Brain Center Rudolf Magnus, Department of Translational Neuroscience, University Medical Center Utrecht, Utrecht 3508 GA, The Netherlands.
Department of Population Health Sciences, Animals in Science and Society, Faculty of Veterinary Medicine, Utrecht University, Utrecht 3584 CM, The Netherlands.
J Neurosci. 2021 May 12;41(19):4293-4304. doi: 10.1523/JNEUROSCI.0477-20.2020. Epub 2021 Apr 9.
Deficits in impulse control and attention are prominent in the symptomatology of mental disorders such as attention deficit hyperactivity disorder (ADHD), substance addiction, schizophrenia, and bipolar disorder, yet the underlying mechanisms are incompletely understood. Frontostriatal structures, such as the nucleus accumbens (NAcb), the medial prefrontal cortex (mPFC), and their dopaminergic innervation from the ventral tegmental area (VTA) have been implicated in impulse control and attention. What remains unclear is how the temporal pattern of activity of these VTA projections contributes to these processes. Here, we optogenetically stimulated VTA dopamine (DA) cells, as well as VTA projections to the NAcb core (NAcbC), NAcb shell (NAcbS), and the mPFC in male rats performing the 5-choice serial reaction time task (5-CSRTT). Our data show that stimulation of VTA DA neurons, and VTA projections to the NAcbC and the mPFC immediately before presentation of the stimulus cue, impaired attention but spared impulse control. Importantly, in addition to reducing attention, activation of VTA-NAcbS also increased impulsivity when tested under a longer intertrial interval (ITI), to provoke impulsive behavior. Optogenetic stimulation at the beginning of the ITI only partially replicated these effects. In sum, our data show how attention and impulsivity are modulated by neuronal activity in distinct ascending output pathways from the VTA in a temporally specific manner. These findings increase our understanding of the intricate mechanisms by which mesocorticolimbic circuits contribute to cognition. Deficits in impulse control and attention are prominent in the symptomatology of several mental disorders, yet the brain mechanisms involved are incompletely understood. Since frontostriatal circuits have been implicated in impulse control and attention, we here examined the role of ascending projections from the midbrain ventral tegmental area (VTA) to the nucleus accumbens (NAcb) and prefrontal cortex (PFC). Using optogenetics to individually stimulate these projections with time-locked precision, we distinguished the role that each of these projections plays, in both impulse control and attention. As such, our study enhances our understanding of the neuronal circuitry that drives impulsive and attentive behavior.
冲动控制和注意力缺陷在精神障碍的症状中很明显，如注意缺陷多动障碍（ADHD）、物质成瘾、精神分裂症和双相情感障碍，但潜在的机制尚不完全清楚。额-纹状体结构，如伏隔核（NAcb）、内侧前额叶皮层（mPFC）及其来自腹侧被盖区（VTA）的多巴胺能神经支配，与冲动控制和注意力有关。目前尚不清楚这些 VTA 投射的活动时间模式如何促进这些过程。在这里，我们通过光遗传学刺激 VTA 多巴胺（DA）细胞，以及 VTA 投射到 NAcb 核心（NAcbC）、NAcb 壳（NAcbS）和 mPFC，在执行 5 选择序列反应时间任务（5-CSRTT）的雄性大鼠中。我们的数据表明，刺激 VTA DA 神经元，以及 VTA 投射到 NAcbC 和 mPFC，在刺激线索呈现之前立即进行，会损害注意力，但不会影响冲动控制。重要的是，除了降低注意力外，激活 VTA-NAcbS 也会在更长的试验间间隔（ITI）下增加冲动性，从而引发冲动行为。在 ITI 开始时进行光遗传学刺激仅部分复制了这些效果。总之，我们的数据表明，注意力和冲动性是如何通过 VTA 的不同上行输出途径的神经元活动以时间特异性的方式进行调节的。这些发现增加了我们对边缘皮质回路如何通过复杂的机制对认知做出贡献的理解。冲动控制和注意力缺陷在几种精神障碍的症状中很明显，但涉及的大脑机制尚不完全清楚。由于额-纹状体回路与冲动控制和注意力有关，我们在这里检查了从中脑腹侧被盖区（VTA）到伏隔核（NAcb）和前额叶皮层（PFC）的上行投射的作用。使用光遗传学以时间锁定的精度单独刺激这些投射，我们区分了这些投射中的每一个在冲动控制和注意力中的作用。因此，我们的研究增强了我们对驱动冲动和注意行为的神经元回路的理解。
