Timing and dopamine in frontostriatal circuits

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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.