青少期社会应激诱导成年小鼠时序性记忆损害的脑功能活动特征
文献类型：学位论文
| 作者 | 井海洋
|
| 答辩日期 | 2022-06 |
| 文献子类 | 硕士 |
| 授予单位 | 中国科学院大学 |
| 授予地点 | 中国科学院心理研究所 |
| 其他责任者 | 王玮文 |
| 关键词 | 青少期社会应激 时序性记忆 谷氨酸能神经元 小胶质细胞 内侧前 额叶 外侧內嗅 |
| 学位名称 | 理学硕士 |
| 学位专业 | 应用心理 |
| 其他题名 | Adolescent social stress-induced temporary order memory impairment in adult mice and its characteristics of brain functional activity |
| 中文摘要 | Adolescent negative experiences are the main risk factors for various mentaldisorders. However, how stress exposure at this stage affects brain development and theunderlying psychological and brain mechanisms are still largely unknown. Episodicmemory is the basic cognitive function that enables individuals to adapt to dynamicenvironment changes. Temporal order memory (TOM) refers to memory for thetemporal order of events and the broader temporal context, that is a critical feature ofepisodic memory. The structure and function of brain regions and neural circuitsinvolved in TOM undergo rapid developmental changes during childhood andadolescence. But it remains unclear whether and how stress exposure at this stage maycause lasting effects on TOM relevant behavior and brain function. To investigate the effects of periodic exposure to social stress (Postnatal Day28-37) on temporal memory function in adult mice, we use an animal model of social defeatstress to mimic companion bullying at adolescence and object temporal order memorytask (TOMT) to evaluate the performance of TOM. Immunofluorescence,morphological analysis, and Western blot were used to detect the effects of adolescentstress on the functional activities of brain regions involved in temporal order memory,including prefrontal cortex (PFC), hippocampus, and lateral entorhinal cortex, and themain types of neural cells and related molecular expressions. The immediate-early gene(c-FOS) expression was determined to reflect neuronal activation level, c-FOS andglutamate neuron-specific Ca2+/ CAM-Activated protein kinases II-α(CAMKⅡ -α)double-labeling was used to further identify the neuronal types activated. Microglia-specific protein expression, including ionization-calcium binding adaptor molecule 1(Iba1), differentiated antigen Cluster of Differentiation molecule 11b (CD11b) andCX3C chemokine receptor 1 (CX3CR1) was examined, then in combination withmorphological analysis of microglia, its functional activity was further evaluated.Finally, the Pearson Correlation Analysis was performed to analyze the relationshipbetween the performance in TOMT and functional changes of neural cells in related brain regions. Results: 1) Compared with the control group, the temporal order memory functionof adult animals exposed to adolescent social stress was significantly impaired, but theirworking memory and anxiety-like behavior in the elevated plus maze and open fielddid not show significant changes; 2) Compared with the control group, the expressionof c-FOS in PrL subregion of medial PFC and LEC of adult animals with adolescentsocial stress exposure was significantly decreased, suggesting that stress causesinsufficient activation of neurons in these brain regions during temporary order memoryprocess. Further correlation analysis showed that temporal memory impairment wassignificantly associated with c-FOS expression in the mPFC PrL subregion and LEC.3) By double-labeling c-FOS and CAMKII-α, it was found that glutamatenergic neuronwas the main type of neurons activated in PrL subregion and LEC, and the activationnumber of glutamatenergic neurons in these regions was significantly decreased in adultanimals after adolescent social stress exposure. 