| 其他摘要 | Learning and memory is one of the most fundamental processes of nervous system, in which organics receive, encode and store information from environment, and finally make changes to their behavioral pattern. This process is normally functioned in the acquisition of skill or knowledge etc.. However, it can also be maladaptive to environment and lead to mental illness. Depressive disorder is one of the psychiatric disorders that involves both genetic and environmental factors. Uncontrollable stressful events are one of the major risk factors in its etiology. In the expect of learned behavior, depressive disorder can be considered as maladaptive to stressful events, thus the malfunctioned learning and memory process may be crucially involved in the etiology and pathology in depressive disorder.Hippocampus is the essential brain region in memory formation. Hippocampal neural plasticity, including synaptic plasticity such as long-term potentiation (LTP) and long-term depression (LTD), structure plasticity, neurogenesis etc., is the cellular mechanism of learning and memory. It is also sensitive to stress events. Stress impaires induction of LTP, facilitate induction of LTD, induces hippocampal neural thrinkage, and impaires neurogenesis. Furthermore, hippocampus also play a role in the pathophysiology of depressive disorder, and is likely to be an important action site of many types of antidepressants. However, the role of hippocampal synptic plasticity in depressive disorder is not clear.In this research, we studied the role of hippocampal synaptic plasticity in the etiology and pathology of depressive disorder using rat forced swimming test (FST). FST, in which rat forms learned depressive-like behavior (learned-depression) after exposure to a single trial of forced swimming, is the most commonly used rodent depression model in evaluating antidepressant effect. We found that learned-depression is inescapable stress-related memory which required activation of glucocorticoid receptor by corticosterone. This learned depression can be blocked by intrahippocampal infusion of known amnesic drugs, or by intraperitoneal or intrahippocampal injection of NMDA receptor antagonists. We also found rapid phosphorylation of synaptic AMPA receptor subunit GluR1, and more directly, we detected that forced swimming process induced LTP in hippocampal CA1 area in freely moving rats. Furthermore, artificially activation of hippocampal neurons by Optogenetics tools can modulate depressive-like behavior in FST. Thus, the depressive-like behavior in FST is stress related learned behavior, which requires hippocampal memory function and NMDA receptor mediated synaptic plasticity. In addition, we found that hippocampal synaptic plasticity was an action site of newly developed antidepressant CXZ-123, which could prevent the synaptic functional damage caused by stress. Thus, the hippocampal synaptic plasticity can also be a target of antidepressant.In summary, this research found that the learned depression induced by inescapable stress is dependent on hippocampus and causes functional changes in hippocampal synapses. Restoring the hippocampal synaptic function after stressful events is one of the antidepressant target site of CXZ-123. These results suggest that: (1) the hippocampus dependent learned-depression may participate in the etiology of depression disorder; (2) hippocampal synaptic function altered by repeated stressful events may be one of the pathology of depressive disorder; (3) hippocampal synaptic plasticity is a potential target for developing new antidepressant. |
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