Effect Of Chronic Multiple-Stress On Learning And Memory And The Role Of Neurogranin In Its Mechanism

Stress refers to the integrative response to any physical or psychological stimulus that disrupts homeostasis, which includes the response of mind, endocrine and immune. It is characterized by the excitability potentiation of the hypothalamic-pituitary-adrenal (HPA) axis, which leads to the elevation of glucocorticoids in blood. The effects of stress depend on many aspects containing stress's mode, intensity, duration and body's responsitivity. The influence of stress on the cognitive function is especially complex. Most of present study demonstrated that exposure to chronic stress impaired learning and memory, while some other studies discovered that chronic stress might enhance learning and memory.The hippocampus has a high concentration of receptors of glucocorticoid(GRs), which is the most in central nerve systerm, so it is the regulatory center of the stress response and one of the major targets for GCs. As the hippocampus has wide fibre connections with many other brain regions and the anatomic lacation of it, it plays an important role in learning and memory. Neurogranin(Ng)consisting of seventy eight amino acids, is the neuronal specific protein and distributes mainly in cerebral cortex, the hippocampus and the olfactory bulb. There is an IQ domain in its sequence, which contains a binding site with Ca2+ and a phosphorylation site. As a member of calpacitin protein family, it is not only the natural substrate of Protein kinase C(PKC), but also the CaM binding protein. Ng usually binds to CaM, forming CaM-Ng complex. When it is phosphorylated or oxidized, the affinity between Ng and CaM begins to attenuate, which leads to the resolution of CaM-Ng complex and the release of free CaM. So does the density of Ca2+ starts to increase. The series of changes results in the regulation of protease and protein kinase dependent on CaM and Ca2+ /CaM. Most of these proeases and protein kinases participate in the induction of long-term potentiation (LTP), which represents the enhancement of synaptic transmission. LTP is the key parameter of synaptic plasticity and the basis of plasticity of central nervous systerm. Moreover the plasticity of central nervous systerm is the critical mechanism of. Then Ng may play an important role in learning and memory.In the present study, we used 4 stressors to imitate the modern complicated social environment and kept the stress for 6 weeks to explore the possible mechanism of chronic multiple-stress that influences learning and memory. We also studied the role of Ng in this mechanism. Adult male Wistar rats were randomly divided into 2 groups: (1) the control group Rats in this group were housed in normal situations without any treatment; (2) the chronical multiple stress group Rats in this group were irregularly and alternatively exposed to sleep deprivation, vertical rotation, restraint and exposure to light at night for 6 weeks. During the stress experiment the effects of chronic multiple stress on the body weight and behavior of rats were observed. After the chronical multiple stress, all rats were tested for the performance of learning and memory by Morris water maze. The expression of Ng protein in every subfield of hippocampus was measured by immunohistochemical method. The level of Ng mRNA in hippocampal tissues was assayed by reverse transcription-polymerase chain reaction(RT-PCR).The results of experiment are presented as follow:1. The vigilance of animals in the chronical multical stress was sharpened; the multiple-stressed animals presented more fighting behaviors and excreted more than the control group;2. Compared with the control group, the growth in body weight was much less in stressed groups (p<0.05);3. The results of Morris water maze displayed that the spatial learning and memory of rats in the chronically multiple stress group were enhanced significantly, the latency to search the hidden platform in Morris water maze was obviously shortened in the stressed group than that of the control group;4. Compared with the control group, the expression of Ng protein in the hippocampal area DG and CA3 was markedly increased in the stressed group (p<0.05), but no apparent difference was observed in CA1 area;5. The level of Ng mRNA was also distinctively up-regulated in the hippocampus of the stressed group (p<0.05).From the results of the experiment, we supposed that the chronic multiple stress could enhance the hippocampus-dependent spatial learning and memory function; the elevation of the expression of Ng protein and the level of Ng mRNA in the hippocampus, which was related to stress, revealed that Ng might participate in the mechanism of the enhanced performance.