Magnetic Resonance Imaging Studies On Animal Models Of Schizophrenia And Long-term Insulin-treated Type 1 Diabetes Mellitus

It is well known that in pathological research,preclinical models can monitor disease progression promptly.The benefits of animal model contain invasive studies of structural and molecular changes during disease development,and relatively simple testing of potential therapeutic agents.Animal models are helpful to understand the occurrence and development of human diseases more effectively and conveniently,and to study the prevention and cure measures.Since each kind of animal model only targets a specific area of disease,appropriate animal models need to be developed specifically.Schizophrenia is a unique heterogeneous mental disorder with complex clinical symptoms.It is known that schizophrenia is often associated with deficits in olfaction and olfactory system.For example,structural alterations in the olfactory system,including volume loss of olfactory bulb(OB),depth abnormalities in the olfactory sulcus and atrophy of the entorhinal cortices are frequently reported in schizophrenia patients;Schizophrenia is also shown to be associated with functional deficits like impairments in odor identification,detection threshold,discrimination and memory.Previous studies on olfactory animal models of schizophrenia have been limited to mimic the behavioral responses to olfactory changes.Few studies have investigated the olfactory architecture in neuroanatomy.Type 1 diabetes mellitus(T1DM)is an autoimmune disease characterized by the loss or destruction of insulin-producing beta cells in the pancreas mediated by T cells.T1DM has a negative effect on the structure and function of the brain,which can lead to diabetic encephalopathy.Patients may have multiple signs of diabetic brain damage,such as grey matter atrophy,white matter abnormal changes,abnormal brain metabolism,cognitive impairment,and decreased brain function.T1DM patients need to take exogenous insulin for life because of the absolute lack of insulin.At present,there are few imaging studies on insulin treatment of diabetic encephalopathy.In this paper,we used repeated administration of MK-801,an N-methyl-D-aspartic-acid receptor antagonist,establishing a schizophrenia-like model in adult rats,to investigate the possible neurogenesis mechanism behind OB atrophy and olfactory injury.We also established a model of long-term T1DM rats with high blood glucose induced by streptozocin(STZ),and a model of long-term insulin-treated T1DM rats with well-controlled blood glucose,to investigate the changes of brain structure and hippocampal metabolism in TIDM rats after insulin treatment.For the schizophrenia-like animal model,the effects of repeated administration of MK-801 on the OB structure in adult rats were measured by the rapid acquisition with relaxation enhancement(RARE)T2-weighted imaging and diffusion tensor imaging(DTI).Combined with olfactory behavioral experiment(buried food pellet test)and immunohistochemical experiments,we successfully constructed the rat model showing schizophrenia-like olfactory dysfunction and OB grey matter volume atrophy.At the meantime,the numbers of proliferating cells in subventricular zone(SVZ)and OB were decreased.These abnormalities in olfactory function and OB volume caused by MK-801 were found to be spontaneously restored 4 weeks after drug administration,and the survival of newborn cells in OB was increased.These results suggested that neuroplasticity of adult neurogenesis may be associated with changes in olfactory function and OB volume induced by MK-801.For the T1DM animal model,firstly,we established T1DM rats induced by STZ and long-term insulin treated T1DM rats.The blood glucose and body weight of the insulin-treated T1DM rats were well controlled.On the contrary,the blood glucose in T1DM group was significantly increased and the body weight of the T1DM group was significantly decreased.The whole brain volume was measured by RARE T2-weighted imaging.Compared with the rats in the insulin-treated T1DM group and control group,T1DM rats showed a whole brain atrophy.Compared with T1DM rats,the whole brain volume of long-term insulin-treated T1DM rats was significantly increased,and there was no significant difference in macroscopic volume between insulin-treated T1 DM rats and control rats.The specific performance of insulin-treated T1DM rats included the ventricle volume expansion;grey matter volume atrophy in the corpus callosum small forceps and the ventral pallidus;white matter volume expansion in dorsal medial iris nucleus,anterior commissure,caudate putamen,ventral globus pallidus and medial preoptic area;white matter volume atrophy in the piriform cortex and hippocampus.Our results showed that long-term insulin therapy could successfully ameliorate the brain volume damage caused by TIDM.Then we used 1H MRS to analyze the metabolites in the hippocampus of STZ-induced T1DM rats and T1DM rats treated with long-term insulin.The results showed that the concentrations of inositol(Ins),taurine(Tau)and glutamate(Glu),Glu/glutamine(Gln),Glu/N-acetyl aspartate(NAA)in T1DM group were significantly higher than those in control group.The concentration of Ins and Tau in insulin-treated group were significantly lower than that in T1DM group,but the concentration of Glu,Glx(Glu+Gln),Glu/NAA were significantly higher than that in control group.The results showed that the concentration of Ins and Tau in hippocampus of T1DM rats were sensitive to insulin treatment.The results suggested that long-term insulin treatment could ameliorate gliosis in hippocampus of T1DM rats,and the osmotic pressure was not out of balance.Long-term insulin therapy did not change the increase of Glu concentration in hippocampus of T1DM rats,which may be related to the increase of brain metabolic activity or neurotrophic effects of insulin.In conclusion,the work presented in this dessertation can be divided into two parts.First,it was found that repeated administration of MK-801 could induce OB volume atrophy and olfactory impairment in adult rats,similar to olfactory system impairment in clinical schizophrenia patients.Besides,the OB volume was related to olfactory function in MK-801-treated rats.And MK-801 altered the adult neurogenesis in SVZ-OB,suggesting that the plasticity of adult neurogenesis may be involved in the effect of MK-801 on olfactory system.Second,it was found that long-term insulin treatment could reduce or restore most STZ-induced brain damage in T1DM rats.And the concentrations of neuroglia and osmotic pressure-related metabolites Ins and Tau in the hippocampus of T1DM rats were sensitive to long-term insulin therapy.Long-term insulin therapy may exert neurotrophic effects.