The cortico-striatal-thalamo-cortical (CSTC) pathway is a brain circuit that controls movement execution, habit formation and reward. Hyperactivity in the CSTC pathway is involved in obsessive compulsive disorder (OCD), a neuropsychiatric disorder characterized by the execution of repetitive involuntary movements. The striatum shapes the activity of the CSTC pathway through the coordinated activation of two classes of medium spiny neurons (MSNs) expressing D1 or D2 dopamine receptors. The exact mechanisms by which balanced excitation/inhibition (E/I) of these cells controls the network dynamics of the CSTC pathway remain unclear. Here we use non-linear modeling of neuronal activity and bifurcation theory to investigate how global and local changes in E/I of MSNs regulate the activity of the CSTC pathway. Our findings indicate that a global and proportionate increase in E/I pushes the system to states of generalized hyper-activity throughout the entire CSTC pathway. Certain disproportionate changes in global E/I trigger network oscillations. Local changes in the E/I of MSNs generate specific oscillatory behaviors in MSNs and in the CSTC pathway. These findings indicate that subtle changes in the relative strength of E/I of MSNs can powerfully control the network dynamics of the CSTC pathway in ways that are not easily predicted by its synaptic connections.

The cortico-striatal-thalamo-cortical (CSTC) pathway is a brain circuit that controls movement execution, habit formation and reward. Hyperactivity in the CSTC pathway is involved in obsessive compulsive disorder (OCD), a neuropsychiatric disorder characterized by the execution of repetitive involuntary movements. The striatum shapes the activity of the CSTC pathway through the coordinated activation of two classes of medium spiny neurons (MSNs) expressing D1 or D2 dopamine receptors. The exact mechanisms by which balanced excitation/inhibition (E/I) of these cells controls the network dynamics of the CSTC pathway remain unclear. Here we use non-linear modeling of neuronal activity and bifurcation theory to investigate how global and local changes in E/I of MSNs regulate the activity of the CSTC pathway. Our findings indicate that a global and proportionate increase in E/I pushes the system to states of generalized hyper-activity throughout the entire CSTC pathway. Certain disproportionate changes in global E/I trigger network oscillations. Local changes in the E/I of MSNs generate specific oscillatory behaviors in MSNs and in the CSTC pathway. These findings indicate that subtle changes in the relative strength of E/I of MSNs can powerfully control the network dynamics of the CSTC pathway in ways that are not easily predicted by its synaptic connections.The cortico-striatal-thalamo-cortical (CSTC) pathway is a neuronal circuit that controls movement selection and initiation, reinforcement and reward 1 . Our current understanding of the wiring diagram of the CSTC pathway, based on functional neuroimaging studies, indicate that this circuit has an equivalent organization in rodents and humans of either sex and age (Fig. 1A,B) 2 . In normal conditions, oscillations and synchronous activity in distinct domains of the CSTC pathway are crucial to ensure the execution of habitual actions [3][4][5] . In contrast, hyperactivity in specific domains or throughout the circuit are thought to underlie the manifestation of obsessive compulsive disorder (OCD) and Tourette's syndrome 2,6 . The basal ganglia nucleus of the striatum plays an important role in regulating the activity of the CSTC pathway through the coordinated interplay of two populations of long-projections GABAergic neurons: the D1 and D2 dopamine receptor expressing medium spiny neurons (D1-and D2-MSNs, respectively) 3,7 . D1-MSNs project directly to the internal capsule of the globus pallidus (GPi) and the substantia nigra pars reticulata (SNr; Fig. 1C), whereas D2-MSNs project indirectly to the SNr by way of intermediate synaptic connections in the external capsule of the globus pallidus (GPe) and the sub-thalamic nucleus (STN; Fig. 1C). Activation of D1-MSNs facilitates movement initiation and activation of D2-MSNs inhibits initiation of competing actions 8,9 . Recent findings indicate that repetitive optogenetic activation of cortico-striatal glutamatergic afferents to the striatum triggers OCD-like behaviors in mice 10 , whereas optogenetic stimulation of ...