Behavioural Brain Research:典型抗精神病药对谷氨酸功能连接的调节:基于突触后即刻早期基因网络分析

2021-02-23 MedSci原创 MedSci原创

精神分裂症是一种毁灭性的精神疾病,具有很高的终生患病率,包括幻觉、妄想、逃避和认知障碍,已经被概念化为突触可塑性和皮质下连接障碍。作为精神分裂症药物治疗的基石,抗精神病药物虽然不同程度地占据多巴胺D2

精神分裂症是一种毁灭性的精神疾病,具有很高的终生患病率,包括幻觉、妄想、逃避和认知障碍,已经被概念化为突触可塑性和皮质下连接障碍。作为精神分裂症药物治疗的基石,抗精神病药物虽然不同程度地占据多巴胺D2受体,这一特征被认为是抗精神病作用的关键机制。多种证据表明,抗精神病药物可显著影响突触可塑性、化塑性和树突棘结构,影响突触后密度(PSD),这是谷氨酸能神经元树突棘远端的电子致密增厚,含有谷氨酸受体,信号转导分子、离子通道和支架蛋白。值得注意的是,突触结构的破坏可能反过来导致神经元群体间相互作用的改变和神经系统功能整合的异常,即连接障碍。目前的理论认为,精神分裂症症状源于大脑无法正确整合神经过程,以及由此产生的功能性“错误连接”。本文检验了这样一个假设,即急性给药的原型抗精神病药物氟哌啶醇将显着调节脑网络整合。

26只平均体重为250克的雄性大鼠被用于我们的研究。动物被安置在一个温度和湿度控制的群体室中,食物和水可以随意获得。所有给药均为全身注射。将氟哌啶醇溶解于盐水中,调节至生理pH值,然后给药至最终体积为1ml/Kg。氟哌啶醇以行为活跃剂量给药。给药90min后处死动物。大脑被迅速取出并冷冻在干粉干冰上,然后在−70°C下保存,直到切片。放射自显影信号的定量通过计算机图像分析系统进行,该系统包括透明胶片扫描仪(Microtek Europe B.V.,荷兰鹿特丹)、iMac计算机和ImageJ软件(V.1.29,W.Rasband,NIMH,Bethesda,MD,USA)。保留了扫描图像的原始特征。对测量特定感兴趣区域(ROIs)内平均光密度的数字化放射自显影图进行信号强度分析,ROI内的平均光密度测量值使用基于暴露在截面上的标准比例co的校准曲线进行转换。从4到12的14C标准值先前交叉校准到35S脑糊标准,以便通过校准曲线将每分钟崩解/毫克(dpm/mg)组织湿重值分配给每个光密度测量值。

Fig. 1

分别使用HAL组和VEH组的Pearson相关系数计算了33个roi之间所有可能的成对相关。为了检测治疗组之间每对相关系数的统计显著性差异,本文使用了基于Fisher z变换的排列检验。比较的显著性水平为0.05。相关矩阵用于定义两个网络,分别显示每个治疗组大脑区域之间的功能联系。任何两个区域之间的联系由相关系数给出。为了可视化一些拓扑特性,通过观察到的每个治疗组相关系数分布的百分位数定义的多个阈值计算不同的网络统计数据。计算的第一个网络统计数据是连接密度,定义为所有可能连接中存在的连接数。我们还评估了拓扑特性,如全局效率和聚类系数,它们是功能集成和分离的度量,也是小世界拓扑的特征。

Fig. 8

非标准化数据之间的比较显示, 溶解质和氟哌啶醇仅在尾壳核的背外侧和腹外侧存在显著差异,在尾壳核的背内侧(p=0.08)和腹内侧(p=0.06)存在显著性趋势。正常化后,氟哌啶醇在尾壳核和伏隔核以及斜角带垂直肢核中的Homer1a mRNA表达均显著高于溶解质。在隔肩枕核也发现了显著性趋势(p=0.069)。 排列检验用于比较两个治疗组之间的两两相关性。36对相关roi中,VEH组和HAL组的相关系数有显著性差异。值得注意的是,VEH矩阵中的相关系数比HAL矩阵中的相关系数显著高出数倍。连接密度,也通常被称为“连接”,即现有连接相对于可能的总数量的比例,通过目测发现HAL处理的网络和VEH处理的网络的连接密度相似,AL网络中信息在整个网络中整合的有效性度量略高于VEH网络。尾壳核的所有分支(腹外侧、腹内侧、后外侧和后内侧分支)在HAL网络中似乎高度相连,而在VEH网络中则没有。此外,尾状壳核与伏隔核核的核和壳之间的强相关性在VEH网络中可以识别,但在HAL网络中没有检测到。结果显示氟哌啶醇影响背侧纹状体、体感皮层、岛叶皮层和辅助运动皮层的中心性,这些结果可能表明抗精神病药物可以影响相关的节点属性,调节精神分裂症患者不同脑中枢的中心性。

观察到的网络参数变化表明,急性氟哌啶醇给药后,脑网络的功能组织发生了多模式适应。本文研究结果证实,抗精神病药物可能通过影响特定的网络特性、节点属性和特定疾病相关回路中的交互作用来调节大脑网络的拓扑结构。

Annarita Barone, Simona Signoriello, Gianmarco Latte, Licia Vellucci, Giuseppe Giordano, Camilla Avagliano, Elisabetta F Modulation of glutamatergic functional connectivity by a prototypical antipsychotic: Translational inference from a postsynaptic density immediate-early gene-based network analysis, Behavioural Brain Research,

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