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Ras, Raf and recall
JUPITER, Fla.—It’s well known that short- and long-term memories are stored in certain parts of the brain, but the fact that specific genes play a role in long-term memory, not just specific lobes, is likely news to many. Prof. Ronald Davis of Scripps Research, Florida, and his lab detailed in a recent publication how Ras and Raf both play a role in the process of memories transitioning from short-term to long-term storage in the brain. Their research was published in the Proceedings of the National Academy of Sciences (PNAS) in a paper titled “Ras acts as a molecular switch between two forms of consolidated memory in Drosophila.”
The work focused on a type of memory known as “protein-synthesis dependent long-term memory,” or PSD-LTM, and used Drosophila melanogaster (fruit flies) for their models. Using RNA interference, the researchers lowered the expression of several genes in the brains of flies, and found that lowering the expression of the Ras gene and Raf, a downstream molecule, led to two results: intermediate-term memories were significantly enhanced while PSD long-term memories of a negative experience were eliminated entirely, according to Davis.
“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 authors explain. “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.”
Or, put another way, a memory can either be shuffled into intermediate storage or long-term storage, but not both.
To test the flies' memories, the researchers exposed them to certain odors in one part of a glass tube while simultaneously administering a shock to the flies' feet, thereby associating the odor with a negative experience and leading to a tendency in the flies to avoid the odor when exposed in the future. However, Dr. Nathaniel Noyes, a research associate in the Davis lab and first author of the PNAS paper, noted that when Ras and Raf were knocked down, the flies consistently forgot the association of the odor with the shock, regardless of how many times they'd been exposed to that series of events previously.
“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,” the authors reported. “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 … We conclude that MBn Ras/Raf inhibition of ROCK suppresses the consolidation of ARM, which permits the formation of PSD-LTM.”
This work also identified the Ras enzyme Ras85D as a key player in the establishment of long-term memories. The team found that Ras85D is pivotal in determining whether some experiences become intermediate memories that fade or long-term PSD memories. Noyes theorized that further research will show that dopamine is also a factor in this process.
“We believe that dopamine signals to the brain that this memory is important enough to be stored long-term. We speculate that Ras and Raf receive this dopamine signal and thereby block intermediate memory and promote PSD long-term memory,” he explained.
Noyes added that additional study will be required to determine exactly how closely their Drosophila results translate into human memory.
Davis' lab is working on a variety of other projects as well related to memory in D. melanogaster, among them a survey of memory suppressor genes identified through an RNAi-expression based behavioral screen, as noted on the lab's website. As “genes are generally well conserved between Drosophila and human,” these suppressor genes could offer answers or even drug targets in humans.
The lab is also exploring memory with relation to aging. While it's well known that human memory deteriorates with age, previous research in the Davis lab revealed that in Drosophila, it's intermediate-term memory specifically that is compromised, “and that activating a specific neuron known as the dorsal posterior medial neuron (DMPn) reverses this impairment. This suggests an age-dependent defect in DPMn function or connectivity. In addition, protein-synthesis-dependent long-term memory is also impaired in aged flies, and this impairment might also be due to lowered function or connectivity of DPMn with mushroom body or other neurons. We are continuing our aging studies with a focus on the DPMn and how age alters its function and connectivity.”