2010 Fiscal Year Final Research Report
Understanding the mechanisms of regulation of brain function by fat-soluble nutrient factors and application of these mechanisms for the improvement of brain function and treatment for brain diseases
| Project/Area Number |
20380078
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Food science
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| Research Institution | Tokyo University of Agriculture |
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Principal Investigator |
KIDA Satoshi Tokyo University of Agriculture, 応用生物科学部, 教授 (80301547)
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| Project Period (FY) |
2008 – 2010
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| Keywords | 学習・記憶 / ビタミンA / 不飽和脂肪酸 / トランスジェニックマウス / 脳機能障害 / レチノイン酸 / 情動行動 / 長期増強(LTP) / カナビノイド / 恐怖記憶 / 記憶不安定化 |
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| Research Abstract |
Understanding roles of nutrient factors in brain function and mechanisms of the regulation of brain function by nutrient factors is important to develop the treatment for brain diseases. To do this, we have investigated roles of fat soluble-nutrient factors (Vitamin A (Retinoic Acid) and cannabinoids) in brain function.
Retinoic acid receptors (RARs) ubiquitously and highly express in brain. Previous studies have shown that RA-deficient mice and RARs knock out mice exhibit impairments of both hippocampal LTP and spatial memory, suggesting an essential role of RARs in learning and memory. To clarify the roles of RARs in learning and memory, we generated conditional mutant mice that enable to regulate forebrain-specific overexpression of RAR-alpha or dominant negative mutant (dn) of RAR-alpha using tetracycline system. We showed that dnRAR mice display impairments of AMPA receptor-mediated excitatory postsynaptic potentials and LTP in the hippocampus and hippocampus-dependent memory forma
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tion in a dnRAR expression-dependent manner. These observations suggest that RARs play important roles in hippocampus-dependent learning/memory and hippocampal LTP. Interestingly, we also found that dnRAR mice display down-regulation of PSD-95 and AMPA receptor subunit GluR1, but not NMDA receptor subunit NR1, in the hippocampus in a dnRAR expression-dependent manner. Therefore, we suggest that down-regulations of PSD-95 and GluR1 lead to impairments of hippocampus-dependent learning/memory and hippocampal LTP in dnRAR mice.
There is growing evidence that the reactivated long-term memory is de-stabilized and then re-stabilized through a gene expression dependent reconsolidation process. However, little is known about molecular mechanisms underlying destabilization of retrieved memory. Therefore, we examined roles of cannabinoid receptor CB1 in the destabilization of reactivated spatial and fear memory using Morris water maze and contextual fear conditioning tests. Infusion of an antagonist of CB1 receptor (SR141716A) together with anisomycin into hippocampus immediately after memory retrieval prevented the disruption of reactivated memory by protein synthesis inhibition. These results suggest that reactivated memory is destabilized through activation of hippocampal CB1 receptor.
From these studies, we suggest that vitamin A and endogenous cannabinoid are important to maintain and improve brain functions such as learning and memory. We are now examining effects of these fat-soluble factors on brain diseases using mouse model of brain diseases such as PTSD, memory deficits and anxiety. Less
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Research Products
(116 results)
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[Journal Article] Impaired hippocampal spinogenesis and neurogenesis and altered affective behavior in mice lacking heat shock factor 1.2011
Author(s)
Uchida S., Hara K., Kobayashi A., Fujimoto M., Otsuki K., Yamagata H, Hobara T., Abe N., Higuchi F., Shibata T., Hasegawa S., Kida S, Nakai A., Watanabe Y.
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Journal Title
Proc.Natl.Acad.Sci.U.S.A. 108
Pages: 1681-6 doi:10.1073/pnas.1016424108
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[Journal Article] Activin plays a key role in the maintenance of long-term memory and late-LTP.2010
Author(s)
Ageta H., Ikegami S., Miura M., Masuda M., Migishima R., Hino T., Takashima N., Murayama A., Sugino H., Setou M., Kida S, Yokoyama M., Hasegawa Y., Tsuchida K., Aosaki T., Inokuchi K.
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Journal Title
Learning and Memory 17
Pages: 176-185 doi:10.1101/lm.16659010
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[Journal Article] Transgenic up-regulation of alpha-CaMKII in forebrain leads to increased anxiety-like behaviors and aggression.2009
Author(s)
Hasegawa S, Furuichi T, Yoshida T, Endoh K, Kato K, Sado M, Maeda R, Kitamoto A, Miyao T, Suzuki R, Homma S, Masushige S, Kajii Y, Kida S
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Journal Title
Molecular brain 2
Pages: 6
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[Journal Article] Neuroreport2009
Author(s)
Isosaka T, Kida S, Kohno T, Hattori K, Yuasa S, Hippocampal Fyn activity regulates extinction of contextual fear.
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Journal Title
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[Journal Article] Upregulation of calcium/calmodulin-dependent protein kinase IV improves memory formation and rescues memory loss with aging.2008
Author(s)
Fukushima H, Maeda R, Suzuki R, Suzuki A, Nomoto M, Toyoda H, Wu LJ, Xu H, Zhao MG, Ueda K, Kitamoto A, Mamiya N, Yoshida T, Homma S, Masushige S, Zhuo M, Kida S
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Journal Title
The Journal of neuroscience 28
Pages: 9910-9
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[Journal Article] Up-regulation of CREB-mediated transcription enhances both short- and long-term memory.
Author(s)
Suzuki A., Fukushima H., Takuya Mukawa T., Toyoda H., Wu L-J., Zhao M-G., Hui Xu H., Shang Y., Endoh K., Iwamoto, Mamiya N., Okano E., Hasegawa H., Mercaldo V., Yue Zhang Y., Maeda R., Ohta M., Josselyn S.A., Zhuo M., Kida S
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