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Bdnf IV调节的GABA能突触传递在抑郁样行为发生和治疗中的作用
Alternative TitleRoles of BDNF promoter IV-regulated GABAergic synaptic transmission in the onset and treatment of depression-like behavior
徐航
Subtype博士
Thesis Advisor王玮文
2018-12
Degree Grantor中国科学院大学
Place of Conferral中国科学院心理研究所
Degree Name理学博士
Degree Discipline健康心理学
Keyword青少期社会应激 抑郁样行为 内侧前额叶皮质(Mpfc) 脑源性神经营养 因子(Bdnf) Gaba能突触传递
Abstract

目的:社会应激是青少年群体的主要应激来源,与抑郁症患病风险增加密切相关。神经可塑性降低是抑郁症的重要病理生理改变。己知脑源性神经营养因子(BDNF)是调节神经可塑性并参与抑郁症发病和抗抑郁治疗过程的关键因子,但其物化属性、效应复杂性及缺乏快速效应等限制了其应用。本研究旨在探讨BDNF参与抑郁症的分子机理和下游介导通路,以加深对于疾病病理的认识和建立新的治疗策略。

方法:利用青少期社会挫败应激诱发成年小鼠抑郁样行为,综合采用行为学、分子生物学、转基因以及电生理方法,探讨了内侧前额叶皮质(mPFC ) Bdnf IV剪切体调节的GABA能突触传递在抑郁样行为发生与治疗中的作用。

)青少期社会应激诱导成年小鼠社交兴趣缺失和认知灵活性损伤等抑郁样行为及共病的焦虑行为增加,同时导致mPFC BDNF mRNA和蛋白表达水平降低以及GABA能突触传递功能减弱。2 ) mPFC BDNF表达降低与Bdnf IV剪切体抑制有关,后者受其启动子区表观修饰负调节因子H3 K9 me3表达增加的影响。3 ) Bdnf IV剪切体敲除直接诱发抑郁样行为和mPFC GABA能突触传递水平降低。4)慢性抗抑郁药物干预改善青少期社会应激诱导的多种改变,包括抑郁样行为、mPFC Bdnf IV活动抑制和表观修饰改变以及GABA能突触传递功能减弱。5 )mPFC单次微注射TrkB受体激动剂快速改善应激组小鼠的抑郁样行为和恢复降低的mPFC GABA能突触传递。

些结果表明,mPFC BdnfIV调节的GABA能突触传递是BDNF参与抑郁样行为发生及快速抗抑郁治疗的重要分子和通路机制。

Other Abstract

Objectives: As the main source of stress during adolescence, social stress can increase the risk of depression in adulthood. It is known that brain-derived neurotrophic factor (BDNF) is involved in the pathophysiology and anti-depression treatment of depression. However, its physical and chemical properties and lack of quick effect limit its application. In order to deepen the understanding of pathogenesis and establish a new treatment strategy, the present study aimed to investigate the molecular and pathway mechanism of BDNF involved in depression.

Methods: Using adolescence social defeat stress, we adopted an integrative approach, including behavioral studies, molecular biology and electrophysiology to investigate the roles of BDNF promoter IV-regulated GABAergic synaptic transmissionin the onset and treatment of depression-like behavior.

Results: 1)Adolescence social defeat stress induced a set of depressive phenotypes, including decreased social interest, increased anxiety behavior and a cognitive flexibility deficits, in parallel with reduced levels of total BDNF and impairment of GABAergic inhibitory synaptic transmission in the medial prefrontal cortex(mPFC). 2) The reduced levels of BDNF were related to the inhibition of isoform IV transcripts, which was influenced by the increased expression of H3K9me3, a negative regulator of this promoter region. 3) The specific deletion of BDNF promoter IV directly caused depressive behavioral phenotypes and attenuation of mPFCGABAergic pathway. 4) The chronic treatment with antidepressant reversed depressive phenotypes as well as the attenuations of molecules and GABAergic inhibitory synaptic transmission, in previously stressed adult mice. 5) Single microinjection of BDNF TrkB receptor agonist into mPFC rapidly improved depression-like behavior induced by dolescence social defeat stress. Meanwhile, the vitro electrophysiological experiments showed that this agonist also rapidly restored the reduction of GABAergic synaptic transmission in the mPFC of previously stressed adult mice.

Conclusion: These results demonstrated that BDNF promoter IV-regulated GABAergic transmission in the mPFC may be important molecular and pathway mechanisms underlying the pathophysiology of depression and rapid antidepressant action.

Pages99
Language中文
Document Type学位论文
Identifierhttp://ir.psych.ac.cn/handle/311026/28662
Collection健康与遗传心理学研究室
Recommended Citation
GB/T 7714
徐航. Bdnf IV调节的GABA能突触传递在抑郁样行为发生和治疗中的作用[D]. 中国科学院心理研究所. 中国科学院大学,2018.
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