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NNeurocircuitry for modeling drug effects

机译：用于模拟药物作用的神经回路

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The identification and functional understanding of the neurocircuitry that mediates alcohol and drug effects that are relevant for the development of addictive behavior is a fundamental challenge in addiction research. Here we introduce an assumption-free construction of a neurocircuitry that mediates acute and chronic drug effects on neurotransmitter dynamics that is solely based on rodent neuroanatomy. Two types of data were considered for constructing the neurocircuitry: (1) information on the cytoarchitecture and neurochemical connectivity of each brain region of interest obtained from different neuroanatomical techniques; (2) information on the functional relevance of each region of interest with respect to alcohol and drug effects. We used mathematical data mining and hierarchical clustering methods to achieve the highest standards in the preprocessing of these data. Using this approach, a dynamical network of high molecular and spatial resolution containing 19 brain regions and seven neurotransmitter systems was obtained. Further graph theoretical analysis suggests that the neurocircuitry is connected and cannot be separated into further components. Our analysis also reveals the existence of a principal core subcircuit comprised of nine brain regions: the prefrontal cortex, insular cortex, nucleus accumbens, hypothalamus, amygdala, thalamus, substantia nigra, ventral tegmental area and raphe nuclei. Finally, by means of algebraic criteria for synchronizability of the neurocircuitry, the suitability for in silico modeling of acute and chronic drug effects is indicated. Indeed, we introduced as an example a dynamical system for modeling the effects of acute ethanol administration in rats and obtained an increase in dopamine release in the nucleus accumbens-a hallmark of drug reinforcement-to an extent similar to that seen in numerous microdialysis studies. We conclude that the present neurocircuitry provides a structural and dynamical framework for large-scale mathematical models and will help to predict chronic drug effects on brain function.
机译：对介导与成瘾行为发展有关的酒精和药物作用的神经回路的识别和功能理解是成瘾研究的一项基本挑战。在这里，我们介绍了一个无假设的神经回路构造，该回路仅基于啮齿动物的神经解剖结构介导对神经递质动力学的急性和慢性药物作用。考虑了两种类型的数据来构建神经回路：（1）从不同的神经解剖学技术获得的每个感兴趣的大脑区域的细胞结构和神经化学连通性信息; （2）有关每个关注区域在酒精和药物作用方面的功能相关性的信息。我们使用数学数据挖掘和层次聚类方法来实现这些数据的预处理中的最高标准。使用这种方法，获得了包含19个大脑区域和7个神经递质系统的高分子和空间分辨率的动态网络。进一步的图论分析表明，神经回路是连接的，不能分为其他组件。我们的分析还揭示了由9个大脑区域组成的主要核心子回路的存在：前额叶皮层，岛状皮层，伏隔核，下丘脑，杏仁核，丘脑，黑质，腹侧被盖区和沟phe核。最后，通过神经回路同步性的代数标准，表明了计算机模拟急性和慢性药物作用的适用性。实际上，我们以动态动力学系统为例，该系统用于模拟大鼠急性乙醇的给药效果，并获得伏隔核中多巴胺释放的增加（这是药物增强的标志），其程度与许多微透析研究中所见的程度相似。我们得出的结论是，当前的神经回路为大规模数学模型提供了结构和动力学框架，并将有助于预测慢性药物对脑功能的影响。

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