Research in several species shows that rapidly stopping action activates the subthalamic nucleus (STN) of the basal ganglia (BG) ? and that the STN may be recruited via a hyperdirect pathway (HDP) from prefrontal cortical stopping nodes. Human research also shows that unexpected events (such as a surprising tones) also recruit the stopping system (including the STN), and interrupt working memory (WM). At the core of this proposal is the idea that WM is maintained via a recurrent cortico-BG loop, and that this can be interrupted via HDP recruitment of the STN. The interruption is induced via stop signals and unexpected events, and could function to `clear cognition'. This is a radical new theory: that a fronto-BG circuit for stopping underlies cognitive interruptions. Validating this theory has broad implications for understanding the BG, for mechanisms of cognitive interruptions, and for potential cognitive under-and-over flexibility in Parkinson's disease (PD) and ADHD. Here we propose to systematically test this theory using parallel human-mouse studies, based on extensive preliminary data and using several novel approaches, including event-related Deep Brain Stimulation (eDBS).
Aim 1 (motor stop) will use STN eDBS in humans and optogenetic stimulation in mice to test whether the STN is causally important for stopping action.
Aim 2 (cognitive stop) will use eDBS and functional MRI in humans and optogenetics in mice to test whether the STN is causally important for decrementing WM.
Aim 3 (HDP) will use combinatorial optogenetics in mice and novel combinations of transcranial magnetic stimulation with concurrent local field recordings in human STN to test whether motor and cognitive Stops are implemented via HDP inputs to STN from frontal cortex. Throughout the proposal we focus on designing complementary experiments across species, so that what is learned in mice can directly inform our understanding of human neural circuit function and behavior.

Public Health Relevance

New, unexpected, or conflicting information puts the brakes on our behavior (motor stop) and also interrupts our cognition (cognitive stop). This proposal uses a circuit-based approach to test a causal role for the subthalamic nucleus (STN), and specifically cortico-STN projections, in implementing such motor and cognitive stops.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS106822-03
Application #
9927692
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Babcock, Debra J
Project Start
2018-05-15
Project End
2023-04-30
Budget Start
2020-05-01
Budget End
2021-04-30
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California, San Diego
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093