| 其他摘要 | 记忆是人们进行正常生活所必须具有的一种认知功能，它的神经机制目前仍然不清楚。大量研究发现，在学习记忆过程中，中枢神经系统中的神经元及其网络具有一种在接受到外源或者内源的刺激时，结构和功能发生适应性改变的性质，即神经可塑性，主要包括神经元兴奋性、突触结构可塑性以及突触可塑性中的长时程增强（Long-term potentiation，LTP）和长时程抑制（Long-term depression，LTD）等。而无论是工作记忆，短时记忆还是长时记忆，它们与神经可塑性间的关系仍然知之甚少。迄今研究发现大脑颞叶中的海马结构与记忆有十分密切的关系，而海马中的神经可塑性与记忆的关系还不完全清楚。因此，研究记忆的神经可塑性机制具有重要意义。博士期间的主要研究内容是社交记忆及其神经可塑性机制。社会性动物的个体间普遍存在社会交往行为，在社交过程中识别并记忆同一物种中的其他个体，并在随后社交中使用该记忆进行交流、抉择等，这种社交记忆作为正常社交的必要条件，对于群居动物中个体的生存与繁衍很重要。本论文以小鼠为动物模型探索社交记忆及其神经机制。首先，利用三箱社交行为学范式深入研究小鼠社交记忆的行为学特征，发现小鼠表现出时间、空间以及新颖程度依赖的社交工作记忆，简称社交记忆；之后利用药理学手段干扰小鼠的天冬氨酸受体的正常功能，在导致小鼠的社交记忆受损的同时，背侧海马CA1区中天冬氨酸受体介导的LTD受损；小鼠背侧海马中注射天冬氨酸受体拮抗剂同样损伤小鼠的社交记忆；最后利用光遗传手段，在小鼠社交过程中干扰小鼠背侧海马CA1区的锥体神经元放电活动，也显著损伤小鼠的社交记忆。以上结果证明背侧海马中的天冬氨酸受体以及锥体神经元的放电活动都参与调控小鼠社交记忆。近年来，社交行为异常的临床病人的数量迅速增加，主要包括孤独症和精神分裂症，目前认为基因突变是该类疾病的主要病因，其中部分孤独症患者的易感基因PTEN和PREX1存在突变，但基因突变是否影响以及如何影响社交记忆，其神经机制如何都几乎不清楚。本论文中在小鼠的前脑条件性敲除Pten，或者在背侧海马CA1区域下调Pten基因的表达都会导致小鼠社交记忆损伤，但社交主动性、物体识别能力与嗅觉能力没有受损。离体全细胞电生理检测发现，海马CA1区锥体神经元在Pten下调后的兴奋性降低，在体多通道电生理检测发现Pten前脑敲除小鼠海马神经元放电频率变化率降低。因此，社交记忆受损有可能与PTEN蛋白表达下调后干扰了背侧海马的神经元兴奋性有关。另外，将Prex1在小鼠全脑或者海马的表达下调，行为学检测发现该小鼠社交记忆受损，电生理检测发现该小鼠海马CA1区中，天冬氨酸受体介导的LTD受损，不同方法恢复受损的LTD的同时也能恢复受损的社交记忆。以上结果证明了背侧海马CA1中PTEN蛋白、P-Rex1蛋白及其相关的神经可塑性参与调控小鼠社交记忆。博士论文的另外一个内容是基于持续光照应激损伤大鼠海马依赖的长时空间记忆的现象，发现背侧海马多巴胺系统调控慢性光应激导致的LTP后期受损，该结果证明了光照节律影响海马中多巴胺信号通路依赖的突触可塑性。综上，我们首次报道了背侧海马CA1区参与调控社交记忆，干扰背侧海马CA1区的神经可塑性导致社交记忆受损，恢复异常可塑性的同时也能恢复受损的社交记忆；另外，长时空间记忆的损伤与背侧海马CA1区的突触可塑性受损相关。以上结果提示，神经可塑性异常可能与最终的记忆损伤有关，加深了对调控记忆的神经可塑性机制的理解。; Memory is one type of cognitive functions essential for normal daily life. However, its neural mechanism is largely unknown. It has been found that central nervous system has the ability to adopt new structural or functional state in neurons or neural networks in response to extrinsic or intrinsic stimuli during learning and memory. Such ability is defined as neural plasticity, including neuronal excitability, synaptic plasticity (long-term potentiation, LTP and long-term depression, LTD), and synaptic structural plasticity. Nonetheless, the underlying neural mechanisms of memory, including working memory, short-term memory or long-term memory, are not fully understood. In addition, hippocampus, which is located in temporal lobe, is found to be highly correlated with memory, whereas the role of neural plasticity in hippocampus remains to be elucidated. Thus, it is significantly important to study the neural plasticity mechanisms of memory.My main research is the study of social memory and its neural plasticity mechanisms. Forming and employing memory of conspecifics is crucial for survival and reproduction of individuals during normal social interactions. By using three-chamber social interaction task, I found that na?ve mice displayed a delay-, position- and novelty-dependent social working memory, or social memory in short. Pharmacological inhibition of N-methyl-D-aspartate acid receptor (NMDAR) in whole brain or dorsal hippocampus of mice led to social memory loss and NMDAR-LTD impairment in dorsal hippocampal CA1 region. Direct inhibition of dorsal hippocampal pyramidal neural firing by optogenetic tools during social interaction still can cause social memory impairment. These data demonstrated that the dorsal hippocampal NMDA receptors and neural activities were vital in regulating social memory of mice.Recently, the number of patients of Autism spectrum disorder (ASD) or Schizophrenia characterized by persistent social interaction deficits is growing prominent recently. It has been reported that PTEN and PREX1 mutations are correlated with ASD. While the genetic mutations are thought to be the main cause of the mental disorders, whether and how the mutations affect social memory and neural mechanisms remain to be elucidated. By using forebrain specific Pten conditional knockout mice and dorsal hippocampal Pten knockdown mice, I found the social memory was impaired without affecting sociability, object recognition and olfactory. In vitro and in vivo electrode recordings showed diminished neural excitability in dorsal hippocampus of PTEN loss mice. These results indicated that reduced neural firing relating to PTEN loss may involve in the social memory deficit. Besides, we found that Prex1 knockout mice exhibited social memory deficit and NMDAR-LTD impairment in dorsal hippocampal CA1. Furthermore, rescuing LTD impairment in hippocampus lead to alleviation of social memory deficit. Taken together, these data proved the role of neural plasticity pertaining to PTEN and P-Rex1 in dorsal hippocampal CA1 in regulating social memory. Beyond the studies listed above, based on previous findings that chronic constant light lead to hippocampus-dependent spatial memory impairment, we found the late phase LTP impairment due to constant light stress could be modulated by dopaminergic signaling pathway in dorsal hippocampal CA1. These results proved that circadian rhythm was involved in regulating hippocampus-dependent memory and dopaminergic signaling-dependent synaptic plasticity. In sum, we found for the first time that dorsal hippocampal CA1 are involving in regulating social memory. Interruption of neural plasticity in dorsal hippocampal CA1 may lead to social memory impairment; rescuing impaired plasticity may also restore social memory deficit. All results indicated the correlation between neural plasticity abnormalities and memory impairments, offered new insights into the neural plasticity mechanism underlying memory regulation. |
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