Biological Imaging Center, Beckman Institute, California Institute of Technology, Pasadena, California, United States of America.
PLoS One. 2010 Jul 9;5(7):e11506. doi: 10.1371/journal.pone.0011506.
The plasma membrane transporters for the monoamine neurotransmitters dopamine, serotonin, and norepinephrine modulate the dynamics of these monoamine neurotransmitters. Thus, activity of these transporters has significant consequences for monoamine activity throughout the brain and for a number of neurological and psychiatric disorders. Gene knockout (KO) mice that reduce or eliminate expression of each of these monoamine transporters have provided a wealth of new information about the function of these proteins at molecular, physiological and behavioral levels. In the present work we use the unique properties of magnetic resonance imaging (MRI) to probe the effects of altered dopaminergic dynamics on meso-scale neuronal circuitry and overall brain morphology, since changes at these levels of organization might help to account for some of the extensive pharmacological and behavioral differences observed in dopamine transporter (DAT) KO mice. Despite the smaller size of these animals, voxel-wise statistical comparison of high resolution structural MR images indicated little morphological change as a consequence of DAT KO. Likewise, proton magnetic resonance spectra recorded in the striatum indicated no significant changes in detectable metabolite concentrations between DAT KO and wild-type (WT) mice. In contrast, alterations in the circuitry from the prefrontal cortex to the mesocortical limbic system, an important brain component intimately tied to function of mesolimbic/mesocortical dopamine reward pathways, were revealed by manganese-enhanced MRI (MEMRI). Analysis of co-registered MEMRI images taken over the 26 hours after introduction of Mn(2+) into the prefrontal cortex indicated that DAT KO mice have a truncated Mn(2+) distribution within this circuitry with little accumulation beyond the thalamus or contralateral to the injection site. By contrast, WT littermates exhibit Mn(2+) transport into more posterior midbrain nuclei and contralateral mesolimbic structures at 26 hr post-injection. Thus, DAT KO mice appear, at this level of anatomic resolution, to have preserved cortico-striatal-thalamic connectivity but diminished robustness of reward-modulating circuitry distal to the thalamus. This is in contradistinction to the state of this circuitry in serotonin transporter KO mice where we observed more robust connectivity in more posterior brain regions using methods identical to those employed here.
单胺神经递质多巴胺、5-羟色胺和去甲肾上腺素的血浆膜转运体调节这些单胺神经递质的动态变化。因此，这些转运体的活性对整个大脑中单胺的活性以及许多神经和精神疾病都有重大影响。减少或消除这些单胺转运体表达的基因敲除 (KO) 小鼠为这些蛋白质在分子、生理和行为水平上的功能提供了大量新信息。在本工作中，我们利用磁共振成像 (MRI) 的独特特性来探测多巴胺能动力学改变对中尺度神经元回路和整体大脑形态的影响，因为这些组织水平的变化可能有助于解释在多巴胺转运体 (DAT) KO 小鼠中观察到的广泛的药理学和行为差异。尽管这些动物体型较小，但高分辨率结构 MRI 图像的体素统计比较表明，DAT KO 并没有导致形态上的明显变化。同样，在纹状体中记录的质子磁共振谱表明，DAT KO 和野生型 (WT) 小鼠之间可检测代谢物浓度没有显著变化。相比之下，通过锰增强 MRI (MEMRI) 揭示了来自前额皮质到中边缘系统的回路的改变，中边缘系统是一个与中边缘多巴胺奖赏途径功能密切相关的重要大脑成分。对将 Mn(2+)引入前额皮质后 26 小时内采集的共配准 MEMRI 图像进行分析表明，DAT KO 小鼠在该回路中 Mn(2+)的分布被截断，在丘脑之外或对侧注射部位几乎没有积累。相比之下，WT 同窝仔鼠在注射后 26 小时表现出 Mn(2+)向更靠后的中脑核团和对侧中边缘结构的转运。因此，在这种解剖分辨率水平上，DAT KO 小鼠似乎保留了皮质-纹状体-丘脑连接，但丘脑远端的奖赏调节回路的稳健性降低。这与 5-羟色胺转运体 KO 小鼠的情况形成对比，在使用与这里相同的方法时，我们观察到更靠后的大脑区域有更稳健的连接。
