Striatal dopamine modulates timing of self-initiated saccades

Abstract

The authors thank S. Ohmae, T. Suzuki, and other lab members for valuable comments and AbstractThe ability to adjust movement timing is essential in daily life. Explorations of the underlying neural mechanisms have reported a gradual increase or decrease in neuronal activity prior to self-timed movements within the cortico-basal ganglia loop. Previous studies in both humans and animals have shown that endogenous dopamine (DA) plays a modulatory role in self-timing.However, the specific site of dopaminergic regulation remains elusive because the systemic application of DA-related substances can directly alter both cortical and subcortical neuronal activity. To investigate the role of striatal DA in self-timing, we locally injected DA receptor agonists or antagonists into the striatum of two female monkeys (Macaca fuscata) while they performed two versions of the memory-guided saccade (MS) task. In the conventional, triggered MS task, animals made a saccade to the location of a previously flashed visual cue in response to the fixation point offset. In the self-timed MS task, monkeys were rewarded for making a self-initiated saccade within a predetermined time interval following the cue. Infusion of a small amount of a D 1 or D 2 antagonist led to early saccades in the self-timed, but not the triggered MS tasks, while infusion of DA agonists produced no consistent effect. We also found that local administration of nicotinic but not muscarinic acetylcholine receptor agonists and antagonists altered the timing of self-initiated saccades. Our data suggest that the timing of self-initiated movements may be regulated by the balance of signals in the direct and indirect basal ganglia pathways, as well as that between both hemispheres of the brain.

Primate Nigrostriatal Dopamine System Regulates Saccadic Response Inhibition

“…According to the above consideration, the pharmacological blockade should improve the performance of canceling contralateral saccadic eye movements. Consistent with our findings, a previous study in monkeys also reported that D1 and D2 antagonist injections into the caudate nucleus affected ipsilateral saccadic eye movements, but not contralateral ones, in a saccade task named the self-timed memory-guided saccade task (Kunimatsu and Tanaka, 2016). In this task, the monkey was required to wait for a predetermined time interval (e.g., 1,100 ± 300 ms after cue offset) before making a saccadic eye movement to a remembered cue location.…”

Different contributions of preparatory activity in the basal ganglia and cerebellum for self-timing

“…Subjects with Parkinson’s disease, for example, show deficits in the estimation and production of interval timing within the range of seconds ( Pastor et al, 1992 ) and exhibit a significant decrease in the magnitude of CNV ( Ikeda et al, 1997 ). In experimental animals, local application of dopamine receptor antagonists into the striatum alters self-timing in monkeys ( Kunimatsu and Tanaka, 2016 ), and more specifically, optogenetic inhibition of nigro-striatal pathways disrupts temporal discrimination in rodents ( Soares et al, 2016 ). However, the firing of midbrain dopamine neurons is known to be generally phasic ( Bromberg-Martin et al, 2010 ) and therefore appears unlikely to continuously keep track of elapsed time during motor preparation, while the gain of transient sensory response might carry temporal information ( Soares et al, 2016 ).…”

“…To understand the roles of the basal ganglia and the cerebellum in self-timing, we compared activity of single neurons in the anterior part of the striatum (caudate nucleus) with those in the posterior part of the cerebellar dentate nucleus in monkeys performing the self-timed saccade task ( Ashmore and Sommer, 2013 ; Kunimatsu and Tanaka, 2012 , 2016 ; Tanaka, 2006 , 2007 ). Because the previous studies have demonstrated that these subcortical regions have common anatomical connections with the medial and lateral frontal cortices involved in temporal processing ( Dum and Strick, 2003 ; Strick et al, 2009 ; McFarland and Haber, 2001 ), we reasoned that these areas might have functional interactions.…”

A cerebellar mechanism for learning prior distributions of time intervals

“…For example, in the RSG task, evaluation of behavioral performance is likely to engage higher cortical areas 107 , and the processing of feedback on timing performance is likely to engage the basal ganglia 108 . Furthermore, numerous studies have found neural correlates of interval timing across the cortico-basal ganglia circuits 93,[109][110][111][112][113] . Indeed, even within the context of the RSG task, cortico-basal ganglia circuits are likely to be involved in the conversion of a Bayesian estimate computed at the time of Set to an ensuing motor plan for the reproduction of that interval 114 .…”