| Project/Area Number |
21K06403
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Multi-year Fund |
|---|
| Section | 一般 |
|---|
| Review Section |
Basic Section 46010:Neuroscience-general-related
|
|---|
| 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) |
2021-04-01 – 2025-03-31
|
| Project Status |
Granted (Fiscal Year 2023)
|
| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2023: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
|
|---|
| Keywords | Learning / Memory / Drosophila / Aging / Memory Engrams |
|---|
| Outline of Research at the Start |
Animals can learn and retain memories of what they learn. In Drosophila, memories are formed and stored in neural networks
called memory engrams. These engrams are found in a brain structure known as the mushroom bodies (MBs). In this study we will
examine how odor-shock engrams are made. We will identify neurons in the brain memory center that are activated by an odor
prior to training, and then identify memory engrams at various time points after training. This will help us understand the
relationship between sensory input and memory formation.
|
| Outline of Annual Research Achievements |
I collaborated with Tomoyuki Miyashita and Minoru Saitoe at the Tokyo Metropolitan Institute of Medical Science to describe how aversive information is transmitted to memory centers in the brain during aversive olfactory learning. We demonstrated that glial cells rather than neurons transmit pain information to the mushroom bodies via vesicular glutamate release. We also developed models of how glutamate release from glia may be more suited for transmitting information to a large number of downstream neurons through a process of volume release. This work was published in Science in December 2023.
I also contributed to mathematical modeling work demonstrating that forgetting in Drosophila consists of an increase in uncertainty rather than a loss of memory. Forgetting is measured as a decrease in a memory-associated behavior over time, and I demonstrated that this decrease is not caused by the loss of the memory, but instead, caused by a decrease in the ability of the memory to influence behavior.
I collaborated with Motomi Matsuno and Nozomi Uemura at the Tokyo Metropolitan Institute of Medical Science to demonstrate that aging impairs memory through an increase in memory generalization. We determined that glutamate signaling needs to be inhibited during consolidation of long-term memories. Old flies are unable to inhibit glutamate signaling, resulting in activation of downstream dopaminergic pathways. This causes memory engram cells to be activated in inappropriate situations, leading to memory generalization.
|
| Current Status of Research Progress |
Current Status of Research Progress
3: Progress in research has been slightly delayed.
Reason
I had to take some time off for personal reasons, so my research progress has been slightly delayed, and I have postponed my funding for an extra year. My mother was in poor health, and I took care of her until she passed away in January of this year. In addition, my father is also ill, and I also spent time caring of him. Despite these issues, I was able to collaborate with Drs. Miyashita and Saitoe to publish our work on the role of glia in transmitting pain information to memory-associated brain regions during learning. Publication of two other papers has been slightly delayed, however. I am currently in the process of finishing writing paper demonstrating that forgetting consists of a decrease in memory strength instead of a loss of memory and a second paper identifying the molecular and cellular pathways involved in loss of long-term memories upon aging and the behavioral consequences of alterations in these pathways. I am further designing and continuing experiments to identify the molecular and cellular components necessary for trace versus delayed memory formation.
|
| Strategy for Future Research Activity |
In the current year, our main goal is to map the different memory traces that are required for the different temporal requirements during associative memory formation. Flies form associative memories between a neutral odor and aversive electrical shocks when the odor and shocks are given in a specific temporal order. If flies are exposed to the odor at the same time as electrical shocks (delayed conditioning), flies form associations between the odor and pain and subsequently avoid the odor. If flies are exposed to the odor at short time points before electrical shocks (trace conditioning), flies learn that the odor is a predictor of pain and again avoid the odor. Although similar, we find that these two types of memory are distinct and have different cellular and molecular requirements. Memories are formed and stored in the mushroom bodies, and memory-associated behaviors require neuronal output from the mushroom bodies. We plan to map the mushroom body output neurons to identify ones that are differentially required for recall of trace associative memories versus delayed associative memories. We have also determined that trace and delayed memories have different requirements for distinct glutamate receptors. We will identify the cell types where these different glutamate receptors need to be expressed for formation of trace and delayed memories.
|
