Early-life stress can lead to sustained alterations in regional resting-state brain functions, but the underlying molecular mechanism remains unclear. Stress can also induce sustained changes in epigenetic modificatio...Early-life stress can lead to sustained alterations in regional resting-state brain functions, but the underlying molecular mechanism remains unclear. Stress can also induce sustained changes in epigenetic modifications across brain regions, which are not limited to a few genes;rather, they often tend to produce global levels of change. The functional implication of these changes also remains to be elucidated. We hypothesize that global epigenetic changes may partly modulate the resting-state functions of brain regions to influence behavior. To test this hypothesis, we used an adolescent social stress (ASS) model in mice and examined the relationship between epigenetic modifications and regional resting-state brain activity using resting-state functional magnetic resonance imaging (rs-fMRI). The results showed that, compared to the control mice, the stressed mice showed increased anxiety and social avoidance behaviors and greater levels of dimethylation of histone H3 at lysine 9 (H3K9me2) in the medial prefrontal cortex (mPFC). In addition, the resting-state activity represented by the amplitude of low-frequency fluctuation (ALFF) was significantly lower in the mPFC of stressed mice. To verify the relationship of H3K9me2 and ALFF, the specific inhibition of H3Kme2 was performed by using the drug UNC0642, which reversed the anxiety behavior induced by ASS and significantly increase the ALFF value of mPFC in both normal and ASS animals. Our study is the first to report an association between histone modifications and rs-fMRI findings, providing a new perspective for understanding of the significance of regional brain epigenetic changes and a possible molecular explanation for rs-fMRI findings.展开更多
Post-traumatic stress disorder(PTSD)is a severe neuropsychiatric disorder characterised by reexperiencing,avoidance and hyperarousal.Memory abnormalities manifested as intrusive thoughts and prolonged distressful emot...Post-traumatic stress disorder(PTSD)is a severe neuropsychiatric disorder characterised by reexperiencing,avoidance and hyperarousal.Memory abnormalities manifested as intrusive thoughts and prolonged distressful emotions are postulated as key roles in PTSD development and persistence.Over the past decades,convergent results from human and animal studies have systematically investigated contributions of the amygdala,hippocampus and medial prefrontal cortex(mPFC)in fear memory processes,including fear acquisition,storage,reconsolidation and extinction.These findings provide mechanistic insights for cognitive-behavioural therapy and aid in developing pathological region-targeted neuromodulation treatment for PTSD.Taking advantage of advances in cell-type selective labelling and manipulation technologies,recent studies have focused on the spatiotemporal regulation of neural circuits underlying distinct phases of fear memory processes.These findings have revealed that multiple distributed brain areas participate in the fear memory encoding network.Moreover,the functional role of distinct neuronal ensembles within the amygdala-hippocampus-mPFC pathway,identified by genetic markers and projection profiles,has been assigned to temporally separate features of fear processing,demonstrating the sophistication of the fear encoding circuit.These results provide mechanistic insights into PTSD pathology and might shed light on aetiology-based clinical interventions for PTSD.Therefore,the present review will mainly focus on the recent progress in elucidating neural circuit mechanisms underlying the dynamic regulation of fear memory,with an emphasis on the spatial distribution of fear memory encoding neural networks and the temporal coherence between neuronal ensemble activity and fear expression.展开更多
目的观察创伤后应激障碍(PTSD)大鼠前额皮质(mPFC)神经元未折叠蛋白反应(unfolded protein response,UPR)标志物葡萄糖调节蛋白78(GRP78)和内质网调节蛋白57(ERP57)的表达变化,探讨内质网分子伴侣在PTSD发病机制中的作用。方法采用国际...目的观察创伤后应激障碍(PTSD)大鼠前额皮质(mPFC)神经元未折叠蛋白反应(unfolded protein response,UPR)标志物葡萄糖调节蛋白78(GRP78)和内质网调节蛋白57(ERP57)的表达变化,探讨内质网分子伴侣在PTSD发病机制中的作用。方法采用国际认定的PTSD动物模型-SPS大鼠模型,取80只成年雄性健康Wistar大鼠,随机分为正常组和SPS模型组(SPS1d,SPS4d,SPS7d),采用逆转录-聚合酶链式反应、免疫组织化学法和免疫印记检测PTSD-SPS大鼠m PFC神经元中GRP78和ERP57的表达变化。结果 SPS刺激后大鼠m PFC神经元细胞内GRP78和ERP57蛋白表达于1d开始逐渐升高,7d时表达最多;GRP78和ERP57的m RNA水平的变化与其蛋白表达变化相一致。结论 GRP78和ERP57在PTSD大鼠mPFC过表达可能参与SPS刺激诱导的UPR反应。展开更多
基金the National Natural Science Foundation of China(Grant Nos.82071517,U21A20364,31771217,and 31900731)National Key R&D Program of China(Grant No.2017YFE0126500),and the Scientific Foundation of Institute of Psychology,Chinese Academy of Sciences(No.E2CX4115CX).
