2007 Fiscal Year Final Research Report Summary
Elucidation of the epigenetic mechanism of stress-related mental disorders-Identification of the transcriptional dysfunction in response to early environments and development of a new therapeutic strategy-
| Project/Area Number |
17591214
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Psychiatric science
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| Research Institution | Hiroshima University |
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Principal Investigator |
MORINOBU Shigeru Hiroshima University, Graduate School of Biomedical Sciences, Associate Professor (30191042)
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| Project Period (FY) |
2005 – 2007
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| Keywords | BDNF / GDNF / neonatal isolation / immobilization stress / histone acetylation / epigenetics / hippocampus / IGF-1R |
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| Research Abstract |
The purpose of this study is to elucidate the molecular mechanisms for the development of stress reactivity in response to an early environment.
1. We measured the influence of a single immobilization stress (SIS) on the levels of BDNF and GDNF mRNA in the rat hippocampus, and found the significant decrease in the levels of exon I and III mRNA We measured the hippocamof the BDNF gene using real-time PCR. The chromatin immunoprecipitation assay indicated the significant decrease in the acetylation levels of histone (H)3, but not H4 at the promoter of exon 1 and III.
2. We measured the hippocampal levels of BDNF, GDNF, NGF, and NT-3mRNA of the rats subjected to neonatal isolation (NI) alone and NI with SIS in adulthood, and found that SIS significantly decreased the levels of GDNF mRNA and downregulated the induction of NGF mRNA in the rats subjected to NI.
3. The hippocampal gene expression profiles between the sham-treated rats and neonatal-isolated rats with SIS were compared using a cDNA microarray followed by real-time PCR and immunoblot. The analyses demonstrated that the mRNA as well as protein levels of IGF-1R were significantly reduced in the neonatal-isolated rats with SRS.
4. The difference in the hippocampal gene expression between the sham-treated rats not exhibiting learned helplessness (nLH) in the LH test and neonatal-isolated rats exhibiting LH was examined. The analyses showed that the both mRNA and protein levels of LIMK-1 in the LH rats significantly lower than those in the nLH rats. In contrast, environmental enrichment ameliorated the stress vulnerability in response to the LH test in the rats subjected to NI.
5. Based on these finding, it is postulated that early environments regulated the development of stress reactivity through the signals of neurotrophic and growth factors in the hippocampus.
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