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神经发生在中枢炎性免疫所致抑郁样行为中的作用
其他题名The role of neurogenesis in depressive-like behavior induced by neuroinflammation
汤明明
学位类型博士
导师林文娟
2016-05
学位授予单位中国科学院研究生院
学位授予地点北京
学位专业心理学
关键词神经发生 中枢炎性免疫 抑郁样行为 成纤维细胞生长因子
摘要目的:炎性免疫是抑郁症的重要病因之一,这一观点自抑郁症的炎性假说提出至今,经过二十多年的探索已经获得了许多支持证据。但炎性免疫引起抑郁样行为的细胞和分子机制仍有很多未被阐释清楚。炎性反应通过多条途径引起抑郁症状,最新证据显示炎性免疫还作用于神经发生过程,提示神经发生可能是炎性免疫引起抑郁症状的途径之一,但目前还没有研究对神经发生途径做详细探讨。
与外周炎性免疫相比,中枢神经系统的炎性免疫与精神疾病的联系更为紧密,并且更直接地影响神经发生。在这些证据基础上,本研究的目的是探索神经发生在中枢炎性免疫所致抑郁样行为中的作用。
    方案:本研究由四个部分组成。研究一检验侧脑室多次LPS  注射是否引起大鼠显著的中枢炎性免疫激活,为后续研究提供动物模型基础。研究二首先检验中枢炎性免疫在糖精水偏好测验、旷场测验、悬尾测验以及新奇抑制摄食测验等中的行为效应,然后从增殖、存活、分化及发育等方面检验中枢炎性免疫对大鼠神经发生的影响,并探讨行为效应与神经发生之间的相关性。研究三检验抑郁样行为和神经发生在LPS 注射前后多个时间点上的变化情况,从时间维度探讨中枢炎性免疫激活引起的抑郁样行为与神经发生改变之间的联系。研究四通过调节神经发生有关分子通路,探讨能否从神经发生途径改善中枢炎性免疫所致抑郁样行为。
    结果:研究一建立了中枢炎性免疫激活大鼠模型,伴有脑内小胶质细胞激活增加,以及促炎性细胞因子表达水平升高。研究二结果显示中枢炎性免疫激活引起显著的抑郁样行为,包括糖精水偏好下降、自发活动和探索活动减弱、悬尾但不影响新生细胞的分化方向。并且行为指标与神经发生指标之间具有显著的相关性。研究三结果显示末次LPS 注射后24 h 和72  h 抑郁样行为症状显著,此后行为效应逐渐消退。神经细胞增殖水平存在与行为症状一致的变化趋势。研究四结果显示中枢炎性免疫激活抑制具有维持神经发生功能的 FGF2-ERK1/2不动时间延长、以及新奇抑制摄食潜伏期延长等。与此同时,中枢炎性免疫激活抑制了神经发生活动中细胞增殖、新生细胞存活、以及新生神经元发育等过程,但不影响新生细胞的分化方向。并且行为指标与神经发生指标之间具有显著的相关性。研究三结果显示末次LPS 注射后24 h 和72  h 抑郁样行为症状显著,此后行为效应逐渐消退。神经细胞增殖水平存在与行为症状一致的变化趋势。研究四结果显示中枢炎性免疫激活抑制具有维持神经发生功能的 FGF2-ERK1/2信号通路。给予中枢炎性免疫激活动物侧脑室补充FGF2 蛋白,阻断了磷酸化ERK1/2 的下调,减轻了神经发生的抑制,并且改善了抑郁样行为。
    结论:本研究结果表明神经发生参与了中枢炎性免疫引起抑郁样行为的过程,调节神经发生能够改善中枢炎性免疫激活引起的抑郁样行为。这些结果提示神经发生是中枢炎性免疫诱发抑郁症状的重要途径。本研究为解释炎性免疫诱发抑郁症的病理机制提供了新的实验证据,并且为治疗炎性免疫所致抑郁症提供了新的尝试方向。
其他摘要Over the last two decades, new developments in psychiatric research have led to the hypothesis that inflammatory processes are involved in the pathogenesis of major depression      and play an important role. Although this hypothesis has been an interesting research focus,   how neuronal-immune interactions modulate the depressive phenotype is still not fully understood. Inflammatory processes may affect more than one pathway, which is thought to   be important in the pathogenesis of depression. Recent data suggest that adult neurogenesis, as a novel pathway, may also be involved in depressive disorders caused by inflammation. This new pathway has not been adequately investigated yet. The inflammatory processes in the central nervous system is associated with mental disorders more closely than peripheral inflammatory.
Neuroinflammation affects neurogenesis more directly. Therefore, the aim of the present study was to investigate the role of neurogenesis in depressive-like behavior induced by neuroinflammation.
     This study consists of four parts. Part one examined  whether multiple LPS infusions   into lateral ventricle could evoke the neuroinflammatory state. Part two examined the effects of neuroinflammation on behavior and neurogenesis. Part three traced the changes of behavioral symptoms and neurogenesis at several points of time after multiple LPS infusions. Part four   examined whether FGF2 supplement could alleviate dysfunction of neurogenesis and reverse   the depressive-like behavior induced by neuroinflammation.
     Multiple LPS infusions evoked neuroinflammation in rat,  which was marked by increased number of activated microglia and elevated protein levels of pro-inflammatory cytokines. This neuroinflammatory state induced significant depressive-like behaviors in the   rats and inhibited neurogenesis, including reduced saccharin preference and locomotor   activity as well as increased  immobility time in the tail suspension test and latency to feed in   the novelty suppressed feeding test. Adult neurogenesis was concomitantly inhibited, including decreased cell proliferation and newborn cell survival. The degree of inhibition in adult   neurogenesis was closely correlated with the level of depressive-like behaviors. The changes of behavior were significant at 24 h and 72 h after the last LPS infusion, which were synchronized with the changes of cell proliferation. Neuroinflammation inhibited the expression of FGF2 and   phosphorylated ERK1/2. Under neuroinflammatory state, FGF2 supplement to lateral ventricle  blocked the decreased activation of ERK1/2 signal, alleviated  the impairment in neurogenesis, and reversed the depressive-like behavior.
     These findings provide the first evidence that neurogenesis dysfunction is associated     with neuroinflammation-induced depression, and demonstrate that modulation of   neurogenesis play an antidepressant role under neuroinflammatory state. These results also  suggests that neurogenesis might be one of biological mechanisms underlying depression induced by neruoinflammation, and might be new target in the treatment of neuroinflammation-induced depressive-like behavior.
学科领域医学心理学
语种中文
文献类型学位论文
条目标识符http://ir.psych.ac.cn/handle/311026/19821
专题健康与遗传心理学研究室
作者单位中国科学院心理研究所
推荐引用方式
GB/T 7714
汤明明. 神经发生在中枢炎性免疫所致抑郁样行为中的作用[D]. 北京. 中国科学院研究生院,2016.
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