Investigations of the substantia nigra pars reticulata function and their implications for the disinhibition model of basal ganglia output

The substantia nigra pars reticulata (SNr) is an output nucleus of the basal ganglia, a group of neuronal circuits important for movement. According to a widely recognised model of the functional organisation of basal ganglia circuits, GABAergic SNr neurons contribute to action selection and execution through decreasing their firing rates and thus, disinhibiting their targets in the thalamus, midbrain and/or brainstem. Nonetheless, significant increases in SNr neuron firing rates have been reported during different motor behaviours in non-human primates and songbirds. Furthermore, it has been suggested that SNr neurons might not only encode for and control movement execution, but also movement preparation. Despite recent advances, relatively little is known about how SNr neurons function in rodents to control movement.
To elucidate the functional role of SNr in motor behaviours, I first developed a novel delayed-Go task for head-fixed mice that incorporates aspects of both movement preparation and execution. I then used combinations of optogenetics and electrophysiology to manipulate and/or monitor the activity of GABAergic SNr neurons during different moments of the task.
In the delayed-Go task, mice were first exposed to an auditory Delay Cue, and after a variable period (Delay Window) in which mice had to refrain from licking, they had to respond to a visual Action Cue by licking a spout to collect a water reward. Trial outcomes included ‘Hit’ (licked in good time in response to the Action Cue), ‘Premature Hit’ (inappropriately licked during the Delay Window) and ‘Miss’ (failed to lick in response to Action Cue). Mice learned to perform the delayed-Go task to satisfactory levels of success (i.e., acceptable rates of Hit trials) in about two weeks of non-consecutive daily sessions. Optogenetically-driving SNr neurons during the Action Cues of Hit trials delayed the reaction time to move (first licks). However, reaction times were shortened in Premature Hit and Hit trials when SNr neurons were optogenetically-driven during specific phases of movement preparation (Delay Cue and Delay Window, respectively). Overall, optogenetic manipulations showed that SNr neuron activity has a causal impact on movement preparation and execution. Electrophysiological recordings revealed that, in Hit trials, many SNr neurons engage in firing-rate modulations around the time of Action Cue and movement onset. Critically, these modulations mainly consisted of increased firing rates. Examination of SNr neuron activity in Premature Hit and Miss trials helped disambiguate the encoding of movement vs. cues. Irrespective of trial type, SNr neurons did not show the ‘ramping up’ activity that is typical of neurons encoding motor preparation. Overall, electrophysiological recordings suggest that most SNr neurons encode the execution of, but not preparation for, licking movements by increasing their firing rates.
In conclusion, my investigations do not support classical models that posit appropriately-timed decreases in the activity of many SNr neurons as the fundamental mechanism that allows movement execution to occur. Furthermore, my studies do not provide evidence of SNr neurons encoding motor preparation with changes in firing rates. Finally, my research suggests that the causal impact of SNr neuron activity on movement depends on context, that is, whether an animal is preparing to move or is executing movement.

Keywords: disinhibition models
Substantia Nigra pars reticulata
optogenetics
Advisor: Magill, P
Nakamura, K