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Xiaoyaosan stagnation and spleen deficiency syndrome model rat hippocampus and amygdala AMPAR regulation mechanism

Author: YueLiFeng
Tutor: ChenJiaXu
School: Beijing University of Traditional Chinese Medicine
Course: Diagnostics of Chinese Medicine
Keywords: Xiaoyao san Liver invading the spleen syndrome regulation channel AMPAR CNQX hippocampus amygdala chronic immobilization stress(CIS)
CLC: R285.5
Type: PhD thesis
Year: 2008
Downloads: 366
Quote: 1
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Abstract


Liver invading the spleen syndrome, a common type of depression patterns, is also known as“the wood overacting the earth”. With good operability and repeatability, our group ensure the rat model subjected to chronic immobilization stress(CIS)was an ideal model for research on this syndrome. Xiaoyao san can effectively regulate the behavior abnormality in CIS rats. Considerable interest in this paper has focused on the molecular mechanisms and regulation channel underly Xiaoyao san affording effective protection agaist this depression syndrome.The main function of Liver is to ensure the smooth flow of qi in TCM. So it has a deep influence on the emotional state. Limbic system, the center of motivation and emotion, is the regulation and control center of liver governs smoothing qi flow(LGSQF). Hippocampus and amygdala are important parts of Limbic system. They act different or even the opposite role in hippocampus and amygdala on chronic stress response. Chronic immobilization stress(CIS) induces contrasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons. In agreement with vyas’s reports, CIS induced dendritic atrophy and debranching in CA3 pyramidal neurons of the hippocampus. In striking contrast, pyramidal and stellate neurons in the basolateral complex of the amygdale(BLA) exhibited enhanced dendritic arborization in response to the same CIS. More importantly, recent studies have demonstrated that CNQX, AMPA receptor antagonist, blocking or suppressing both amygdaloid excitability, increases adult neurogenesis in the rat hippocampus and could afford protection against CIS.It has been suggested that AMPA receptors are most exclusively postsynaptic in location and play a primary postsynaptic role in mediating hippocampal and amygdaloid input. Although NMDA receptors likely contribute critically to neuronal injury in various stress conditions, several observations support the hypothesis that AMPA receptors may be of greater importance to the neurodegenerative process in CIS rats. AMPA receptors play a ubiquitous role in the CNS in mediating fast excitatory transmission. AMPA receptor channels are assembled from four subunits (GluR1 to GluR4). AMPAR subunits have shown that LTP expression involves the trafficking of AMPA receptors, and more specifically, of the GluR1 subunit to the membrane. The molecular basis of this activity-dependent regulation of GluR1 has been studied in great detail. Recent studies found an increased expression of GluR1 mRNA after CIS. Evidently, the increase in GluR1 was directly or indirectly responsible for all the changes induced by inactivity, and GluR2-containing AMPARs were not critical for the adaptation. The presence of the GluR2 subunit renders heteromeric AMPA receptor assemblies Ca2+ impermeable. downregulation of GluR2 gene expression may serve as a‘molecular switch’leading to the formation of Ca2+ permeable. Recent studies involving animal models of transient forebrain ischemia and epilepsy show that GluR2 mRNA and GluR2 subunit expression are downregulated in vulnerable neurons especially hippocampal neurons.There is now general consensus that antagonists of AMPA receptors, such as CNQX, appear to be much more effective than NMDA antagonists in preventing CA3 cell from atrophy even death following CIS. This experiment was designed to explore CIS rats’behaviors, Immunohistochemistry findings and RT-PCR results in hippocampal subregions CA1, CA3 and DG and amygdaloid subregion BLA after suppressing both amygdaloid AMPARs by microinjection of CNQX. Compared with Xiaoyao san group, analysis of these findings may reveal the possibility of molecular mechanisms and effective regulation channel of Xiaoyao san treating this syndrome. This project was supported by National Science Foundation Committee of China(No.30672578). This experiment is composed of four parts. Part 1, to establish an animal model of depression induced by CIS in accord with syndrome of liver invading the spleen in TCM and assess the effects of Xiaoyao san on CIS. The CIS rats were examined dynamically at the 1th, 7th, and 14 th and 21st days by the following three aspects.