Magnetic Resonance Imaging Studies On Animal Models Of Mental Illness And Effects Of Antidepressant Fluoxetine On Neurodevelopment

Mental illness is a mental or behavioral dysfunction pattern that causes either suffering or a poor ability to function in ordinary life. The etiology of mental illness involves both the genetic factors and environmental factors. Mental illness is also a common comorbidity or sequelae of other diseases including chronic neuropathic pain, cancer and diabetes. Clinical and animal model studies have shown that mental illness is associated with brain atrophy and/or white matter (WM) lesions. Such brain structural changes are likely the manifestation of cellular-level neuropathological changes, including neuronal loss, reduced dendritic arborization, axonal injuries and demyelination. Generally they are also regarded as the pathological basis of cognitive impairment and emotional dysfunction in patients with mental illness.Animal model of mental illness is a powerful tool to invest this disease. However, there are also some shortcomings in the study of animal model. First, the studies were apart from clinical practice, manifest as little achievements convert to clinicl indicators. Second, it’s not establish the relationship between behaviorial sympotom with brain structure change. Thus caution should be also exercised when interpreting the behavioral assessment data in these models. These treatments for modeling may cause significant atrophy in Ml in implying that the motor functions of these animals may have been compromised.As the morbidity of major depressive disorder increased in adolescence, the prescription volume on adolescence is increased. Fluoxetine (trade name prozac), a selective serotonin reuptake inhibitor (SSRI), is the first drug approved for pediatric MDD. There are still lack of studies for fluoxetine impact on development of brain pathways dramatically influencing neurobiological functioning later in life and what mechanism underlied.The main work of this paper is to use magnetic resonance imaging (MRI) techniques, along with behavioral assessments, electrophysiological recording and immunohistology, to study 1) brain structural changes in an NMDA receptor antagonism model of schizophrenia; 2) brain structural changes in a rat model of chronic neuropathic pain with depression-like symptoms; 3) the effects of antidepressant fluoxetine on neurodevelopment; 4) the role of calcium channel TRPC1 in the modulating effects of fluoxetine on neurodevelopment.First, we used MRI and immunohistology to exam brain structural changes in a rat model of schizophrenia induced by repetitive administration of NMDA receptor antagonist MK801. Voxel-based morphometry (VBM) and diffusion tensor imaging (DTI) were used to detect brain atrophy and WM injuries. The results showed that this model is associated with significant grey matter (GM) atrophy in the hippocampus, ventral striatum and cortex, as well as microstructural impairments in the corpus callosum (cc). Histopathological results corroborated the MRI findings, showing that both gross neuronal loss and dendrite plasticity contributed to the MRI-derived GM atrophy, and demyelination/WM edema to the diffusion abnormalities in the cc. It was concluded that repetitive MK801 administration induces MRI-observable brain structural changes that are comparable to those observed in schizophrenia patients, supporting the notion that NMDAR hypofunction contributes to the pathology of schizophrenia. Imaging-derived brain structural changes in animal models of NMDAR antagonism may be useful measurements for studying the effects of treatments and interventions targeting schizophrenia.Second, we examined the brain structural changes in a rat mode of chronic neuropathic pain induced by spared nerve injury (SNI), and the association between such brain changes and exhibition of depression-like behaviors. The SNI animals showed depression-like behaviors, such as anhedonia, at about 4 months after the surgery. Compared to control, the SNI animals had atrophy in the prefrontal cortex (PFC) and bilateral dorsal hippocampus, as well as volumetric expansion in the contralateral granular insular cortex. It was postulated that SNI-induced brain structural changes might have contributed to the depression-like behaviors in these animals.We also dealt with how chronic fluoxetine exposure during adolescence affects on normal neurodevelopment. It was found that fluoxetine exposure in adolescent rats increased functional and structural plasticity of dorsal hippocampus during adulthood, manifesting as enhanced survival of newborn neurons, increased dendritic arborization, amplified long-term potentiation (LTP) and improvement in hippocampus-dependent spatial memory. It was also found that calcium TRPC1 might have played a pivotal role in the modulating effects of fluoxetine on neurodevelopment.We used TRPC1 knock-out mice to confirm our presumption that the effects of fluoxetine on brain development, especially in the hippocampus, are mediated by TRPC1-related signaling.The work in this dissertation enriched our knowledge on pathological pattern in animal models of psychiatry, and improve the application of MRI to the pathological study and preclinical assessments of psychiatry therapy. There two innovation points in this dissertation. First, we introduced the advanced MRI sequencd in clinical to the study of animal model of mental illness, and promote transformation of achievements to clinical. Second, we found a time window of fluoxetine to enhace cognition, and underlied molecular mechanism.