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前额叶皮质 TNFα在青少期社会应激诱发 的成年小鼠行为改变中的作用
其他题名The effect of TNFα in the prefrontal cortex on adolescent social stress induced behavioral changes in adult mice
张帆
学位类型硕士
导师王玮文
2015-05
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
关键词社会击败应激 青少期 社会交互 认知功能 TNFα
摘要青少期负性社会经历导致神经和行为的长期后果,增加成年期罹患精神疾病的风险。 我们前期的研究发现青少期早期社会击败应激诱发成年动物社交行为和前额叶介导的认知灵活性持久改变,但其分子机制尚不清楚。越来越多的证据显示中枢TNFα 参与正常神经发育和脑生理功能的维持,情绪和认知功能以及应激反应调节。 本研究通过三个实验考察了应激后饲养条件(群养/单养,实验一)和应激发生时发育阶段(青少期早期/晚期,实验二)因素对青少期社会击败应激诱发的成年小鼠行为和前额叶皮质 TNF表达的影响,以及慢性中和前额叶皮质TNF对上述行为的影响(实验三) 。行为检测包括社会交互和注意定势转移任务测试。采用免疫组织化学方法检测前额叶皮质不同亚区的TNF表达水平。
实验一的结果显示,青少期早期社会击败应激复合不同饲养条件(单养/群养)差异性影响成年小鼠行为。应激后无论单养还是群养,青少期早期社会击败应激都稳定降低成年小鼠各项社交行为指标,包括交互区域停留时间和社交指数。
然而,只有青少期早期复合社会应激(社会击败应激结合应激后单养)明显损害成年小鼠内侧前额叶皮质介导的外维度转移能力,应激后群养则显著缓解应激诱导的认知功能缺陷。与行为一致,青少期早期复合社会应激选择性降低内侧前额叶皮质而非眶额叶皮质TNF表达水平,上述改变在应激后群养条件下恢复。
实验二的结果显示,无论青少期早期或晚期复合社会应激都显著降低成年小鼠的社交行为。然而,只有青少期早期而非晚期发生的复合社会应激稳定地诱导成年小鼠的外维度定势转移能力损伤和内侧前额叶皮质 TNF表达水平降低。实验三的结果显示,内侧前额叶皮质微注射慢性中和TNF活动并不影响成年小鼠的社交行为,但选择性损伤其外维度定势转移能力。
综合上述发现,青少期社会击败应激对成年小鼠行为和前额叶皮质 TNF表达的差异性作用受应激后饲养条件和应激时发育阶段因素的影响。其中内侧前额叶皮质是青少期早期应激敏感的部位,该部位TNF活动抑制参与介导青少期早期社会应激诱导的成年小鼠认知灵活性损伤。
其他摘要 Negative social experience during adolescence causes long-term  behavioral and neural  consequences,  and increases the risk of mental illness in adulthood. Our previous studies  found that social defeat stress  (SDS) during early adolescence  (EA) induced  the decrease in  social behavior and  the deficit of cortically-mediated cognitive flexibility in adult mice, but its molecular mechanism is unclear.  In recent years, growing evidence  has shown that  central  tumor necrosis factor alpha (TNF) exerts extensive effects on the  normal neural development, the maintenance of neuronal activity, as well as various behaviors like emotional behavior and cognitive function. The changes in the expression and activity of central TNF under stressful conditions are related with neural and behavioral limbs of stress response. In the present study, three experiments were conducted in tandem to  investigate the influences  of rearing condition (grouping v.s.  isolation)  after stress and  the developmental stage (EA starting from PND 28 v.s.  late adolescence  (LA) starting from PND 38)  when the  stressor  occurred  on the effects  of  10d SDS  during adolescence on behavior and prefrontal cortical TNF  expression  in adult mice, and the effect of chronically  neutralizing TNF   in  the medial prefrontal cortex  (mPFC) on behavior. Behavioral measurements were performed in  social interaction  test and the  attention set shifting  task (AST).  TNF    expression in different subregions  of prefrontal cortex was determined by immunohistochemical method. The main results as followed:
    In experiment 1, it was  shown  that  EA SDS  followed by different rearing conditions  differentially altered  social  behavior  and cognitive  function.  No matter which  rearing condition  was  after stress,  EA SDS  significantly decreased defeated context relevant  social interaction behavior  in adult mice. However, only compound social stress (EA SDS plus isolated rearing after stress)  induced  impairment in adulthood in extra-dimensional shifting (EDS)  in the AST, which can be ameliorated by rearing  in group after EA SDS. In line with the behavioral changes, the compound social stress selectively reduced  the TNF   expression  in  the mPFC rather than the orbitofrontal cortex  (OFC),  and changes  above also  recovered  by  rearing in  group after EA SDS.  
In experiment 2, it was shown that compound social stress happened during either EA or LA significantly reduced the social interaction behavior of adult mice. However, compound social stress  happened  during  EA  rather than  LA selectively caused the deficit of EDS performance in the AST  and the decrease in the mPFC  TNF expression in adult mice.
In experiment 3, it was  shown  that  chronic mPFC TNF   neutralization did not affect social  interaction  behavior, but selectively  damaged EDS  performance in the AST and decreased mPFC TNF expression in adult mice.
These findings suggested  that the differential effects  of  SDS  in adolescence on behavior and prefrontal cortical TNF  expression of adult mice were  influenced by rearing condition after stress and developmental stage  when stress happened. The mPFC  is  especially  sensitive  to social stress during  early adolescence,  and the decreased expression of TNF  in this area might be involved in the adult impairment of cognitive flexibility induced by early adolescent social stress.
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/311026/19756
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
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张帆. 前额叶皮质 TNFα在青少期社会应激诱发 的成年小鼠行为改变中的作用[D]. 北京. 中国科学院研究生院,2015.
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