①signs and symptoms, weight-gain, food intake and rate of urinary D-fructose excretion;②open field test;③syndrome was evaluated by prevention and treatment of xiaoyaosan. In part 2, 3 and 4, Rats were randomly divided into 5 groups, control group, model group, sham operation group, CNQX group and Xiaoyao san group. Details see preface and part 2. In CNQX group, both amygdaloid AMPARs were blocked by CNQX and some behaviors and biochemical indexes were significantly changed in hippocampal subregions CA1, CA3 and DG and amygdaloid subregion BLA. To my expect, Tendency of changes of these indexes such as GluR1 and GluR2/3 were coherent in CNQX and Xiaoyao san group in Immunohistochemistry test, so did GluR1,2,3 mRNA in these two group in RT-PCR test. The balance coordination between hippocampus and amygdala may be the key in transformation from adaption to damage in a state of stress, is one of the central mechanisms of LGSQF on regulating the stress. These three parts focus on the molecular mechanisms and regulation channel underly Xiaoyao san affording effective protection agaist this depression syndrome respectively through behavior, Immunohistochemistry and RT-PCR test.Main results and conclusion:Part 1:RESULTS: CIS group: The results revealed that subjected to CIS resulted in a decrease of behavioral activity, weight-gain, food intake, low rate of urinary D-fructose excretion, and weak ambulation, rising and decoration in the open field test especially during the period of 14th to 21st day. Xiaoyao san group: Xiaoyao san treatment significantly reversed the behavioral deficit of these depression model rats especially during the period of 14th to 21st day.CONCLUSION: With good operability and repeatability, the CIS rat model is an ideal model for research on syndrome of liver invading the spleen. Long term depression leads to liver invading the spleen, that is to say, results in syndrome of depression in combination with spleen deficiency. Xiaoyao san can regulate the behavior abnormality in CIS rats.Part 2:RESULTS: Signs and symptoms of Liver invading the spleen syndrome were seen in model group rats; anxiety-related behaviors were shown in sham operation group; anxiety-related behaviors were controlled in CNQX group revealing antidepressant treatment of CNQX; rats of Xiaoyao san group resist the injury of CIS and operation and has little difference with control group.CONCLUSION:①Suppression of both amygdaloid excitability by microinjection of CNQX, AMPA receptor antagonist, can relieve anxiety acting as an antidepressant drug.②Xiaoyao san can effectively regulate the rats’behavior abnormality.Part 3:Immunohistochemistry findings:①the number of c-fos positive cells increased in CA1, CA3 and DG region of hippocampus and basolateral amygdale(BLA) with high intensity of stressor;②compared with control group, the number of GluR1 positive cells and immunoreaction products increased in CA1 and DG regions of hippocampus in model group and sham operation group while decreased in CA3 and BLA region; statistical analysis showed that no difference existed in control, CNQX and Xiaoyao san groups in hippocampus, whereas in BLA, only both control and Xiaoyao san group has no difference. CNQX blocking AMPAR in BLA, so the least positive cells were seen in CNQX group. In other group, tendency of changes of were contradictory in BLA and CA1 region.③compared with control group, the number of GluR2/3 positive cells and immunoreaction products decreased in all subregions of hippocampus. In addition, statistical analysis showed that no difference existed in control, CNQX and Xiaoyao san groups in hippocampus. Except CNQX group, tendency of changes of were also contradictory in BLA and CA1 region. In addition, the least in BLA in CNQX group.CONCLUSION:①the number of c-fos positive cells increased in CA1, CA3 and DG region of hippocampus and BLA in model and sham operation group especially in the latter group triggered by operation, the same as behavior test. Furthermore sham operation has little impact on changes of expression of GluR1 and GluR2/3.②the expressional tendency of AMPA receptors subunits GluR1 and GluR2 was different in hippocampus; so did the region of hippocampus and amygdala.③respectively compared with model or sham operation group, the expressional tendency of AMPA receptors subunits was almost the same in CNQX and Xiaoyao san group. This finding revealed that Xiaoyao san may act the same as CNQX, thus Xiaoyao san afforded effective protection agaist this depression syndrome through suppression of both amygdaloid excitability.Part 4:RT-PCR results was respectively perfectly coincident with indexes of part 3 to ensure the correction of this experiment and this hypothesis.In all, the balance coordination between hippocampus and amygdala may be the key in transformation from adaption to damage in a state of stress, is one of the central mechanisms of LGSQF on regulating the stress. Xiaoyao san may effectively regulate the balance of the excitability of hippocampus and amygdala. This hypothesis may reveal the molecular mechanisms and regulation channel on Xiaoyao san affording effective protection agaist Liver invading the spleen syndrome.

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