| Background:The pathogenesis of depression is complicated and involves multiple genetic, psychological, and environmental factors. The most important environmental factor is stress. The connection between stress and depression is still far from clear.The hippocampus is only one of two brain regions where robust neurogenesis continues into adulthood, and nerve cells in the hippocampus are among the most sensitive to the deleterious effects of stress. There are reports that stress can cause damage and atrophy of neurons in certain brain structures, most notably the hippocampus o A decrease of hippocampal volume is detected by MRI in both depressive patients and in postmortem studies. Increasing evidences indicate that hippocampus plays an important role in the pathogenesis of depression.Molecular and cellular studies of stress, depression, and antidepressants have moved the field of mood disorder research beyond the monoamine hypothesis. The neuroplasticity hypothesis emerged. It hypothesized that stress can modulate the expression of various factors involved in cell survival and growth/anti-apoptotic factors, such as brain-derived neurotrophic factor (BDNF), cyclic adenosine monophosphate response element binding protein (CREB), B cell leucemia protein2(Bcl-2), and mitogen-activated protein (MAP) kinases, which may, in turn, affect neuroplasticity in the hippocampus, ultimately resulting in depression.A number of animal models were developed to study the molecular effects of stress and the underlying neurobiological mechanisms of depression. Chronic mild stress (CMS) model (long-term exposure (i.e, greater than1weeks) to multiple, mild and inescapable stressors) is a commonly used model because it mimics depression-like phenotypes satisfactorily. Its rationale is based on the underlying stress-induced difficulties found in many depressed patients.Many researches have studied different stress (acute stress or chronic stress) effect on different neuroplasticity-related proteins. But less is known about how chronic mild stress influences neuroplasticity-related proteins expression in the hippocampus by the time of the stress. This may be an important clue to the pathogenesis of depression. We made some changes in the classic CMS model.7different classic mild stressors were used randomly in a7-days period, and then repeated in the next7-days period. We subjected rats treated with chronic mild stress of three different periods (1week of exposure to CMS group,2weeks of exposure to CMS group and3weeks of exposure to CMS group),Our experiments therefore address the following questions:(1) What are the effects of different CMS on the levels of neuroplasticity-related proteins BDNF/CREB/Bcl-2expression?(2) Is there a relationship between the changes of neuroplasticity-related proteins BDNF/CREB/Bcl-2and depressive-like behaviors in the CMS rats?Objective:To address these questions, we subjected rats treated with CMS of three different periods, investigated their depression-like behavioral changes and hippocampal neuroplasticity-related proteins’changes, and wanted to explore the possible mechanism.Method:(1)Animals were sepatated into one of four groups rcontrol group, rats without stress:M1group, rats subjected to CMS for1week:M2group, rats subjected to CMS for2weeks:and M3group, rats subjected to CMS for3weeks.(2) The CMS procedure, which involves the sequential exposure to various unpredictable mild stressors, is designed to maximize the unpredictable nature of the stressors..(3) Rats’ depression-like behaviors were observed in opening field test and1%sucrose preference test were tested before and after the experimentation of each group.(4) After bahvior test, rats were sacrificed and hippocampus were isolated. Neurogenesis in hippocampal dentate gyrus was detected by using immunohistochemistry method.(5)Using reverse transcription-polymerase chain reaction (RT-PCR) and Western blot, we analyzed BDNF/CREB/Bcl-2mRNA and protein expression in the rat hippocampus.(6) Statistics:All values were expressed as mean±SD. A one-way ANOVA was used for comparisons among groups and the Least-significant Difference was used for post-hoc multiple comparisons. Statistical significance was defined as p<0.05.Results:(1) Compared with Controlled group, total diatance(cm) in10minutes/center distance(cm) in10minutes/rearing counts were decreased in MI group (P <0.05), M2group (P<0.05), and M3group (P<0.05) There was no significant difference in the total diatance in10minutes/center distance(cm) in10minutes/rearing counts among the M1, M2and M3groups (p>0.05). Compared with Controlled group, levels of total fluid consumption/sucrose consumption/sucrose preference consumption were decreased in MI group (P<0.05), M2group (P<0.05), and M3group (P<0.05). There was no significant difference in levels of total fluid consumption among the M1, M2and M3groups (p>0.05).(2) Compared with Controlled group (31.75±8.48),BrdU-labeled cells in the dentate gyrus were decreased in M1group (22.19±6.08):(P<0.05),and M3group(19.57±5.28)(P<0.05), there was no significant difference in the levels of BrdU-labeled cells in the dentate gyrus between Ml group and M3group(P>0.05).There was no significant difference in the levels of BrdU-labeled cells in the dentate gyrus between M2group(29.78±6.78) and control group(P>0.05).(3) RT-PCR analysis:Compared with controlled group, levels of BDNFmRNA/CREBmRNA/Bcl-2mRNA were decreased in MI group (P<0.05),and M3group (P<0.05), there was no significant difference in the levels of BDNFmRNA between M1group and M3group(P>0.05).There was no significant difference in the levels of BDNFmRNA between M2group and control group(P>0.05).(4) Immunoblotting analysis:Compared to that in the controlled group,the amount of BDNF protein/CREB protein/Bcl-2protein in MI group and M3group both decreased significantly (p<0.05), there was no significant difference in the amount of BDNF protein between M1group and M3group(P>0.05).however,2week’s chronic mild stress did not affect the amount of BDNF protein (p>0.05).Conclusion:Our findings illustrated that different chronic mild stress might have different effects on proteins implicated in neuroplasticity, providing insight into the role of neuroplasticity-related proteins in the depression. |
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