The modulation of stress on the hippocampal long-term synaptic plasticity

• Main Authors: Chih-haoYang, 楊志豪
• Other Authors: 許桂森
• Format: Others
• Language: en_US
• Published: 2009
• Online Access: http://ndltd.ncl.edu.tw/handle/94526272608727271449

博士 === 國立成功大學 === 基礎醫學研究所 === 98 === Extensive evidences from animal and human studies showing that psychological stress has a biphasic influence on cognitive function depend on the severity and context. Brief periods of stress can potentiate memory formation, where as more severe or prolonged stressors may cause neuron degeneration or synaptic plasticity blockade and exhibit marked deficits in various learning and memory tasks. However, the underlying cellular and molecular mechanisms by which stress exerts its effects on learning and memory remain unclear. By using unpredictable and inescapable restraint tail-shock, we found that animals experienced behavioral stress show marked impairment of long term potentiation (LTP), however enhancement of long term depression expression. Meanwhile, the effects of stress on synaptic plasticity may originate from the corticosterone-induced sustained activation of Erk1/2 signaling cascades. As the changes of synaptic functions can be inhibited by intraperitoneal injection of glucocorticoid receptor antagonist before the stress, and also can be blocked by intrahippocampal injection of specific inhibitors of MEK1/2 (U0126), protein kinase C (Bis-I), tyrosine kinase (K252a), and BDNF antisense oligonucleotides. Besides, we found a significant reduction in the glutamate transporter activity after stress which may contribute to a temporal summation of glutamate and then spillover to activate the NMDA receptors at the extra-synaptic sites that in turn result in the enhanced expression of long term depression in the stressed animals. Furthermore, we found that manipulations which could modulate neuronal activity, such as reduced in anesthetized rats or increased after novelty stimulation, may prolong or shorten the duration of stress effects on synaptic plasticity. We also provide certain evidences showing that fluctuations in neuronal activity may control the tempo of extinguishing the stress effects through modulating the balance between kinases and phosphatases activity. Moreover, we found that different subnuclei of the amygdala (BLA and CEA) may exhibit different roles in mediating the formation and elimination of stress effects. As the administration of ERK1/2 inhibitor (U0126) or NMDA receptor antagonist (APV) into the BLA, but not the CEA, blocked the stress effects on the hippocampal synaptic functioning. In other hand, novelty exploration-induced reversal of stress effects was prevented when animals were injected U0126 or APV into the CEA, but not the BLA, before subjected to the novel environment. Because of the repetitive replaying of stressful experiences precipitates the incidence of many psychiatric disorders; in the last part of our work, we are interested in studying the mechanisms involved in the removing of distressing bad memories linked to the stress events. As we found that extinction therapy with a single paired cue result in a “cue-specific” extinction effect, but left all other cues untouched. The invalidity of extinction therapy persisted even we combined the treatment with the extinction enhancer: D-cycloserine, which these results may reveal the existing of certain handicaps for clinical explosure therapy. In the other hand, targeting memory reconsolidation processing by an in vivo inducible transgenic manipluations of CREB-CBP signaling can remove all the cues and fear memory connections comprehensively. Also we provide novel directions that could extend the accessible time windows for the disrupting of elder bad memories. Here by series of experiments, we understand more about the mechanisms involved in stress on the regulation of brain functioning, and hope that we could ultimately develop new therapeutic strategies or effective pharmacological management in treatment of individuals with defeated learning performances following distressing events.