Abstract
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.
Highlights
The cortico-striatal-thalamo-cortical (CSTC) pathway is a neuronal circuit that controls movement selection and initiation, reinforcement and reward[1]
The two major pieces of evidence that motivate our study are: (1) the CSTC pathway controls important physiological functions, like movement execution; (2) the CSTC pathway is a major site of synaptic dysfunction in neurospychiatric disorders like obsessive compulsive disorder (OCD) and Tourette’s syndrome, which are characterized by the repeated execution of involuntary movements[2, 24]
Coordinated activation of D1- and D2-medium spiny neurons (MSNs) is crucial for action selection and inhibition of unwanted behaviors as well as to control the overall level of activity in the CSTC pathway[26, 27]
Summary
The cortico-striatal-thalamo-cortical (CSTC) pathway is a neuronal circuit that controls movement selection and initiation, reinforcement and reward[1]. 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 feed-forward inhibition onto D1- and D2-MSNs relieves OCD-like behaviors in a genetic mouse model of OCD11. These findings are important because they suggest that a fine regulation of excitation and inhibition (E/I) onto D1- and D2-MSNs might be crucial to control the onset of hyperactivity in the CSTC pathway[6]. By using coupled Wilson-Cowan models and bifurcation theory[16], we determine how global and local changes in excitation and inhibition contribute to orchestrate the activity of D1- and D2-MSNs and of the entire CSTC pathway
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