Ras acts as a molecular switch between two forms of consolidated memory in Drosophila

Abstract

Long-lasting, consolidated memories require not only positive biological processes that facilitate long-term memories (LTM) but also the suppression of inhibitory processes that prevent them. The mushroom body neurons (MBn) in Drosophila melanogaster store protein synthesis-dependent LTM (PSD-LTM) as well as protein synthesis-independent, anesthesia-resistant memory (ARM). The formation of ARM inhibits PSD-LTM but the underlying molecular processes that mediate this interaction remain unknown. Here, we demonstrate that the Ras→Raf→rho kinase (ROCK) pathway in MBn suppresses ARM consolidation, allowing the formation of PSD-LTM. Our initial results revealed that the effects of Ras on memory are due to postacquisition processes. Ras knockdown enhanced memory expression but had no effect on acquisition. Additionally, increasing Ras activity optogenetically after, but not before, acquisition impaired memory performance. The elevated memory produced by Ras knockdown is a result of increased ARM. While Ras knockdown enhanced the consolidation of ARM, it eliminated PSD-LTM. We found that these effects are mediated by the downstream kinase Raf. Similar to Ras, knockdown of Raf enhanced ARM consolidation and impaired PSD-LTM. Surprisingly, knockdown of the canonical downstream extracellular signal-regulated kinase did not reproduce the phenotypes observed with Ras and Raf knockdown. Rather, Ras/Raf inhibition of ROCK was found to be responsible for suppressing ARM. Constitutively active ROCK enhanced ARM and impaired PSD-LTM, while decreasing ROCK activity rescued the enhanced ARM produced by Ras knockdown. We conclude that MBn Ras/Raf inhibition of ROCK suppresses the consolidation of ARM, which permits the formation of PSD-LTM.

Dopamine-based mechanism for transient forgetting

“…Electric shock: conditioned flies were briefly exposed to mild electric shock using clean and fresh training tubes. Blue light: a 34 x 13 x 19 cm box was lined with reflective mirror boards and a computer fan for internal cooling 32 . Two rows of three 448 nm emitting LED modules (Luxeon SP-01-V4) were attached to the top inside the box, with a projected light intensity of 0.15 mW/mm 2 .…”

Cold Shock Disrupts Massed Training-Elicited Memory in Drosophila

“…Despite evidence suggesting that both of these operationally and temporally distinct memory types engage common, or similar mechanisms [ 4 , 7 , 8 ], it is unclear whether they reflect the same cognitive outcome assayed at different time points or are in fact distinct memory types. While both cold shock and five or ten-round MC protocols are widely used to address questions regarding ARM [ 3 , 4 , 7 ], data acquired by one training method are not typically cross-checked with the other.…”

Associative Learning Requires Neurofibromin to Modulate GABAergic Inputs to Drosophila Mushroom Bodies

“…Ras1 hyperactivation has been shown to result via PKC z activation in suppression of Ga s and therefore reduced cAMP in vertebrate cultured neurons (Anastasaki and Gutmann, 2014), suggesting that this may also occur in the MBs of dNf1 E2 homozygotes. Interestingly, an inhibitory role for Ras/Raf signaling for protein synthesis-dependent memory formation in MBs has been described recently (Noyes et al, 2020).…”