A fundamental task of the brain is to choose what to do next, and an impaired ability to select appropriate behaviors and repress inappropriate actions is thought to underlie conditions including schizophrenia, addiction, and Huntington's disease. How the brain weighs available actions to choose and execute the most adaptive is not understood. In the canonical model, effector structures such as the superior colliculus (SC) are constantly poised to generate behaviors, but are repressed by tonically active GABAergic neurons of the basal ganglia (BG) output nuclei substantia nigra pars reticulata (SNr) and internal globus pallidus; before an action, the specific subset of BG output neurons inhibiting that action pause firing to ?release? its effector pathway. However, several studies have revealed that SNr harbors multiple GABAergic inhibitory cell types of which some are only phasically active, and both tonic and phasic inhibitory SNr neurons can converge on the same target neurons in structures such as SC. These cell types are intermingled in SNr, which has hindered efforts to apply the genetic tools of modern neuroscience to decipher how their convergent phasic and tonic inhibitory signals influence downstream neural processing to control behavioral choice and execution. To surmount this obstacle, my lab has developed approaches to selectively express genetic tools in either phasic or tonic SNr neurons. Here I propose to apply our approach to reveal how phasic and tonic inhibitory BG subtypes coordinate behavior. First, we will test the hypothesis that phasic SNr neurons encode both behavioral choice and execution by recording their activity during behavior. Second, we will test the hypothesis that phasic inhibitory neurons shape both choice and execution of the chosen behavior using targeted manipulations. Third, to understand the transcriptional basis of physiologic differences between these phasic and tonic types, we will define the genetic identities of both using a novel barcoding approach in single-cell sequencing. Collectively, these studies will provide a comprehensive portrait of how phasic and tonic inhibitory BG cell types coordinate behavioral choice and execution. The findings from these studies may help us to understand the etiology of and lead to new treatments for conditions including addiction, schizophrenia, Parkinson's, and Huntington's disease.
The most basic function of the brain is to choose what to do next, and aberrant choices characterize conditions ranging from schizophrenia and addiction to Huntington's disease. This proposed studies describe novel approaches to address longstanding questions regarding how diverse cell types coordinate behavioral choice, and to generate multiplexed, connectivity-based barcodes to reveal the genetic identities of these neurons. The findings from these studies may lead to treatments for a range of conditions, including schizophrenia, addiction, and Huntington's disease.
