| 下边缘皮层促肾上腺皮质激素释放因子系统在慢性应激损伤目标导向行为中的作用 | |
| 其他题名 | The role of corticotropin-releasing factor system in stress-impaired goal-direct behavior performance |
| MIRMOHAMMADALI MIRRAMEZANIALIZAMINI | |
| 导师 | 隋南 ; 梁璟 |
| 2023-05 | |
| 摘要 | 漫性应激可导致目标导向行为及执行功能(包括行为灵活性、抑制控制等)受损。然而，损伤机制尚不清楚。内侧前额叶皮层(medial prefrontal cortex, mPFC)是调控目标导向行为及执行功能的重要脑区，且mPFC的促肾上腺皮质激素释放因子(corticotropin-releasing factor, CRF)系统参与应激反应。mPFC的CRF系统是否通过调控神经传递的可塑性改变参与慢性应激导致的目标导向行为和/或执行功能的损伤仍然未知。本实验室的前期研究显示，慢性社会应激显著易化动物习惯化行为的建立，此行为改变与IL脑区异常激活有关。因此，我们推测，慢性社会应激可能导致IL的CRF系统异常激活，进而使得此脑区调控兴奋性、抑制性突触传递功能异常，伴有IL高度兴奋状态的动物表现出目标导向行为受损，行为灵活性下降以及习惯化行为增多等异常行为表现。在此项研究中，我们针对上述假设展开了实验验证工作。 此研究采用了动物行为学、行为药理学、分子生物学以及离体脑片膜片钳电生理记录等实验技术。 首先，基于行为操作任务，我们探测了慢性社会挫败应激(chronic social defeat stress CSDS)对于小鼠目标导向行为、注意定势转移(attention set-shifting)以及反转学习（ reversal learning)的影响。结果显示，CSDS仅对以视觉线索为基础的目标导向行为具有损伤作用，未对其他认知灵活性造成明显影响。随后，我们进一步阐明，在视觉线索学习过程中给予IL脑区CRFI型受体(CRF receptor 1, CRFR1)选择性拮抗剂NBI 27914可以有效修复由慢性社会应激造成的目标导向行为损伤。上述结果提示，IL脑区的CRF受体系统可能参与慢性应激导致的行为改变。 接下来，采用实时荧光定量PCR技术，我们对于CSDS之后的多个时间点(应激后1天、7天以及14天)下丘脑以及mPFC的CRF和CRF受体基因表达水平进行了检测。然而，在mPFC或者下丘脑区域，CRF或者CRFR1的mRNA水平未呈现出显著性变化。此阴性结果的产生可能由于CRF系统对于IL功能的调控并不体现于mRNA水平的变化，同时也不能排除取材范围过于宽泛的局限性缘由。之后，使用离体脑片膜片钳电生理记录技术，我们证实了小鼠在经历连续十天的社会性挫败后，IL区域的自发抑制性突触后电位(spontaneous inhibitory type of postsynaptic currents, sIPSC)和自发兴奋性突触后电位(spontaneous excitatory type of postsynaptic currents, sEPSC)的频率呈现显著性升高，并且受到CRFR1的调控。我们的研究也显示，慢性社会应激提升了刺激诱发的兴奋性突触后电位(evoked EPSC)与刺激诱发的抑制性突触后电位(evoked IPSC)的比值(excitation/inhibition ratio, E/I ratio )，并且CRFR 1选择性拮抗剂逆转了此变化。综上，基于此项目的研究方法，我们虽然未能捕捉到IL脑区CRF系统在调质含量或者受体水平的变化，但是证实了慢性社会应激可以造成以视觉信号为基础的目标导向行为的损伤，并且改变了IL脑区的神经突触传递功能。我们也深入揭示了应激造成的行为及神经电生理改变可以被CRFR1的抑制所对抗，而CRFR1的受体激动剂可以一定程度上模拟应激引起的抑制性和兴奋性突触功能改变。由此，我们提出，IL脑区的CRFR1可能是漫性应激损伤目标导向行为的潜在调节因子，也有望成为干预或治疗由慢性应激导致精神类疾病的潜在生物靶点。 |
| 其他摘要 | The reaction to the stress is governed by activity of the corticotropin-releasing factor (CRF) network within medial part of prefrontal cortex (mPFC) region, which is related to lots of executive activities in the brain. One of the important subregions of the PFC is infralimbic (IL) region which is believed to be responsible for the controlling of the inhibitory currents relevant to the decision making. However, lines of evidence showed the involvement of excitatory neurotransmission within IL. Besides, IL also seems to contribute in modulation of chronic stress-induced dysregulations in brain because of its CRF receptors. In contrary, stress in its chronic shape, has been related to a broad spectrum of brain dysfunctions, especially depressive behaviors. The significance of PFC CRF system in regulation of depression disorder resulted from the stress in clinical/preclinical studies (or models) has been systematically reviewed here and it reveals that PFC performs a substantial regulatory participation in the management of stress-involved depression, and PFC CRF receptors agonist/antagonist are important for modulation of these sorts of abnormalities. In human research, both CRF gene expression and immunoreactivity were shown to be elevated and immunoreactivity or excitatory/inhibitory CRF currents inside the PFC modulated depressive disorders in animal experiments. On the other hand, mPFC itself involves regions like IL and prelimbic (PL) region which are well-known for being responsible of controlling goal-directed and habitual behavior. After establishing the significance of PFC CRF system in regulation of stress-induced impairments, to go further with understanding of its involvement in modulation of stress-impaired goal-directed behavior and cognitive flexibility (behavioral&behavioral pharmacology approach) and also mechanism of altered IL activity (electrophysiological approach), we conducted sets of experiments. We divided the major goal of this thesis in two parts: The first aim of the thesis was to assess the impact of chronic stress on goal-direct performance