2016 Fiscal Year Annual Research Report
Mechanisms of memory consolidation in sleep
| Project/Area Number |
26285161
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| Research Institution | University of Tsukuba |
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Principal Investigator |
Pavlides C 筑波大学, 人間系, 教授 (50712808)
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| Co-Investigator(Kenkyū-buntansha) |
小川 園子 筑波大学, 人間系, 教授 (50396610)
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| Project Period (FY) |
2014-04-01 – 2018-03-31
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| Keywords | sleep / memory / hippocampus / amygdala / fear conditioning |
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| Outline of Annual Research Achievements |
eep plays a significant role in memory consolidation, however, the mechanisms involved are not well understood. It is also well known that protein kinase A (PKA) is required for long-term memory. In a study conducted during the previous funding period, we showed that PKA may affect memory consolidation in sleep in that pharmacologically blocking PKA specifically in sleep produced long-term fear memory deficits (Cho, et al. submitted). In a second set of experiments we investigated the time course of PKA phosphorylation (pPKA) in sleep following fear conditioning. We found that fear conditioning enhanced pPKA in sleep, however, this was not time dependent (Pavlides, et al. 2016). Sharp-wave ripples (SPWr), seen in the hippocampal EEG during learning and again in slow wave sleep, have been reported to be involved in spatial memory consolidation. During the last funding period we are testing the hypothesis that SPWr may produce their effects on memory via activation of PKA. A first step for this study was to test whether SPWr suppression in sleep also produces fear memory deficits. Having confirmed this, we are currently testing brain samples to measure PKA activity. In preliminary experiments we found that SPWr suppression during sleep does indeed affect pPKA, however, instead of the hypothesized suppression, we found an increase in pPKA levels. These experiments are being extended to confirm these results (the findings will be presented at the IBNS meeting in Hiroshima; Pavlides, et al. 2017).
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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
The research was done relatively smoothly, however, as usually slower than anticipated. The reasons for this included getting the electrophysiological setup working properly, and training students in animal surgery, electrophysiology, etc, took some time. Further, selecting the appropriate stimulation parameters required for SPWr suppression, without affecting other physiological parameters was crucial for the study and required performing a number of pilot experiments to ensure that all was optimal. For example, one possibility that our preliminary results showing an enhancement in pPKA following SWPr suppression (instead of the anticipated suppression) may have been the stimulation parameters used, which we are currently retesting. The studies are also very demanding in that we are working with freely behaving animals. Chronic recordings, from a number of brain sites, muscles, etc have to work over an extended period of time. During the actual experiment, the animals have to sleep, which is not always the case. Having worked out all of these issues, it is now a matter of increasing the number of subjects tested in order to complete the study. We believe that the significance of the findings warrant the extended effort.
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| Strategy for Future Research Activity |
We have, thus far, used contextual fear conditioning, which involves both the hippocampus and amygdala, to test for long-term fear memory, A critical question is whether cued fear conditioning which involves the amygdala, but not the hippocampus, is dependent on similar mechanisms. SWRr are mainly seen in the hippocampus, but may also influence other closely associated structures. However, cued memory consolidation may involve the amygdala and pPKA but not SPWr. If indeed we find that SPWr affect memory consolidation by their effects on PKA, another set of experiments will test whether pharmacologically enhancing/suppressing PKA may alleviate the memory deficits. Other gene cascades (e.g., MAPK; PI3K) are also involved in fear memory consolidation and may be affected by SPWr. Furthermore, these gene cascades may be triggered at different time intervals, including awake states. During the next funding period, we will investigate these possibilities.
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| Causes of Carryover |
Initially, custom built equipment for the electrophysiological recordings and behavior had to be tested, prior to ordering a complete setup. We have recently purchased such equipment and are using it to speed up the studies. Given the fact that we were running pilot studies to test equipment, stimulation parameters, etc, required a smaller number of animals, drugs (which are expensive and have short expiration dates) were also small. However, as we proceed with the full scale of the experiments, we will be using the funds during the next funding period. Also a person trained in animal surgery, and recordings is now part of the project.
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| Expenditure Plan for Carryover Budget |
During the 2017 budget year, we will be conducting many more experiments which will require significantly more animals, pharmacological, histological and other supplies. Salary for a part time technician will also be required. Finally, during the 2017 funding period a number of studies will be coming to completion which will require publication fees, meetings attendance for decimation of the results, etc.
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Research Products
(4 results)
