| Co-Investigator(Kenkyū-buntansha) |
HASHIMOTO Hitoshi Osaka Univ, Grad Sch of Pharmaceutical Sci, Associate Professor, 薬学研究科, 助教授 (30240849)
MATSUDA Toshio Osaka Univ, Grad Sch of Pharmaceutical Sci, Professor, 薬学研究科, 教授 (00107103)
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| Research Abstract |
This study examined the physiological and pathophysiological roles of endogenous PACAP in the central and peripheral nervous system using PACAP gene knockout (PACAP^<-/->) mice, transgenic mice overexpressing PACAP in the pancreas (PACAP-Tg), and PACAP (PAC_1) receptor exon 2-targeted (PAC_1^<-/->) mice which were recently generated in this laboratory. Through these in vivo mutagenesis studies, we obtained the following results.
1. Psychomotor function
(1) PACAP^<-/-> mice exhibited hyperactive and explosive jumping behaviors in an open field, and increased exploratory behavior and less anxiety. These aberrant behaviors are ameliorated by the antipsychotic drug and SSRI.
(2) PACAP^<-/-> mice exhibited a significant impairment of prepulse inhibition of the acoustic startle response.
These results provide evidence that PACAP plays a previously uncharacterized role in the regulation of psychomotor behaviors and suggest that the phenotype of PACAP^<-/-> mice in part resembles those in human sc
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hizophrenia and/or attention deficit/hyperactivity disorder (ADHD).
2. Hippocampal function
PACAP^<-/-> mice and PAC_1^<-/-> mice showed an impairment of hippocampal long-term potentiation (LTP). In addition, the behavioral study revealed a deficit in hippocampus-dependent associative learning, implicating PACAP-ergic neurons in regulation of higher brain functions.
3. Pain transmission
Allodynia and hyperalgesia in the neuropathic and inflammatory pain models were significantly reduced in PACAP^<-/-> mice.
4. Circadian rhythm
The light-induced phase resetting and c-Fos expression in the suprachiasmatic nucleus (SCN) were attenuated in PACAP^<-/-> mice, highlighting the in vivo role of PACAP in circadian photoentrainment.
5. Glucose and insulin homeostasis
(1) The PACAP transgene ameliorated streptozotocin-induced diabetes in PACAP-Tg mice. Notably, an increase in 5-bromo-2-deoxyuridine (BrdU)-positive β cells in the streptozotocin-treated PACAP-Tg mice was observed.
(2) We crossed PACAP-Tg and lethal yellow KKA^y mice, a genetic model for obesity-diabetes. KKA^y mice showed marked hyperglycemia associated with compensatory hyperinsulinaemia and islet hyperplasia; however, both hyperinsulinemia and islet hyperplasia were significantly suppressed in KKA^y mice carrying the PACAP transgene.
The present data suggest a protective role for PACAP against type I diabetes as well as obesity-associated (type II) diabetes, and the possible involvement of PACAP in the β cell neogenesis. This is the first report suggesting in vivo roles of PACAP on islet hyperplasia and β cell neogenesis, providing the possibility that drugs associated with PACAP-signaling pathways might be of therapeutic value for the treatment of diabetes. Less
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