Dissociating Cortico-Striato-Thalamo-Cortical Neural Circuitry Using Rodent Models of Cognitive Flexibility

Abstract

Mental illness is the single largest cause of disability worldwide. These disorders are characterized by breakdowns in neuronal communication between and among different areas of the brain. In order to restore proper functioning, treatment strategies have increasingly focused on modulating specific neuronal circuits. Deep brain stimulation (DBS) allows for targeted circuit-based neuromodulation and has shown to be a promising treatment for mental disorders. Despite its success, the mechanisms underlying its therapeutic effects remain unclear. Further investigating cortico-striato-thalamo-cortical (CSTC) circuits, often impaired in those with major depressive (MDD) or obsessive-compulsive disorder (OCD), may provide mechanistic clues. MDD and OCD can be characterized by impairments in cognitive control—the ability to organize, plan, and schedule mental operations in different environments. Cognitive control depends on distinct subregions of the prefrontal cortex (PFC) which project into the striatum. Here we show that DBS applied to the mid-striatum in an attentional set-shifting task improves cognitive flexibility in outbred rats (n=12) by significantly decreasing reaction time (p < 0.01). Furthermore, we developed a novel touchscreen two-armed bandit task which may help in determining which parts of the PFC are responsible for DBS’ effects on cognitive flexibility. Our results demonstrate that DBS is able to modulate the neural circuitry underlying cognitive flexibility and that Long-Evans rats can serve as a viable animal model in translating the two-armed bandit behavioral paradigm. Our future study will evaluate the effects of DBS in both set-shifting and the two-armed bandit. Behavioral paradigms with an increased dependency on more ventral parts of the PFC, involved in the two-armed bandit, are hypothesized to not benefit from mid-striatum DBS treatment. Our results may translate to human behavioral tasks and serve as a predictor for DBS’ effectiveness.