α-Synuclein Selectively Impairs Motor Sequence Learning and Value Sensitivity: Reversal by the Adenosine A2A Receptor Antagonists.

Parkinson's disease (PD) is characterized pathologically by alpha-synuclein (α-Syn) aggregates and clinically by the motor as well as cognitive deficits, including impairments in sequence learning and habit learning. Using intracerebral injection of WT and A53T mutant α-Syn fibrils, we investigate the behavioral mechanism of α-Syn for procedure-learning deficit in PD by critically determining the α-Syn-induced effects on model-based goal-directed behavior, model-free (probability-based) habit learning, and hierarchically organized sequence learning. 1) Contrary to the widely held view of habit-learning deficit in early PD, α-Syn aggregates in the dorsomedial striatum (DMS) and dorsolateral striatum (DLS) did not affect acquisition of habit learning, but selectively impaired goal-directed behavior with reduced value sensitivity.

Striatopallidal adenosine A receptors in the nucleus accumbens confer motivational control of goal-directed behavior.

The ability to learn the reward-value and action-outcome contingencies in dynamic environment is critical for flexible adaptive behavior and development of effective pharmacological control of goal-directed behaviors represents an important challenge for improving the deficits in goal-directed behavior which may underlie seemingly disparate symptoms across psychiatric disorders. Adenosine A receptor (AR) is emerging as a novel neuromodulatory target for controlling goal-directed behavior for its unique neuromodulatory features: the ability to integrate dopamine and glutamate signaling, the "brake" constraint of various cognitive processes and the balanced control of goal-directed and habit actions. However, the contribution and circuit mechanisms of the striatopallidal ARs in nucleus accumbens (NAc) to control of goal-directed behavior remain to be determined.

Striatopallidal Pathway Distinctly Modulates Goal-Directed Valuation and Acquisition of Instrumental Behavior via Striatopallidal Output Projections.

The striatopallidal pathway is specialized for control of motor and motivational behaviors, but its causal role in striatal control of instrumental learning remains undefined (partly due to the confounding motor effects). Here, we leveraged the transient and "time-locked" optogenetic manipulations with the reward delivery to minimize motor confounding effect, to better define the striatopallidal control of instrumental behaviors. Optogenetic (Arch) silencing of the striatopallidal pathway in the dorsomedial striatum (DMS) and dorsolateral striatum (DLS) promoted goal-directed and habitual behaviors, respectively, without affecting acquisition of instrumental behaviors, indicating striatopallidal pathway suppression of instrumental behaviors under physiological condition.

Pharmacological Blockade of Adenosine A but Not A Receptors Enhances Goal-Directed Valuation in Satiety-Based Instrumental Behavior.

The balance and smooth shift between flexible, goal-directed behaviors and repetitive, habitual actions are critical to optimal performance of behavioral tasks. The striatum plays an essential role in control of goal-directed versus habitual behaviors through a rich interplay of the numerous neurotransmitters and neuromodulators to modify the input, processing and output functions of the striatum. The adenosine receptors (namely AR and AR), with their high expression pattern in the striatum and abilities to interact and integrate dopamine, glutamate and cannabinoid signals in the striatum, may represent novel therapeutic targets for modulating instrumental behavior.

Habit Formation after Random Interval Training Is Associated with Increased Adenosine A Receptor and Dopamine D Receptor Heterodimers in the Striatum.

Striatal adenosine A receptors (ARs) modulate striatal synaptic plasticity and instrumental learning, possibly by functional interaction with the dopamine D receptors (DRs) and metabotropic glutamate receptors 5 (mGluR5) through receptor-receptor heterodimers, but evidence for these interactions is lacking. Using proximity ligation assay (PLA), we studied the subregional distribution of the AR-DR and AR-mGluR5 heterodimer complexes in the striatum and their adaptive changes over the random interval and random ratio training of instrumental learning. After confirming the specificity of the PLA detection of the AR-DR heterodimers with the AR knockout and DR knockout mice, we detected a heterogeneous distribution of the AR-DR heterodimer complexes in the striatum, being more abundant in the dorsolateral than the dorsomedial striatum.