文摘Early-life stress can lead to sustained alterations in regional resting-state brain functions, but the underlying molecular mechanism remains unclear. Stress can also induce sustained changes in epigenetic modifications across brain regions, which are not limited to a few genes;rather, they often tend to produce global levels of change. The functional implication of these changes also remains to be elucidated. We hypothesize that global epigenetic changes may partly modulate the resting-state functions of brain regions to influence behavior. To test this hypothesis, we used an adolescent social stress (ASS) model in mice and examined the relationship between epigenetic modifications and regional resting-state brain activity using resting-state functional magnetic resonance imaging (rs-fMRI). The results showed that, compared to the control mice, the stressed mice showed increased anxiety and social avoidance behaviors and greater levels of dimethylation of histone H3 at lysine 9 (H3K9me2) in the medial prefrontal cortex (mPFC). In addition, the resting-state activity represented by the amplitude of low-frequency fluctuation (ALFF) was significantly lower in the mPFC of stressed mice. To verify the relationship of H3K9me2 and ALFF, the specific inhibition of H3Kme2 was performed by using the drug UNC0642, which reversed the anxiety behavior induced by ASS and significantly increase the ALFF value of mPFC in both normal and ASS animals. Our study is the first to report an association between histone modifications and rs-fMRI findings, providing a new perspective for understanding of the significance of regional brain epigenetic changes and a possible molecular explanation for rs-fMRI findings.
基金supported by the National Natural Science Foundation of China(82401772)the Shanghai Municipal Education Commission(2021-01-07-00-02-E0086).
文摘Post-traumatic stress disorder(PTSD)is a severe neuropsychiatric disorder characterised by reexperiencing,avoidance and hyperarousal.Memory abnormalities manifested as intrusive thoughts and prolonged distressful emotions are postulated as key roles in PTSD development and persistence.Over the past decades,convergent results from human and animal studies have systematically investigated contributions of the amygdala,hippocampus and medial prefrontal cortex(mPFC)in fear memory processes,including fear acquisition,storage,reconsolidation and extinction.These findings provide mechanistic insights for cognitive-behavioural therapy and aid in developing pathological region-targeted neuromodulation treatment for PTSD.Taking advantage of advances in cell-type selective labelling and manipulation technologies,recent studies have focused on the spatiotemporal regulation of neural circuits underlying distinct phases of fear memory processes.These findings have revealed that multiple distributed brain areas participate in the fear memory encoding network.Moreover,the functional role of distinct neuronal ensembles within the amygdala-hippocampus-mPFC pathway,identified by genetic markers and projection profiles,has been assigned to temporally separate features of fear processing,demonstrating the sophistication of the fear encoding circuit.These results provide mechanistic insights into PTSD pathology and might shed light on aetiology-based clinical interventions for PTSD.Therefore,the present review will mainly focus on the recent progress in elucidating neural circuit mechanisms underlying the dynamic regulation of fear memory,with an emphasis on the spatial distribution of fear memory encoding neural networks and the temporal coherence between neuronal ensemble activity and fear expression.
