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电影《我脑中的橡皮擦》中患有阿尔兹海默症的女主角记忆逐渐缺失,男主角不离不弃的守护让观众感动

主题一:海马与精神疾病的那些事

电影《我脑中的橡皮擦》中患有阿尔兹海默症的女主角记忆逐渐缺失,男主角不离不弃的守护让观众感动,《美丽心灵》男主角原型约翰·纳什由于患有精神分裂症一直在现实与妄想之间苦苦探索,通过个人的不懈努力获得诺贝尔奖,令人肃然起敬。然而在这些美丽感人的故事背后隐藏的却是精神疾病对患者及家人正常生活的严重危害和他们对疾病的无奈,因而科学家们致力于探究神经精神疾病的发病机理并试图探寻可能的干预治疗方法,造福人类。

海马在学习和记忆过程中起到重要作用这一观点已被普遍接受,而近期研究发现该脑区蛋白异常表达、形态改变、细胞活性异常等变化和神经精神疾病也密切相关,为精神疾病的理论研究及可能的干预治疗和预防带来了希望。

        阿尔兹海默症患者的临床症状之一为健忘,利用学习依赖细胞标记技术,科学家发现海马区参与巩固记忆的细胞突触强度增强、树突棘密度增加,而健忘症中则缺少这种变化。在逆行性遗忘模型小鼠上进行的动物实验显示,在条件恐惧刺激的记忆提取阶段,利用光遗传学技术特异性调控兴奋海马齿状回(DG)的细胞能够修复恐惧记忆,并且能够重新激活下游脑区如CA3BLA的神经元活动。这种研究方法解析记忆和健忘症的编码、巩固和提取将为如阿尔兹海默症等健忘症提供新的思路与方法,该成果与20155月发表于《Science》。此外,解剖学发现阿尔兹海默症患者的血脑屏障(BBB)出现损伤2015年《Neuron》一篇文章中利用动态增强MRI技术量化人脑的区域血脑屏障(BBB)通透性,发现患者在海马区出现年龄依赖的BBB损伤,而海马的CA1和齿状回区域的BBB损坏严重程度与患者认知障碍有紧密关系,这也表明海马区BBB随着年龄增长出现损伤可能引起阿尔兹海默症等疾病的认知障碍。

        美国精神卫生研究院的Jia JM教授发现海马区异常的多巴胺能受体2型(D2R)信号系统和精神分裂症密切相关,他认为海马区多巴胺能神经元D2R的过表达会引起精神分裂症高致病风险基因Dtnbp1的突变进而造成突触结构异常以及空间记忆障碍(NatNeurosci, 2013)。由于青春期是精神分裂症患病的高发期,而在此期间引起的不正常发育通常会导致成年大脑功能障碍。瑞士和美国科学家发现早期抗氧化治疗能够减少这种障碍,以损毁新生啮齿类动物的腹侧海马作为精神分裂症模型研究发现,用抗氧化N-乙酰半胱氨酸可以阻止前额叶小清蛋白中间神经元活动的减弱,并逆转精神分裂症相关的电生理和行为缺陷(Neuron, 2015),为探究可能的新的治疗方法提供了理论参考。

        此外,海马异常与自闭症的认知功能障碍也有密切联系,美国冷泉港实验室的Mills AA教授的研究发现在表达有自闭症易患基因的转基因小鼠中,海马的谷氨酸能受体5型(mGluR5)依赖的突触可塑性和蛋白生成都有改变,相应记忆也受损伤,而用负性变构调节慢性治疗的方法能够逆转这种认知障碍,因而认为小鼠海马区mGluR5的改变可能是一种致病可能(NatNeurosc,2015)

下面附上五篇海马区和精神疾病相关的文章摘要,以飨对这个领域感兴趣的小伙伴们。

 

1. 论文题目:Engram cells retain memory underretrograde amnesia.Science 29 May 2015:
Vol. 348 no. 6238 pp. 1007-1013.

原文摘要:Memory consolidation is the processby which a newly formed and unstable memory transforms into a stable long-termmemory. It is unknown whether the process of memory consolidation occursexclusively through the stabilization of memory engrams. By usinglearning-dependent cell labeling, we identified an increase of synaptic strengthand dendritic spine density specifically in consolidated memory engram cells.Although these properties are lacking in engram cells under protein synthesisinhibitor–induce damnesia, direct optogenetic activation of these cells resultsin memory retrieval, and this correlates with retained engram cell–specificconnectivity. We propose that a specific pattern of connectivity of engramcells may be crucial for memory information storage and that strengthenedsynapses in these cells critically contribute to the memory retrieval process.

