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腹侧海马Parvalbumin 阳性中间神经元调控社交记忆的 神经机制
Alternative TitleVentral Hippocampus Parvalbumin Positive Interneurons Can Modulate Retrieval of Social Memory in Mice
Thesis Advisor郭建友
Degree Grantor中国科学院心理研究所
Place of Conferral中国科学院心理研究所
Degree Name理学博士
Keyword海马 社交记忆 中间神经元 光遗传学

社交记忆对动物的生存和繁衍至关重要。与其他类型的记忆相同,社交记忆的加工过程也可以被划分为三个基本的阶段: 编码( encoding ) 、巩固(consolidation)和提取(retrieval)。任何一个加工阶段出现了问题,都会引起社交再认的障碍。来自动物和人类的研究表明,海马在情景记忆(episodicmemory)的各个加工阶段都扮演重要角色。情景记忆包括众所周知的四个基本要素:时间,地点,人物,事件,而社交记忆作为情景记忆的重要组成部分之一,提供了关于“人物”的关键信息,也与海马有着密不可分的联系。与此同时,社交记忆障碍也是精神疾病中常见的表型,比如阿尔兹海默、自闭症都存在社交记忆障碍。然而,尽管社交记忆障碍在精神病研究领域获得了较多的关注,却很少有人探讨社交记忆障碍所在的加工阶段及其对应的神经病理机制之间的关系。此外,有研究表明,精神疾病中普遍存在的Parvalbumin 阳性中间神经元(后简称PV 神经元)缺陷可能是导致社交记忆障碍的潜在原因,但PV 神经元是如何影响社交记忆的,作用于哪一个记忆加工阶段,还不得而知。基于此,本研究通过腺相关病毒载体和转基因动物,实现对小鼠海马的PV 神经元的特异性损毁、光遗传调控,试图阐明PV 神经元在社交记忆中的作用机制。研究发现:

(1)对青春早期的小鼠进行为期8 周的社交隔离,可以诱发腹侧海马的CA1和CA2/3 区域的PV 表达减少,同时引起社交记忆障碍。进一步分析发现腹侧CA1 区域(后简称vCA1)的PV 的计数和社交记忆行为指标之间存在显著相关,二者在社交隔离中呈现共变趋势。

(2)对vCA1 的两类中间神经元:PV 神经元和somatostatin 阳性中间神经元(后简称SOM 神经元)进行特异性损毁,发现损毁该区域的PV 神经元干扰了社交记忆,而损毁SOM 神经元则没有影响。

(3)利用光遗传手段,在记忆的提取阶段激活和抑制vCA1 的PV 神经元,能够干扰社交再认,而在编码和维持阶段都不影响最终的社交再认。当靠近熟悉小鼠时激活PV 神经元,会导致实验动物把熟悉的小鼠辨认为陌生的小鼠。

(4)通过钙离子成像和c-Fos 分析,发现当动物趋近陌生的动物时,会有更高的PV 神经元反应,而接近熟悉的动物时则反应更为微弱。

上述结果说明,腹侧海马CA1 区域的PV 神经元可能参与了社交记忆的提取阶段,其激活和去激活可能是辨别新旧同类动物的重要神经机制。

Other Abstract

Social memory is the faculty of the mind to memorize and identify conspecific individuals, which is essential for social interaction, social hierarchy, reproductionand even species survival. Like other types of memory systems, information processing of social memory is made up of multiple subcomponents: encoding,consolidation and retrieval. Therefore there are at least three possible reasons for a failure of social recognition: (1) fail to encode the social information, (2) acquired but cannot maintain the information, (3) remember but cannot recall. Studies on human patient and animals have demonstrated the hippocampal engagement in different processing stages of episodic memory. Episodic memory is the collection of autobiographical experiences consisting of four basic elements: When, Where, Who and What. As a component of episodic memory, social memory provides the critical information about ¡°who¡±, which has also been proved to be closely related with hippocampus. Meanwhile, Abnormality in social memory is also a common phenotype of psychiatry, such as Alzheimer disease and Autism Spectrum Disorder.Although social memory defect has received a lot of attention, however, few studies had investigated the relationship between the processing stages of social memory and corresponding neuropathology. Moreover, there are accumulating evidences showing that the commonly existing abnormality of parvalbumin positive interneurons (PVIs) might be responsible for the impaired social memory in psychiatry. But how PV cells affect social memory, which processing stages do they participate in, is still unknown. In present study, we used AAV virus vector and transgenic mice to selectively manipulate PV interneurons, try to elucidate the role of PV interneurons in social memory. The highlights of our work are shown below:

1) 8-weeks-long social isolation, resulting in a significant reduced number of PV-immunoreactive cells in vCA1 and vCA2/3. Correlation analysis revealed that only in vCA1 the number of PV-staining cells was correlated with SDI, implicating that social isolation-induced change of PV expression in vHPC, especially in vCA1,was partly covaried with social recognition ability.

2) Selectively blocking the synaptic transmission of PVIs but not SOMIs in vCA1 remarkably disrupted social recognition memory, meaning this important form of memory is not mediated by the entire inhibitory interneurons in vCA1.

3) Optogenetic excitation or inhibition of vCA1-PV cells in retrieval stage, but not encoding stage and consolidation stage, could lead to failure of social recognition. PVIs hyperactivation blocked the social discrimination by making the subjected mice indentify the familiar mouse as novel.

4) Data from in vivo Ca2+ imaging in freely moving mice shows PV cells exhibit larger intensity of fluorescence when subject-mice approached the novel mouse. Analysis of c-Fos immunofluorescence supports the result of Ca2+ imaging.

These results demonstrate that PVIs in ventral CA1 subfield of hippocampus might play a crucial role in the retrieval stage of social memory, whose activity is vital for distinguishing the novel individuals from the familiars.

Document Type学位论文
Recommended Citation
GB/T 7714
邓潇斐. 腹侧海马Parvalbumin 阳性中间神经元调控社交记忆的 神经机制[D]. 中国科学院心理研究所. 中国科学院心理研究所,2018.
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