and cognitive flexibility, and also to see if mPFC CRF system especially IL region can regulate it using CRF receptor of type 1 (CRFR1) agents. The reason that we studied goal-directed behavior (and its impaired conjugate, known as habitual behavior) and cognitive flexibility alterations was to see if we can control the related impairments (which leads to impaired decision-making and different mental disorders), especially when it is derived by chronic stress, and from there finding a proper treatment to prevent responding disorders since goal-directed behavior and cognitive flexibility are known to be vulnerable to stress according to previous researches. The second aim is to see if altered activity of infra-IL GABAergic and glutamatergic neurotransmission was associated to altered function of the cortical CRFR1 following chronic stress. For behavior assessment, we firstly found that exposure to chronic social defeat stress (CSDS) impaired the visual-cue learning in mice. Conversely, CSDS induced no effect on the ability in the shift between visual-cue learning to place learning in mice. According to the CSDS-impaired visual-cue learning model, behavioral pharmacology (using NBI 27914, CRFR1 antagonist) approach was used to assess CSDS-induced alterations in behavioral of animals in association with IL region. Mice that were exposed to CSDS and treated with infra-IL NBI 27914 revealed a significant increase in their relative growth rate for accuracy of visual-cue learning compared to stress group. While the results from behavioral experiments revealed that chronic stress altered the social behavior of the mice and impaired goal-direct behavior could be rescued via infra-IL NBI 27914 treatment, qRT-PCR results showed no critical change in mRNA levels of CRF, CRFR1/CRFR2 of neither mPFC nor hypothalamus. Next, using an electrophysiological approach, the results demonstrated that in mice which were subjected to a ten-day CSDS, the frequency of both spontaneous excitatory type of postsynaptic currents (sEPSC) and spontaneous inhibitory type of postsynaptic currents (sIPSC), but not their amplitudes, rose following stress and were controlled by CRFR1 agents. Furthermore, by recording and analyzing evoked EPSC and evoked IPSC, we found that excitation/inhibition (E/I) ratio in IL neurons was significantly enhanced by chronic stress and then regulated by CRFR 1 a potential regulator of CSDS-induced impairments of visual-cue learning and a good candidate for switching habitual behavior to goal-directed one. Furthermore, presynaptic CRFR1 has a significant involvement in stress-engaged or increased glutamatergic/GABAergic presynaptic neurotransmission within the IL region, and that it might be a good target for chronic stress-related diseases. agents. Although qRT-PCR results revealed no significant change in mRNA levels of mPFC CRF, CRFR1/CRFR2 but behavioral (and behavioral pharmacology) results imply to the IL CRFR1 as a potential regulator of CSDS-induced impairments of visual-cue learning and a good candidate for switching habitual behavior to goal-directed one. Furthermore, presynaptic CRFR1 has a significant involvement in stress-engaged or increased glutamatergic/GABAergic presynaptic neurotransmission within the IL region, and that it might be a good target for chronic stress-related diseases. |
| 关键词 | 慢性应激 下边缘皮质 促肾上腺皮质激素释放因子 突触传递 目标导向行为 |
| 学位类型 | 博士 |
| 语种 | 中文 |
| 学位名称 | 理学硕士 |
| 学位专业 | 健康心理学 |
| 学位授予单位 | 中国科学院大学 |
| 学位授予地点 | 中国科学院心理研究所 |
| 文献类型 | 学位论文 |
| 条目标识符 | http://ir.psych.ac.cn/handle/311026/45220 |
| 专题 | 健康与遗传心理学研究室 |
| 推荐引用方式 GB/T 7714 | MIRMOHAMMADALI MIRRAMEZANIALIZAMINI. 下边缘皮层促肾上腺皮质激素释放因子系统在慢性应激损伤目标导向行为中的作用[D]. 中国科学院心理研究所. 中国科学院大学,2023. |
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| MIRMOHAMMADALI MIRRA（3065KB） | 学位论文 | 限制开放 | CC BY-NC-SA | 请求全文 | ||
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