Abstract
As a rodent basal ganglia (BG) output nucleus, the substantia nigra pars reticulata (SNr) is well positioned to impact behavior. SNr neurons receive GABAergic inputs from the striatum (direct pathway) and globus pallidus (GPe, indirect pathway). Dominant theories of action selection rely on these pathways' inhibitory actions. Yet, experimental results on SNr responses to these inputs are limited and include excitatory effects. Our study combines experimental and computational work to characterize, explain, and make predictions about these pathways. We observe diverse SNr responses to stimulation of SNr-projecting striatal and GPe neurons, including biphasic and excitatory effects, which our modeling shows can be explained by intracellular chloride processing. Our work predicts that ongoing GPe activity could tune the SNr operating mode, including its responses in decision-making scenarios, and GPe output may modulate synchrony and low-frequency oscillations of SNr neurons, which we confirm using optogenetic stimulation of GPe terminals within the SNr.
Highlights
The substantia nigra pars reticulata (SNr) is the primary output nucleus of the rodent basal ganglia (BG) and likely plays a key role in the behavioral functions, such as decision-making and action selection, suppression, or tuning, to which the BG contribute
Earlier experiments showed excitatory effects along with inhibitory ones from stimulation of SNr-projecting Str neurons in vivo (Freeze et al, 2013), which could relate to chloride regulation as well. To study this complex combination of effects and their possible functional consequences, we developed a computational model of an SNr neuron including somatic and dendritic compartments and the corresponding GABAergic inputs as well as the dynamics of intracellular chloride and EGABA
The convergence of multiple GABAA receptor-mediated synaptic input streams onto individual neurons, such as pyramidal neurons in cortex, represents a common scenario in neural circuitry, and our results suggest that intracellular Cl* levels should be considered in analyzing the integration of GABAergic inputs by neurons in brain regions beyond the SNr
Summary
The substantia nigra pars reticulata (SNr) is the primary output nucleus of the rodent basal ganglia (BG) and likely plays a key role in the behavioral functions, such as decision-making and action selection, suppression, or tuning, to which the BG contribute. The SNr exhibits intrinsic spiking activity, resulting in ongoing GABAergic outputs to speci c thalamic sites, which are believed to suppress unwanted or spurious movements. Indirect pathway GABAergic projections to SNr arise from the external segment of the globus pallidus (GPe), which engages in tonic spiking activity; occur via basket-like synapses around the soma of SNr neurons; and exhibit short-term depression. The ongoing activity of GPe neurons would likely induce a large tonic chloride load on SNr neurons, potentially depolarizing the GABA reversal potential, EGABA
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