| BackgroundScientific and clinical advances in recent decades have made it clear that the disciplines of Neurology and Psychiatry are moving closer together in the questions they ask, the tools they use, the theoretical frameworks they employ, diagnostic and therapeutic methods they adopt. Neurologists are dealing with more and more psychiatric patients in everyday practice. Many neurological diseases per se are initiated or accompanied by psychiatric symptoms, the prompt diagnosis and treatment of which ,have positive effects on the neurofunctional recovery. Moreover, brain organic abnormalities have been detected in some so-called functional psychiatric diseases, such as Schizophrenia and affective disorders. Further progress in understanding brain diseases and behavior demands extensive collaboration and integration of these two disciplines.PurposeThe research aims to explore the possible brain mechanisms of major depression by analyzing the correlations between the fMRI brain abnormally activated areas and differential protein expression, thus to set a protocol for further study of other neurological disease accompanied psychiatric diseases and human cognitive functions.Methods1. To establish the fMRI emotional stimulation protocol for successfully inducing the emotional reactions.2. A total of twenty first episode drug na?ve severely depressed patients with a diagnosis of major depressive episode, were recruited according to the inclusive and exclusive criteria. The diagnosis was made independently by two experienced psychiatrists employing the Diagnostic and Statistical Manual of Mental Diseases, 4th edition (DSM-IV). Twenty age- and gender-matched healthy controls were enrolled. Clinical data of all subjects were collected with self-made questionnaire. The severity of the disease was evaluated by Hamilton Depression Rating Scale-24(HAMD-24), while the language disturbances were appraised by Aphasia Battery of Chinese (ABC). All subjects were scanned by the Magnetic Resonance Image(MRI)to rule out the structural abnormalities.3. 10 adult male Sprague–Dawley rats from the Chongqing Medical University's animal center, were randomly assigned to one of two groups: chronic stress or no stress. Rats in the chronic stress group were isolated housed, each one in a single cage, subjected to different kinds of stressors each day, known as the chronic unpredictable mild stress (CUMS) protocol. One of the seven stressors was randomly applied daily for total 3 weeks before the behavioral testing of sucrose consumption and open-field test. 4. Referring to the fMRI activated areas, corresponding brain tissues were obtained from the CUMS rats. Proteins were extracted using TCA method, before the two-dimensional gel electrophoresis was applied. After Protein fixation, Coomassie brilliant blue staining and silver staining, mass analyses of the individual samples were carried out using a matrix assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Peptide matching and protein searches were carried out automatically in NCBI nonredundant databases.Results1 . Severe depressive patients evaluated by HAMD-24 were enrolled. Both the factor score of HAMD-24 and ABC ratings, suggested apparent emotional and language disturbances in severe depressive patients. They showed poverty of thought, bradyphasia, slow in response and hard to concentrate. Routine MRI scan revealed no obvious structural abnormalities.2.According to the three principle dimensional theory of emotion, 2-character Chinese words, categorized into the positive, negative and neutral emotion, were selected to establish the fMRI emotional stimulation protocol for successfully eliciting the corresponding emotional reactions.3.The negative task activated the right orbital gyrus(BA11), left rectus(BA11), left anterior central gyrus(BA6), right posterior central gyrus(BA40), left posterior cingulate gyrus, left caudate head and right anterior lobe of cerebellum. While the positive task activated the left precuneus, right superior temporal gyrus(BA38), left superior temporal gyrus(BA38), right parahippocampal gyrus, right hippocampal sulcus(BA34), right caudate head, left caudate body, right insula(BA13) and right fusiform gyrus(BA37).4.Compared with the non-stressed group the sucrose consumption, crossings and rears in open field activity of rats under chronic unpredictable stress was significantly decreased after 3-week treatment(P<0.05).5.The number of spots found in the gels from the stressed group was 1594, 1624, 1609, respectively, with an average of 1609.00±15.0. For stress-free group, the number was 1571, 1628, 1648, respectively, with an average of 1615.67±29.78. The matching rate between the groups was 72%. There were 27 spots showing differential protein expression, ranging from pH4.0～pH 9.7, 25 KD～70KD.6.15 spots showing differential protein expression were identified by their tryptic peptide mass fingerprints. Four of them, calreticulin precursor, tropomyosin 1, alpha isoform I, dual specificity mitogen-activated protein kinase kinase 1 and mitogen activated protein kinase 1, associated with neurogenesis, were notably down-regulated(P<0.05).Conclusion1.The severe depressive patients have apparent emotional and language disturbances which are revealed successfully by the fMRI emotional stimulation protocol.2.The reduced interest in moving and time-dependent reduction of anhedonia, showed by rats subjected to the CUMS protocol are similar to the nucleus symptoms of human major depression. The CUMS protocol is optimal for the research of depression pathogenesis.3.The distinct brain activations in depressive patients suggest the pathogenesis of major depression is not controlled by any single area, but a combination of correlated areas, among which the prefrontal cortex and hippocampus might play a key role.4.Neurogenesis in hippocampus may play an important role in the pathogenesis of major depression.
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