Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands; Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht, Bolognalaan 50, 3584 CJ Utrecht, The Netherlands.
Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.
Neuroimage. 2017 Aug 1;156:109-118. doi: 10.1016/j.neuroimage.2017.05.021. Epub 2017 May 11.
Linking neural circuit activation at whole-brain level to neuronal activity at cellular level remains one of the major challenges in neuroscience research. We set up a novel functional neuroimaging approach to map global effects of locally induced activation of specific midbrain projection neurons using chemogenetics (Designer Receptors Exclusively Activated by Designer Drugs (DREADD)-technology) combined with pharmacological magnetic resonance imaging (phMRI) in the rat mesocorticolimbic system. Chemogenetic activation of DREADD-targeted mesolimbic or mesocortical pathways, i.e. projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAcc) or medial prefrontal cortex (mPFC), respectively, induced significant blood oxygenation level-dependent (BOLD) responses in areas with DREADD expression, but also in remote defined neural circuitry without DREADD expression. The time-course of brain activation corresponded with the behavioral output measure, i.e. locomotor (hyper)activity, in the mesolimbic pathway-targeted group. Chemogenetic activation specifically increased neuronal activity, whereas functional connectivity assessed with resting state functional MRI (rs-fMRI) remained stable. Positive and negative BOLD responses distinctively reflected simultaneous ventral pallidum activation and substantia nigra pars reticulata deactivation, respectively, demonstrating the concept of mesocorticolimbic network activity with concurrent activation of the direct and indirect pathways following stimulation of specific midbrain projection neurons. The presented methodology provides straightforward and widely applicable opportunities to elucidate relationships between local neuronal activity and global network activity in a controllable manner, which will increase our understanding of the functioning and dysfunctioning of large-scale neuronal networks in health and disease.
将大脑整体水平的神经回路激活与细胞水平的神经元活动联系起来，仍然是神经科学研究的主要挑战之一。我们建立了一种新的功能神经影像学方法，利用化学遗传学（设计受体专门被设计药物激活（DREADD）技术）结合药理学磁共振成像（phMRI），在大鼠中脑边缘皮质系统中绘制特定中脑投射神经元局部诱导激活的全局效应。DREADD 靶向中脑边缘或中皮质通路的化学遗传学激活，即分别来自腹侧被盖区（VTA）到伏隔核（NAcc）或内侧前额叶皮层（mPFC）的投射，在具有 DREADD 表达的区域中诱导了显著的血氧水平依赖性（BOLD）反应，但也在没有 DREADD 表达的远程定义的神经回路中诱导了显著的 BOLD 反应。脑激活的时程与行为输出测量（即在中脑边缘通路靶向组中的运动（过度）活动）相对应。化学遗传学激活特异性地增加了神经元活动，而使用静息状态功能磁共振成像（rs-fMRI）评估的功能连接保持稳定。阳性和阴性 BOLD 反应分别明显反映了同时的腹侧苍白球激活和黑质网状部去激活，证明了中脑边缘网络活动的概念，即在刺激特定中脑投射神经元后，直接和间接通路同时激活。所提出的方法学提供了直接和广泛适用的机会，可以以可控的方式阐明局部神经元活动与全局网络活动之间的关系，这将增加我们对健康和疾病中大尺度神经元网络功能和功能障碍的理解。
