2022 Fiscal Year Research-status Report
Mapping memory pathways in the Drosophila brain
| Project/Area Number |
21K06403
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| Research Institution | Tokyo Metropolitan Institute of Medical Science |
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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)
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| Project Period (FY) |
2021-04-01 – 2024-03-31
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| Keywords | Drosophila / Aging / Memory |
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| Outline of Annual Research Achievements |
Our goal is to understand the neural networks that are required for memory formation and storage in the Drosophila brain. Drosophila can learn to form associations between odors and painful stimuli. We train flies by exposing them simultaneously to an odor and painful electrical shocks. Flies learn to associate the odor with pain and subsequently avoid the odor. This association is formed and stored in a brain structure known as the mushroom bodies. Neuronal pathways that transmit odor information to the mushroom bodies are currently known, but pathways that transmit shock information is still unelucidated. In addition, although it is known that aging causes decreases in memory, it has been unclear what processes involved in memory formation or retention are affected by aging.
This past year, I collaborated with Tomoyuki Miyashita and Minoru Saitoe and helped prepare a manuscript demonstrating that shock information is transmitted to the mushroom bodies through vesicular release of glutamate from glial cells instead of neurons. Although glia are known to modulate synaptic activity, this manuscript demonstrates that glia also play a direct role in directly transmitting information to higher order neurons.
I also characterized forgetting in Drosophila. Although forgetting is a major field of study, it has been unclear precisely how forgetting occurs. Is forgetting simply the loss of a memory, or is it a more complex process? We determined that memories are not lost during forgetting. Instead forgetting is caused by an increase in the uncertainty associated with a memory.
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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
This past year, I have participated in the preparation of two manuscripts.
The first, “Forgetting in Drosophila consists of an increase in memory uncertainty instead of a stochastic loss of memory,” has been written and is ready for submission. In this manuscript, we use statistical modeling of behavioral experiments to demonstrate that forgetting consists of a decrease in the probability that a fly will avoid the shock-paired odor, rather than a complete loss of a memory. This indicates that the amount of uncertainty associated with a memory increases over time and contributes to forgetting.
I also collaborated with Tomoyuki Miyashita and Minoru Saitoe, also at the Tokyo Metropolitan Institute of Medical Science in preparing a manuscript, “Glia transmit negative valence information during aversive learning in Drosophila.” In this manuscript, T. Miyashita demonstrates that glia can function similarly to neurons in directly transmitting sensory information required for associative learning to the mushroom bodies. I developed a model that proposes that glial transmission differs from canonical neuronal transmission because it occurs through a mechanism of volume transmission. In volume transmission, transmitters released by glia diffuse onto many different downstream cells rather than onto specific post-synaptic neurons. This allows aversive information to be distributed widely to selectively activate neurons that require this information.
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| Strategy for Future Research Activity |
Currently, I am collaborating with Motomi Matsuno and Minoru Saitoe at the Tokyo Metropolitan Institute of Medical Science to understand why aging causes a decrease in long-term memories in Drosophila and other organisms. To make long-term memories, neural networks consisting of long-term memory engram cells need to be formed/activated in the mushroom bodies. These engram cells need to be reactivated during memory recall. We found that long-term memory engram cells are formed in old flies similarly to young flies. Further, these engram cells are reactivated normally in old flies during memory recall. However, we also found that engram cells in old flies are reactivated at inappropriate times when flies should not be recalling memories. Currently, we believe that memory loss in old flies is due to inappropriate memory reactivation in a process called memory generalization. We plan to test this model in the future by examining whether memory formation in old flies is accompanied by the formation of inappropriate synaptic connections to long-term memory engram cells.
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| Causes of Carryover |
The 706,941 yen remaining from my 2022 budget is because I was unable to attend several international meetings due to the coronavirus pandemic. I plan to use my remaining budget from 2022 in the current year to attend these meetings. Any remaining money will be used for reagents for imaging experiments.
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