Investigating the Role of the Lateral Nigrostriatal Pathway in Modulating Voluntary Movement

Date

2023-04-28

Authors

Young, Penelope Anne

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Abstract

The scientific community has known for decades that nigrostriatal dopamine is required for the initiation of voluntary movement. The dogma has stated that tonic release of dopamine in the striatum, the input center of the basal ganglia, acts as a permissive signal for voluntary movement. However, there is increasing evidence that transient dopaminergic signals are not only involved in reinforcing learning and reward, but also in actively modulating voluntary movement. How exactly transient, or phasic, dopaminergic signals modulate voluntary action is still unclear, in large part due to the heterogeneity of midbrain dopaminergic neurons (DANs) and downstream striatal subregions, and the number of functions phasic dopamine signalling is involved in, including reward prediction error (RPE) encoding, encoding of novel stimuli, and attributing value to stimuli. There is evidence that suggests that the nigrostriatal pathway may be functionally separated along medial and lateral pathways, and consequently that the lateral pathway, namely the lateral substantia nigra pars compacta (SNCL) and the lateral dorsal striatum (DLS), may have a shared functionality in modulating voluntary movement. Although a number of studies have optogenetically stimulated either SNC DAN somata or DAN axon terminals in the DLS, no study to our knowledge has attempted to link the SNCL and DLS functionally regarding voluntary movement. Furthermore, to our knowledge no study has attempted to investigate the role of phasic lateral nigrostriatal dopaminergic signalling in behaviours beyond sub-sec/secs of locomotion, or how the potentially movement-promoting signal of phasic midbrain dopaminergic activity intersects with the novelty encoding function of SNC dopamine transients. To address these gaps in our understanding on how lateral nigrostriatal phasic dopamine modulates voluntary movement, we generated a transgenic mouse line conditionally expressing a light-sensitive channel protein (channelrhodopsin-2, ChR2) in DANs, which would depolarize the neuron when exposed to blue light. We implanted optic fibres over the SNCL or over the DLS and stimulated mice while they explored an open field (OF). The mice were stimulated non-continuously at 12.5Hz, which mimics endogenous DAN phasic activity, and their activity measured for a total of 40 min. The mice were then re-introduced to the same OF and given the same stimulation protocol the next day. We found that phasic stimulation of SNCL somata increased exploratory activity, including rate of horizontal movement, locomotion, and rearing, but not grooming, during the stimulation periods of the first OF day, but not on the second OF day. Specifically, stimulation on the first day increased the number of locomotion initiations without increasing the vigour of initiation. In contrast, on the second OF day we did not observe a stimulus-correlated increase in exploratory activity, but did observe a stimulus-dependant decrease in habituation relative to control (non ChR2-expressing) animals. Stimulation of DAN axons on either OF day in the DLS had no effect on activity. Our findings suggest that phasic activity of SNCL DANs promotes exploratory behaviours in a novelty-dependant manner and may prevent habituation to stimuli of lower novelty.

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Keywords

dopamine, midbrain, optogenetics, voluntary movement

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