Timing and dopamine in frontostriatal circuits

额纹状体回路中的时间和多巴胺

• 批准号: 9905554
• 负责人: Nandakumar Narayanan
• 金额: $ 48.18万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-04 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9905554
• 关键词: Affect; Anterior; Attention; Attention deficit hyperactivity disorder; Automobile Driving; Axon; Basal Ganglia; Basic Science; Behavior; Behavioral; Bipolar Disorder; Brain; Communication; Corpus striatum structure; Data; Decision Making; Dimensions; Disease; Dopamine; Dopamine Receptor; Dorsal; Drug Targeting; Exhibits; Failure; Functional disorder; Goals; Human; Human Activities; Ice; Impairment; Maps; Measures; Medial; Mental disorders; Motivation; Motor; Movement; Mus; Muscimol; Neurons; Pathway interactions; Pattern; Performance; Pharmacology; Play; Process; Publishing; Ramp; Resolution; Rodent; Role; Schizophrenia; Short-Term Memory; Source; Specificity; Symptoms; Techniques; Testing; Time; Walking; Work; base; cell type; cognitive control; cognitive function; cognitive task; cooking; executive function; frontal lobe; human disease; innovation; insight; millimeter; millisecond; neuronal circuitry; optogenetics; receptor; relating to nervous system; response; temporal measurement; therapeutic target

Abstract Timing, or decisions based on temporal information on the scale of seconds, is critical for survival. Capturing prey, foraging, and evading predators require choices to initiate and suppress movements precisely in time. Similarly, daily human activities like communication, cooking, walking, and crossing the street require precise timing. Failures in timing can have disastrous consequences. Despite its importance, the neural basis of timing is unknown, in part because timing is understudied. Because timing is vital to higher-order executive functions such as inhibitory control, reasoning, and planning, there is a critical need to better understand its neural basis. We study this problem using interval timing, which requires subjects to make a motor response after an interval of several seconds. Interval timing requires cognitive functions such as working memory for temporal rules and attention to the passage of time. Therefore, during interval timing subjects must cognitively control their responses based on their estimation of elapsed time. Our objective in this basic-science proposal is to study how dopamine- receptor-expressing neurons in frontostriatal circuits control interval timing. Our recent work demonstrates that interval timing requires neurons in the dorsal prelimbic region of medial frontal cortex (MFC) that express D1- type dopamine receptors (D1DRs; also called MFC D1 neurons). MFC neurons project to medium spiny neurons (MSNs) in the dorsomedial striatum. These MSNs also express dopamine receptors, and our preliminary data suggests that striatal D1 and D2 MSNs play distinct roles during timing tasks. Our hypothesis is that MFC D1 neurons dynamically regulate the activity of D1 and D2 MSNs to control interval timing. In Aim 1, we will determine whether MFC D1 neurons control timing-dependent activity in MSNs. In Aim 2, we will determine whether D1 and D2 MSNs control interval-timing behavior. Finally, in Aim 3, we will determine if frontostriatal stimulation can compensate for MFC inactivation. Findings from our work will be significant in providing fundamental mechanistic insight into how dopamine-receptor-expressing frontostriatal neurons are involved in cognitive control. Our approach is innovative in studying corticostriatal circuits in a cognitive task rather than in movement or motivation. We will also combine neuronal ensemble recording with optogenetics, which facilitates adaptive brain stimulation guided online by brain activity in Aim 3. This approach has the potential to identify and rectify dysfunctional neuronal activity patterns in real time. Because timing involves highly conserved MFC circuits in mice and humans—and is impaired in diseases such as schizophrenia, ADHD, OCD, and bipolar disorder—insights from this basic science proposal are likely to have relevance for humans.

抽象的 时间安排或基于秒数的临时信息的决定对于生存至关重要。 捕获猎物，觅食和逃避掠食者需要精确启动和抑制运动的选择 及时。同样，人类活动，例如交流，烹饪，步行和过马路需要 精确的时机。定时失败可能会造成灾难后果。尽管重要性是神经基础 时间安排是未知的，部分原因是理解时机。因为时机对于高阶高管至关重要 诸如抑制性控制，推理和计划之类的功能，迫切需要更好地理解其 神经基础。我们使用间隔计时研究此问题，这需要受试者做出电动机响应 在间隔几秒钟之后。 间隔定时需要认知功能，例如临时规则的工作记忆和注意 时间的流逝。因此，在间隔时正时，受试者必须认知控制其反应 根据他们对经过的时间的估计。我们在这项基本科学建议中的目标是研究多巴胺如何 额叶电路中表达受体的神经元控制间隔时间。我们最近的工作表明 间隔时间需要在表达d1-的培养基额叶皮层（MFC）的背面前区域中神经元 类型多巴胺受体（D1DR；也称为MFC D1神经元）。 MFC神经元项目中等刺 背侧纹状体中的神经元（MSN）。这些MSN还表达多巴胺受体，我们的 初步数据表明，纹状体D1和D2 MSN在定时任务中起着不同的作用。我们的假设 MFC D1神经元动态调节D1和D2 MSN的活性以控制间隔时间。目标 1，我们将确定MFC D1神经元是否控制MSN中的时间依赖性活性。在AIM 2中，我们将 确定D1和D2 MSN是否控制间隔捕集行为。最后，在AIM 3中，我们将确定是否 额叶刺激可以补偿MFC灭活。 我们工作中的发现将在提供有关如何提供基本的机械洞察力方面重要的 表达多巴胺受体的额叶神经元参与认知对照。我们的方法是 在认知任务中研究皮质纹状体回路的创新性，而不是运动或动机。我们将 还将神经元集合记录与光遗传学结合在一起，哪些设施适应性脑刺激 AIM 3中的大脑活动在线指导。这种方法有可能识别和纠正功能失调 实时的神经元活动模式。因为时间涉及小鼠中高度组成的MFC电路，并且 人类 - 在精神分裂症，ADHD，OCD和躁郁症等疾病中受到损害 这项基础科学建议可能与人类有相关性。