4) The expression and function ofmicroglia in the above brain area with significant changes in neuronal functionalactivities were analyzed. It was found that the number of microglia in mPFC Cg1 andPrL subarea was significantly decreased. The number of microglia in LEC also showeda decreasing trend, and the cell bodies of microglia in LEC were significantly enlarged.Further discriminating the activation states of micriglia by morphological analysis,there was no difference in the proportion of activated microglia in both regions of thetwo groups. The results suggest that adolescent social stress caused a certain degree ofmicroglia activity insufficiency in the above brain regions of adult mice. 5) The CX3Caxis (CX3CL1-CX3CR1) mediates the interaction between neuron and microglia. Theexpression levels of CX3CR1 protein in above brain regions, which is specificallyexpressed in microglia, were further detected. The expression level of CX3CR1 in LECof the stress group was decreased to a certain extent, but the expression of anothermicroglia-related molecular marker, CD11b, did not significantly changed. These results showed that adolescent social stress can induce long-termimpairment of temporal order memory function in adult mice, and the inhibitorychanges in functional activities of PrL subregion of mPFC and LEC, mainly by glutamatenergic neurons,,may mediate the impairment of memory function. Thesefindings extend our understanding on the long-term effects of adolescent social stresson temporal order memory and related brain functions, and provide an experimentalbasis for further exploring the neurobiological mechanisms in the future. |
| 英文摘要 | 儿童青少期负性经历是多种精神疾病发生的主要危险因素。然而，这一阶段的应激暴露如何影响大脑的发育，进而造成跨疾病患病风险增加的心理与脑机制在很大程度上并不清楚。时序性记忆是一种对客观事件发生的具体时间以及对事件发生相对顺序进行记忆的情景记忆功能，是个体适应动态环境变化的基本认知功能。在精神疾病患者和模式动物上都观察到不同程度的时序性记忆功能损害问题。参与时序性记忆调节的脑区和环路的结构和功能在青少期经历快速发展变化，这一阶段应激是否可能通过影响其正常发育，进而构成对行为与脑功能的持续影响尚并不清楚。 利用一种拟人类儿童青少年常见的同伴霸凌建立社会挫败应激动物模型，通过建立小鼠的时序性记忆任务以评价其时序性记忆功能，本研究调查了青少期阶段性（出生后 28-37 天）应激暴露对成年小鼠时序性记忆功能的影响。本研究采用免疫荧光、形态学分析和 Western blot 方法检测青少期应激对时序性记忆调节脑区，包括前额叶、海马和內嗅等部位的功能活动的影响，参与的主要神经细胞类型及相关的分子表达。主要检测指标包括，以即刻早期基因 c-Fos 检测神经元激活水平，对显著变化的脑区进行 c-Fos 与谷氨酸能神经元特异性的钙/钙调蛋白依赖激酶Ⅱ-α（Ca2+/CaM-activated protein kinases Ⅱ-α, CAMKⅡ-α）共标进一步确定参与时序性记忆的神经元类型。检测小胶质细胞特异性的分子，包括离子钙结合衔接分子 1（Ionized-calcium binding adaptor molecule 1, Iba1），分化抗原簇 11b（Cluster of differentiation molecule 11b, CD11b）和趋化因子受体 1（CX3Cchemokine receptor 1, CX3CR1）的蛋白表达水平，并结合形态学功能分析检测小胶质细胞数目及功能活动变化。最后，采用皮尔逊相关分析方法进一步分析了时序性记忆功能变化与相关脑区细胞分子变化间的关系。 主要研究结果如下：1）与对照组相比，经历青少期社会应激的成年动物时序性记忆功能明显受损，但其工作记忆以及在高架十字迷宫和旷场中的焦虑样行为并未表现出明显改变；2）与对照组相比，应激组小鼠内侧前额叶（Medialprefrontal cortex, mPFC）前边缘皮层（Prelimbic cortex, PrL）亚区及外侧内嗅（Lateral entorhinal cortex, LEC）c-Fos 表达减少，提示应激导致上述脑区的神经元在时序性记忆过程中激活不足。进一步的相关分析显示时序性记忆功能损害与mPFC PrL 亚区和 LEC 的 c-Fos 表达水平显著相关。3）通过 c-Fos 与谷氨酸能神经元 CAMKII-α 共同标记，发现 PrL 亚区以及 LEC 激活的神经元主要为谷氨酸能神经元，且青少期应激导致成年小鼠上述区域谷氨酸能神经元激活的数量明显下降。4）对上述神经元功能活动变化脑区的小胶质细胞的表达和功能进行分析，发现应激组小鼠 mPFC Cg1 以及 PrL 亚区的小胶质细胞的数量显著下降；LEC小胶质细胞的数量也呈下降趋势，并且 LEC 的小胶质细胞的胞体显著增大，但两脑区小胶质细胞的功能活化比例均没有明显改变，提示青少期应激导致成年小鼠上述脑区一定程度的小胶质细胞功能活动的改变。5）鉴于神经元与小胶质细胞通过 CX3C 轴（CX3CL1-CX3CR1）交互影响，进一步检测上述脑区的小胶质细胞相关功能分子的表达水平，仅发现应激组小鼠 LEC 的 CX3CR1 蛋白表达水平有一定程度降低，但未发现小胶质细胞增殖相关分子CD11b表达的明显变化。 这些结果表明，青少期社会应激可以诱导成年小鼠时序记忆功能的长期损伤，mPFC 皮质 PrL 亚区以及外侧內嗅的谷氨酸能神经元的抑制性改变和小胶质细胞功能活动的改变可能介导了记忆功能的损害。这些发现扩展了对于青少期应激对时序性情景记忆及相关脑功能长期影响的认识，为进一步开展神经生物学机制研究提供了实验基础。 |
| 语种 | 中文 |
| 源URL | [http://ir.psych.ac.cn/handle/311026/43184]  |
| 专题 | 心理研究所_健康与遗传心理学研究室 |
| 推荐引用方式 GB/T 7714 | 井海洋. 青少期社会应激诱导成年小鼠时序性记忆损害的脑功能活动特征[D]. 中国科学院心理研究所. 中国科学院大学. 2022. |
入库方式： OAI收割
来源：心理研究所
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