Timing and dopamine in frontostriatal circuits

摘要 时间，或基于秒级时间信息的决策，对生存至关重要。 捕捉猎物、觅食和躲避捕食者需要选择精确地启动和抑制运动 及时同样，交流、烹饪、步行和过马路等日常人类活动也需要 精确的时间。时机的错误可能会带来灾难性的后果。尽管它很重要， 时间是未知的，部分原因是时间研究不足。因为时机对于高阶主管来说至关重要 功能，如抑制控制，推理和规划，有一个关键需要更好地了解其 神经基础我们使用间隔计时来研究这个问题，这需要受试者做出运动反应 在几秒钟的间隔之后。 间隔计时需要认知功能，如对时间规则的工作记忆和对时间的注意力。 时间的流逝因此，在间隔计时期间，受试者必须基于 他们对逝去时间的估计。我们在这个基础科学计划中的目标是研究多巴胺- 额纹状体回路中的受体表达神经元控制间隔时间。我们最近的工作表明， 间隔计时需要内侧额叶皮层（MFC）背侧边缘前区的神经元表达D1- 多巴胺受体（D1DR;也称为MFC D1神经元）。MFC神经元投射到中等多刺 神经元（MSN）在背内侧纹状体。这些MSNs也表达多巴胺受体， 初步数据表明，纹状体D1和D2 MSNs在计时任务中发挥不同的作用。我们的假设 MFC D1神经元动态调节D1和D2 MSN的活动以控制间隔定时。在aim中 1，我们将确定MFC D1神经元是否控制MSN中的时间依赖性活动。在目标2中，我们 确定D1和D2 MSN是否控制间隔定时行为。最后，在目标3中，我们将确定 额纹状体刺激可以补偿MFC失活。 从我们的工作中发现将是重要的，在提供基本的机械洞察如何 表达多巴胺受体的额纹状体神经元参与认知控制。我们的做法是 在研究认知任务中的皮质纹状体回路方面具有创新性，而不是在运动或动机方面。我们将 还将联合收割机神经元整体记录与光遗传学相结合，这有助于适应性脑刺激 由Aim 3中的大脑活动在线引导。这种方法有可能识别和纠正功能失调 真实的神经元活动模式。因为定时涉及小鼠中高度保守的MFC回路， 在精神分裂症、多动症、强迫症和双相情感障碍等疾病中受损， 这个基础科学的提议很可能与人类有关。

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.