The Possible Mechanisms Of Gastrointestinal Autonomic Movement Dysfunction In Aging Mice

The normal function of mammalian gastrointestinal autonomic rhythmicity motility is fundamental prerequisite for the digestion and absorption,and it is regulated by the enteric nervous system(ENS)and interstitial cells of Cajal(ICC).ENS is composed of neurons and nerve fibers.ICC in the gastrointestinal(GI)tract were considered to be pacemaker cells for GI movement,it can mediate excitatory and inhibitory neurotransmission and maintain the normal physiological function of GI with ENS.It’s known that ENS neurons are derived from embryonic neural crest cells and being growth,development,and maturation at intestinal wall.ENS is primarily include inhibitory nitrergic neurons and excitatory cholinergic neurons.ICC are widely distributed within the myenteric plexus,intramuscular layer,submucosa plexus,and deep muscular plexus during the early embryonic period and form complete cellular network at late embryonic stages.Gap junction is an important structure between the gastrointestinal smooth muscle and ICC.Connexin43(Cx-43),as the main gap junction protein,plays a key role in integrating the communication between ICC and smooth muscle,and regulating the gastrointestinal motility.The abnormalities of Cx-43 structure and function,developmental and morphological disorder of ENS and ICC,as well as the abnormal network structure and the aging-related neurodegeneration are the critical factors of GI motility disorders,but the its possible mechanisms was poorly understood.Here,from the morphological view,we discussed the features of postnatal development and network formation of ICC,ENS neurons in mouse small intestine and the degenerative changes of ENS,ICC,Cx-43 during aging,aiming to provide new theoretical and experimental basis for the further understanding of the gastrointestinal autonomic rhythmicity motility disorders and development of gastrointestinal dysfunction in the elder people.In the present study,C57BL/6J mice were used as the subjects of the experiment.The first section is Experiment 1.We measured the length and perimeter of the small intestine from mice(P7d,P28 d and P60d),and then immunohistochemistry and histochemistry methods were used to detect the changes of morphology and the number of ICC,nitrergic and cholinergic neurons on the whole mount preparations of small intestine from mice above.The second section is Experiment 2.The gastrointestinal motility function of young(2-month-old)and aged(16-month-old)mice was detected by ink propulsion experiment.The aging condition of GI cells were observed by β-galactosidase staining.Then immunohistochemistry and western blot methods were used to detect the changes of morphology and number of ICC,nitrergic and cholinergic neurons in stomach,small intestine and colon tissues from mice used in experiment 2.The results were as follows:1.The number of ICC increased continuously from P7 d to P60 d,but the density reached the highest point at P7 d and then declined.The total number and density of ICC reached the maturity level at P28 d.2.The total number of nitrergic neurons did not change obviously from P7 d days to P60 d,but its density decreased with aging.The number of cholinergic neurons and its changing trend was similar to nitrergic neurons.3.Compared with young mice,the gastrointestinal ink propulsion rate of aged mice slowed down significantly(p < 0.05).4.The number of ENS neurons and ICC in the stomach of aged mice was significantly decreased with sparser ICC cellular network.The density of nitrergic neurons along with the area of soma and nerve fibers of cholinergic neurons were significantly decreased.5.Compared with young mice,no significant change of the number and cellular networkof ICC,cholinergic and nitrergic neurons in small intestine and colon of aged mice was found.6.Compared with young mice,the expression of Cx-43 in stomach,small intestine and colon of aged mice wwas decreased.Conclusion:(1)The total number of nitrergic and cholinergic neurons in small intestine of the mice after birth has reached the maturity level.The structure and function were improved accompanied with the growth and development of the small intestine.(2)Compared with young mice,the gastrointestinal motility of aged mice was significantly diminished,and the degeneration of ENS neurons and ICC was observed obviously compared with which in small intestine and colon,suggesting that stomach appear change at first in gut during aging.(3)Compared with young mice,expression of Cx-43 in stomach,small intestine and colon of aged mice decreased significantly,suggesting that signal transduction between ENS neurons,ICC and smooth muscle was interrupted with aging.It may be one of the most important reasons of gastrointestinal motility dysfunction in the elderly people.