Mapping working memory networks in the Drosophila brain

2021 Fiscal Year Research-status Report

• Project/Area Number: 18K06496
• Research Institution: Tokyo Metropolitan Institute of Medical Science
• Principal Investigator: 堀内 純二郎 公益財団法人東京都医学総合研究所, 脳・神経科学研究分野, 主席研究員 (80392364)
• Project Period (FY): 2018-04-01 – 2023-03-31
• Keywords: Learning / Memory / Drosophila

Outline of Annual Research Achievements

Learning occurs when an organism forms an association between two previously unrelated stimuli. Thus, if we ring a bell each time we feed a dog, or if we electrically shock a fly each time with expose it to an odor, the dog or fly learns to associate the bell tone with food or the odor with pain. We have been mapping where these associations are formed in the Drosophila brain and studying how the reliability of these associations change upon aging. Odor and pain information converge in structures called the Mushroom Bodies in Drosophila and formation of odor-shock associations increases expression of memory associated transcription factors in a subset of Mushroom Body neurons. Activity of these neurons are required for memory recall and artificial activation of these neurons activates memory-associated behaviors. Memory-associated activity of these neurons is referred to as a memory engram. We have found that memory engrams are formed normally in old flies, but these engrams can be reactivated by inappropriate stimuli leading to a phenomenon called memory generalization.

Current Status of Research Progress

3: Progress in research has been slightly delayed.

Reason

We have been studying where memories are stored in the Drosophila brain and how these memories change upon aging. Currently, we have found that memory engrams are formed in old flies similar to young flies. These engrams are formed when memories are formed and their activity is required for memory recall. Inactivating these engrams prevents recall and artificial activation of these engrams induces memory -associated behaviors. However, we have found that engrams in old flies are reactivated by many different odors instead of just the specific odor paired with electrical shocks during training. Behaviorally, we have found that old flies have an increased avoidance to a shock-paired odor, indicating that they are able to learn an association. However, they also have an increased avoidance to non shock-paired odors, indicating that they lack specificity in what they learn. They learn to avoid many odors in general rather than a specific shock-paired odor. This behavior is consistent with our findings regarding reactivation of memory engrams. We are currently organizing our results in a manuscript.

Strategy for Future Research Activity

In the next year we plan to determine the mechanism by which memory generalization occurs in old flies. Previously, we found that memory formation requires high glutamate activity during learning and reduced glutamate activity during memory consolidation. Old flies are unable to reduce glutamate activity during consolidation resulting in poor memory. Taken together with our current results, we hypothesize that high glutamate activity during consolidation is responsible for memory generalization and inadvertent memory recall at inappropriate times. Thus we plan to identify the brain locations where glutamate activity needs to be reduced during consolidation to determine whether these locations correspond to locations of memory engram cells.

Causes of Carryover

Due to the coronavirus pandemic local and international meetings that I was planning to attend were canceled, and money for attending these meetings remained unused. This year, In the current year I will use those funds to continue my research. Specifically, I will use these funds to examine whether memory formation affects expression of glutamate receptors and whether aging alters this expression.

Research Products

• [Journal Article] High-sucrose diets contribute to brain angiopathy with impaired glucose uptake and psychosis-related higher brain dysfunctions in mice. (2021)
  • Author(s): Hirai S, Miwa H, Tanaka T, Toriumi K, Kunii Y, Shimbo H, Sakamoto T, Hino M, Izumi R, Nagaoka A, Yabe H, Nakamachi T, Shioda S, Dan T, Miyata T, Nishito Y, Suzuki K, Miyashita M, Tomoda T, Hikida T, Horiuchi J, Itokawa M, Arai M, Okado H.
  • Journal Title: SCIENCE ADVANCES Volume: Vol 7, Issue 46 Pages: eabl6077
  • DOI: 10.1126/sciadv.abl6077
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Remarks] Learning and Memory Project
  • URL: https://www.igakuken.or.jp/memory/index.html