broader cross-species memory research.