The basal ganglia regulate cortical function via cortico-striatal-thalamo-cortical loops. Two functionally opposing pathways the direct and indirect pathway either activate or inhibit thalamo-cortical circuits via the basal ganglia output nuclei, the globus pallidus and the substantia nigra. Recent slice physiology experiments, however, suggest an additional more direct link by which the striatum regulates cortical activity. In slices both direct and indirect pathway neurons of the dorsal striatum inhibit cholinergic neurons that project to frontal cortical areas. One area that receives inputs from striatal-inhibited cholinergic neurons is the orbitofrontal cortex (OFC). The OFC supports reversal learning a measure of behavioral flexibility that is affected in several mental disorders including obsessive-compulsive disorder, schizophrenia and drug addiction. Strikingly, not much is known about the regulation of the OFC by cholinergic neurons, whether cholinergic projections to the OFC modulate reversal learning and whether cholinergic projections to the OFC are regulated by the striatum during behavior. This explorative R21 application is a first step to address these gaps in knowledge. We will use the mouse and the modern circuit dissection tools available to the mouse to test the overarching hypothesis that direct and indirect pathways regulate reversal learning via inhibition of OFC-projecting cholinergic neurons. To address this hypothesis we propose the following two aims: Aim 1: To determine whether cholinergic neurons projecting to the OFC support reversal learning In aim 1.1 we will use Ca2+ imaging to measure the activity of OFC-projecting cholinergic neurons. In aim 1.2 we will inhibit OFC-projecting cholinergic neurons and determine how this affects cortical acetylcholine release and reversal learning. Aim 2: To determine whether the striatum regulates reversal learning via the cholinergic system In aim 1.2 and aim 1.2 we will inhibit indirect or direct pathway neurons during reversal learning to determine how this affects cortical acetylcholine release and reversal learning. Understanding the role of the basal ganglia in regulating OFC function and reversal learning will have important implications for brain disorders with abnormalities in cortico-striatal circuitry and impaired reversal learning including schizophrenia, obsessive-compulsive disorder and drug addiction.

This application will study the effects of striatal output pathway inhibition on cholinergic modulation of the orbitofrontal cortex and reversal learning. Understanding the role of the basal ganglia in regulating orbitofrontal cortex function and reversal learning will have important implications for brain disorders with abnormalities in cortico-striatal circuitry and impaired reversal learning including schizophrenia, obsessive-compulsive disorder and drug addiction.