Li Zhixin, Ward B Douglas, Dwinell Melinda R, Lombard Julian H, Pawela Christopher P
Department of Plastic Surgery, Medical College of Wisconsin, Milwaukee, WI, USA.
Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI, USA.
Neuroimage. 2014 Apr 15;90:403-12. doi: 10.1016/j.neuroimage.2013.09.049. Epub 2013 Sep 29.
Genes have been implicated as major contributors to many biological traits and susceptibility to specific diseases. However, the mechanisms of genotype action on central nervous system function have been elusive. It has been previously observed that inbred Brown Norway (BN) rats exhibit a number of quantitative complex traits markedly different from those of inbred Dahl salt-sensitive (SS) rats. These strains have become so important to cardiovascular research that a novel chromosome substitution approach was used to create SS and BN strains that have a single chromosome replaced by the homologous chromosome of the other strain. The present study was conducted in an effort to evaluate whether fMRI neuroimaging measures could be employed as a phenotype of genetic influence on neural biology in SS, BN, and consomic SSBN13 rat strains. Electrical forepaw stimulation evoked robust differential BOLD-fMRI activation along the thalamocortical pathway among the three strains across different stimulus frequencies. Moreover, using the fMRI-guided seeds in thalamus and somatosensory cortex for the analysis of fcMRI, we were able to characterize the strain-specific difference in secondary somatosensory cortex, temporal association cortex, and the CA3 region. We were also able to define the genetic influences of Chr-13 on the projection and integration of sensory information in consomic SS-13(BN) strain. We provided objective imaging evidence supporting the hypothesis that rat strain-specific fMRI and fcMRI combined with consomic strategy can be a useful tool in identifying the complex genetic divergence that is related to neural circuits. These findings prove the concept of neuroimaging-based phenotypes as a novel approach to visualize and fine-map the genetic effects onto brain biology at a systems level.
基因被认为是许多生物学性状以及对特定疾病易感性的主要影响因素。然而，基因型作用于中枢神经系统功能的机制一直难以捉摸。此前已观察到，近交系棕色挪威（BN）大鼠表现出许多数量性状，与近交系达尔盐敏感（SS）大鼠的性状明显不同。这些品系对心血管研究变得如此重要，以至于采用了一种新的染色体置换方法来创建SS和BN品系，其中一个品系的单条染色体被另一个品系的同源染色体所取代。本研究旨在评估功能磁共振成像（fMRI）神经成像测量是否可作为SS、BN和染色体代换系SSBN13大鼠品系中基因对神经生物学影响的一种表型。在前爪电刺激下，三种品系在不同刺激频率下，沿丘脑皮质通路诱发了强烈的差异血氧水平依赖性功能磁共振成像（BOLD-fMRI）激活。此外，利用fMRI引导的丘脑和体感皮层种子点进行功能连接磁共振成像（fcMRI）分析，我们能够表征次级体感皮层、颞叶联合皮层和CA3区的品系特异性差异。我们还能够确定13号染色体对染色体代换系SS-13（BN）品系中感觉信息投射和整合的遗传影响。我们提供了客观的成像证据，支持这样的假设：大鼠品系特异性fMRI和fcMRI结合染色体代换策略可成为识别与神经回路相关的复杂遗传差异的有用工具。这些发现证明了基于神经成像的表型这一概念，作为一种在系统水平上可视化和精细定位基因对脑生物学影响的新方法。
