Diametric neural ensemble dynamics in parkinsonian and dyskinetic states

Abstract

Loss of dopamine in Parkinson's disease is hypothesized to impede movement by inducing hypo- and hyperactivity in striatal spiny projection neurons (SPNs) of the direct (dSPNs) and indirect (iSPNs) pathways in the basal ganglia, respectively. The opposite imbalance might underlie hyperkinetic abnormalities, such as dyskinesia caused by treatment of Parkinson's disease with the dopamine precursor L-DOPA. Here we monitored thousands of SPNs in behaving mice, before and after dopamine depletion and during L-DOPA-induced dyskinesia. Normally, intermingled clusters of dSPNs and iSPNs coactivated before movement. Dopamine depletion unbalanced SPN activity rates and disrupted the movement-encoding iSPN clusters. Matching their clinical efficacy, L-DOPA or agonism of the D dopamine receptor reversed these abnormalities more effectively than agonism of the D dopamine receptor. The opposite pathophysiology arose in L-DOPA-induced dyskinesia, during which iSPNs showed hypoactivity and dSPNs showed unclustered hyperactivity. Therefore, both the spatiotemporal profiles and rates of SPN activity appear crucial to striatal function, and next-generation treatments for basal ganglia disorders should target both facets of striatal activity.

A Proposed Circuit Computation in Basal Ganglia: History‐Dependent Gain

“…Importantly, in each case the magnitude of the activity modulation in STR neurons active in an early phase of movement correlated with movement speed and amplitude. Finally, pharmacological restoration of dopaminergic tone with l ‐dopa reduced bradykinesia and partially restored robust modulation of SPN activity in early phases of movement execution (in addition to other, likely maladaptive, changes). In contrast, there was not clear evidence for an aberrant large average increase above baseline of SPN activity throughout movement, arguing against the proposal that bradykinesia results from multiple conflicting actions being executed .…”

“…In contrast, there was not clear evidence for an aberrant large average increase above baseline of SPN activity throughout movement, arguing against the proposal that bradykinesia results from multiple conflicting actions being executed . Nonetheless, premovement, baseline activity of SPNs was increased in dopamine‐depleted animals (recently shown to be specifically in iSPNs) suggesting that excessive BG output could be associated with akinesia — a point we will return to below.…”

Dyskinesia Matters

“…We thank Chaudhuri and colleagues for acknowledging that investigations in animal models of LID can significantly advance our understanding of basal ganglia pathophysiology. In this vein, it is worth mentioning that recent studies in rodent models of LID have provided major insights into the role and plasticity of striatal output pathways in hyperkinetic versus hypokinetic disorders . In addition, one should consider that the mechanisms of LID have significant commonalities with those underlying other complications of PD therapy, such as motor and nonmotor fluctuations, dopamine dysregulation syndrome, and impulsive–compulsive behaviors.…”

Striatum: Through the looking glass

“…Contrary to the traditional “rate model” proposing that the direct and indirect pathways act in opposition, the main result of the study by Parker and colleagues showed that movement is associated with simultaneous activation of both direct and indirect striatal projection pathways. This particular work shows that the overall rate disturbances following dopamine depletion are accompanied by subtle changes in coding specificity and spatial patterns of neuronal activity.…”

“…Traditional neurophysiological techniques, including electrophysiology and voltammetry, record the temporal aspects of neuronal firing with great precision, but there is always uncertainty concerning the spatial dynamics of neuronal activity. A recent study by Parker and colleagues overcomes this limitation by implanting a fluorescence nanomicroscope in the striatum of freely moving animals. Through an implanted lens, their miniaturized device was able to measure fluorescence associated with intracellular calcium dynamics, thereby providing information about both the temporal and spatial aspects of neuronal activity.…”