The Enemy within: Propagation of Aberrant Corticostriatal Learning to Cortical Function in Parkinson's Disease

Abstract

Motor dysfunction in Parkinson's disease is believed to arise primarily from pathophysiology in the dorsal striatum and its related corticostriatal and thalamostriatal circuits during progressive dopamine denervation. One function of these circuits is to provide a filter that selectively facilitates or inhibits cortical activity to optimize cortical processing, making motor responses rapid and efficient. Corticostriatal synaptic plasticity mediates the learning that underlies this performance-optimizing filter. Under dopamine denervation, corticostriatal plasticity is altered, resulting in aberrant learning that induces inappropriate basal ganglia filtering that impedes rather than optimizes cortical processing. Human imaging suggests that increased cortical activity may compensate for striatal dysfunction in PD patients. In this Perspective article, we consider how aberrant learning at corticostriatal synapses may impair cortical processing and learning and undermine potential cortical compensatory mechanisms. Blocking or remediating aberrant corticostriatal plasticity may protect cortical function and support cortical compensatory mechanisms mitigating the functional decline associated with progressive dopamine denervation.

Keywords: basal ganglia; cortical compensation; corticostriatal plasticity; dorsolateral striatum; striatopallidal pathway.

Figure 1

Simplified schematic of cortico-basal ganglia circuitry and corticostriatal filtering of cortical activity. (A) Dual corticostriatal architecture showing the direct and indirect pathways that express D1 and D2 dopamine receptors, respectively. Arrow colors reflect excitatory and inhibitory neurotransmitters. (B) Schematic diagramming selective facilitatory and inhibitory corticostriatal learning. LTP and LTD in the striatonigral and striatopallidal pathways, respectively (middle panel), facilitate cortical activity while the converse (LTD in striatonigral and LTP in striatopallidal) inhibit cortical activity. Green/red arrows represent striatonigral direct and striatopallidal indirect pathways, respectively. Direction of plasticity (LTP vs. LTD) colored red/green to indicate functional facilitation/inhibition of cortical throughput. The size/intensity of green circles represent the increase/decrease in activity of a synapse-specific cortical afferent induced by basal ganglia modulation.

Figure 2

Role of corticostriatal plasticity and learning in basal ganglia filtering of cortical activity. (top) Conceptual illustration of basal ganglia filtering of cortical activity through corticostriatal plasticity and learning. The naïve, pre-learning state is represented in the left panel and processing through the basal ganglia is undifferentiated (gray arrow loop). After appropriate corticostriatal learning (middle panel), task-related elements are sharpened and highlighted (racquet, ball, arm, other players), represented in the corticostriatal loop as a combination of facilitation and inhibition with strong, task-relevant facilitation (sharp, dark green arrow loop). Under aberrant learning (right panel), inappropriate LTP in the inhibitory striatopallidal pathway induces inappropriate inhibition (red shaded arrow loops) and diminished facilitation (green shaded arrow loops) in the corticostriatal filter causing task-related elements become increasingly noisy and less distinct against background compared even to naïve processing (left panel). (bottom) Schematic showing rudimentary architecture for basal ganglia filter of cortical activity highlighting the general loop architecture. Large green arrows represent cortical inputs to the striatum and re-entrant projections returning to the cortex via the thalamus. The intrabasal ganglia circuitry has been collapsed to highlight the basic loop architecture. The cortical schematic has been expanded to represent the two primary intracortical information flows mediating action selection and motor control. The left cortical box represents traditional frontal motor control where information flows rostral to caudal from the prefrontal cortex to M1. The right cortical box represents parietal processing where information flows caudal to rostral mediating sensorimotor transformations specifying movements. These two are intricately interconnected, represented by reciprocal gray arrows. Image used in top panel licensed from Polka Dot Images/Thinkstock.