Disrupted basal ganglia output during movement preparation in hemiparkinsonian mice is consistent with behavioral...

Parkinsonian motor deficits are associated with elevated inhibitory output from the basal ganglia (BG). However, several features of Parkinson's disease (PD) have not been accounted for by this simple "classical rate model" framework, including the observation in patients with PD that movements guided by external stimuli are less impaired than otherwise identical movements generated based on internal goals. Is this difference due to divergent processing within the BG itself or due to the recruitment of extra-BG pathways by sensory processing? In addition, surprisingly little is known about precisely when, in the sequence from selecting to executing movements, BG output is altered by PD. Here, we address these questions by recording activity in the substantia nigra pars reticulata (SNr), a key BG output nucleus, in hemiparkinsonian mice performing a well-controlled behavioral task requiring stimulus-guided and internally specified directional movements. We found that hemiparkinsonian mice exhibited a bias ipsilateral to the side of dopaminergic cell loss that was stronger when movements were internally specified rather than stimulus guided, consistent with clinical observations in patients with Parkinson's disease. We further found that changes in parkinsonian SNr activity during movement preparation were consistent with the ipsilateral behavioral bias, as well as its greater magnitude for internally specified movements. Although these findings are inconsistent with some aspects of the classical rate model, they are accounted for by a related "directional rate model" positing that SNr output phasically overinhibits motor output in a direction-specific manner. These results suggest that parkinsonian changes in BG output underlying movement preparation contribute to the greater deficit in internally specified than stimulus-guided movements.NEW & NOTEWORTHY Movements of patients with Parkinson's disease are often less impaired when guided by external stimuli than when generated based on internal goals. Whether this effect is due to distinct processing in the basal ganglia (BG) or due to compensation from other motor pathways is an open question with therapeutic implications. We recorded BG output in behaving parkinsonian mice and found that BG activity during movement preparation was consistent with the differences between these forms of movement.