全文链接:http://www.sciencemag.org/content/348/6238/1007.full.pdf

2.论文题目:Age-dependent regulation of synaptic connections bydopamine D2 receptors.Nat Neurosci.2013.16(11):1627-36.

原文摘要:DopamineD2 receptors (D2R) are G protein-coupled receptors that modulate synaptictransmission and are important for various brain functions, including learningand working memory. Abnormal D2R signaling has been implicated in psychiatricdisorders such as schizophrenia. Here we report a new function of D2R indendritic spine morphogenesis. Activation of D2R reduced spine number viaGluN2B- and cAMP-dependent mechanisms in mice. Notably, this regulationoccurred only during adolescence. During this period, D2R overactivation causedby mutations in the schizophrenia risk gene Dtnbp1 led to spine deficiency,dysconnectivity in the entorhinal-hippocampal circuit and impairment of spatialworking memory. Notably, these defects could be ameliorated by D2R blockersadministered during adolescence. Our findings suggest an age-dependent functionof D2R in spine development, provide evidence that D2R dysfunction duringadolescence impairs neuronal circuits and working memory, and indicate thatadolescent interventions to prevent aberrant D2R activity protect againstcognitive impairment.

全文链接:http://www.nature.com/neuro/journal/v16/n11/pdf/nn.3542.pdf

3.论文题目:Contribution of mGluR5 to pathophysiology in a mousemodel of human chromosome 16p11.2 microdeletion.Nat Neurosci.2015.18(2):182-4.

原文摘要:Humanchromosome 16p11.2 microdeletion is the most common gene copy number ariationin autism, but the synaptic pathophysiology caused by this mutation is largelyunknown. Using a mouse with the same genetic deficiency, we found thatmetabotropic glutamate receptor 5 (mGluR5)-dependent synaptic plasticity andprotein synthesis was altered in the hippocampus and that hippocampus-dependentmemory was impaired. Notably, chronic treatment with a negative allostericmodulator of mGluR5 reversed the cognitive deficit.

全文链接:http://www.nature.com/neuro/journal/v18/n2/pdf/nn.3911.pdf

4.论文题目:Juvenile antioxidant treatment prevents adult deficits ina developmental model of schizophrenia.Neuron.2014.3;83(5):1073-84.

原文摘要:Abnormaldevelopment can lead to deficits in adult brain function, a trajectory likelyunderlying adolescent-onset psychiatric conditions such as schizophrenia.Developmental manipulations yielding adult deficits in rodents provide an opportunityto explore mechanisms involved in a delayed emergence of anomalies driven bydevelopmental alterations. Here we assessed whether oxidative stress duringpresymptomatic stages causes adult anomalies in rats with a neonatal ventralhippocampal lesion, a developmental rodent model useful for schizophreniaresearch. Juvenile and adolescent treatment with the antioxidant N-acetylcysteine prevented the reduction of prefrontal parvalbumin interneuron activityobserved in this model, as well as electrophysiological and behavioral deficitsrelevant to schizophrenia. Adolescent treatment with the glutathione peroxidasemimic ebselen also reversed behavioral deficits in this animal model. Thesefindings suggest that presymptomatic oxidative stress yields abnormal adultbrain function in a developmentally compromised brain, and highlight redoxmodulation as a potential target for early intervention.

全文链接:http://www.cell.com/neuron/pdf/S0896-6273(14)00639-4.pdf

5.论文题目:Blood-brain barrier breakdown in the aging humanhippocampus. Neuron. 2015.21;85(2):296-302.

原文摘要:Theblood-brain barrier (BBB) limits entry of blood-derived products, pathogens,and cells into the brain that is essential for normal neuronal functioning andinformation processing. Post-mortem tissue analysis indicates BBB damage inAlzheimer\'s disease (AD). The timing of BBB breakdown remains, however,elusive. Using an advanced dynamic contrast-enhanced MRI protocol with high spatialand temporal resolutions to quantify regional BBB permeability in the livinghuman brain, we show an age-dependent BBB breakdown in the hippocampus, aregion critical for learning and memory that is affected early in AD. The BBBbreakdown in the hippocampus and its CA1 and dentate gyrus subdivisionsworsened with mild cognitive impairment that correlated with injury toBBB-associated pericytes, as shown by the cerebrospinal fluid analysis. Ourdata suggest that BBB breakdown is an early event in the aging human brain thatbegins in the hippocampus and may contribute to cognitive impairment.

相关链接:http://www.ncbi.nlm.nih.gov/pubmed/25611508