|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|
|Alternative Title||The effect of TNFα in the prefrontal cortex on adolescent social stress induced behavioral changes in adult mice|
|Place of Conferral||北京|
|Keyword||社会击败应激 青少期 社会交互 认知功能 TNFα|
|Abstract||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。|
|Other Abstract|| 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.
|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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