Basal Ganglia Pathways for Stopping and Switching

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Behavioral inhibition is central to self-control. Daily life is made immeasurably easier by a repertoire of learned responses to stimuli, yet we need to interrupt and override such responses as circumstances and goals change. Problems with inhibitory function characterize a range of psychiatric disorders including drug addiction, attention-deficit hyperactivity disorder, and Tourette Syndrome. Despite the importance of behavioral inhibition, our understanding of the neural mechanisms involved remains very limited. A standard tool to probe behavioral inhibition is the Stop-signal task. Subjects are signaled to make quick actions, and in a subset of trials are later instructed to cancel those movements before they begin. It has long been hypothesized that Stop-signal performance reflects a race between Go and Stop processes, but how this race corresponds to brain activity is not clear. Although there is a great deal of evidence that deep brain structures called the basal ganglia are involved in stopping, there has been little corresponding investigation of the basal ganglia using the method with the best temporal resolution - electrophysiology of single neurons. We have recently found evidence for a neural race between distinct basal ganglia pathways. Activity in sensorimotor striatum (STR) appeared to correspond to a Go process, while Stop cues instead provoked very fast responses in the subthalamic nucleus (STN). Both of these areas project to the substantia nigra pars reticulata (SNr), which can operate as a gateway to motor output. The relative timing of STR and STN firing determined whether SNr cells responded to the Stop cue (observed when inhibition was successful), or not (when inhibition failed). However, our data also suggest that the STN-SNr pathway actually provides a fast yet transient movement pause, with complete cancellation requiring a separate suppression of STR output. We hypothesize that these two mechanisms serve complementary functions, allowing behavioral inhibition to be both fast and selective. To investigate these processes further, we propose a series of experiments using state-of-the-art techniques for monitoring and manipulating the basal ganglia. For Aim 1 we will compare Stop-related activity in distinct subregions within STR, STN and SNr, to better define how information flows through "motor" and "cognitive" circuits. For Aim 2 we will investigate whether STN signals are specific to stopping, and whether they are driven by the intralaminar thalamus, an area involved in fast orienting reactions. For Aim 3 we will use selective optogenetic suppression and stimulation of the STN-SNr pathway to confirm that it provides a fast motor pause. Finally, for Aim 4 we will explore how the key neuromodulators acetylcholine and dopamine contribute to the suppression of STR output during successfully cancelled actions. Overall, this project would break new ground in determining with unprecedented precision how we are able to rapidly suppress unwanted or inappropriate actions, in the service of adaptive, flexible behavior.