On the substantia nigra pars reticulata : intrinsic function and descending control

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The substantia nigra pars reticulata (SNr) is the primary output nucleus of the basal ganglia, exerting tonic inhibitory control over midbrain, hindbrain, and thalamic targets. Descending afferents, in turn, govern SNr dynamics, ultimately regulating the inhibitory output of the basal ganglia. This thesis presents two complementary studies dissecting synaptic control of the mouse SNr, combining electrophysiological, anatomical, and behavioural strategies with computational approaches.Paper I describes the development of a data-driven in silico model of the SNr. Using the NEURON simulation environment, multicompartmental neuron models were generated from morphological reconstructions of GABAergic SNr neurons. Parameters were optimised such that simulated neurons replicated electrophysiological recordings. Single neurons were incorporated into a full- scale model of the SNr, with a realistic volume, appropriate cell density, sparse interconnectivity, and major input. The network reproduced in vivo-like firing patterns when driven with realistic afferent activity. Simulations suggested that intranigral connectivity is sufficient to account for accounts of paradoxical excitatory responses observed following striatal activation in vivo. Additionally, short-term depression at pallidonigral synapses was shown to confer sensitivity to the duration of pauses in pallidal firing, providing a potential synaptic mechanism for history-dependent modulation of SNr output. This simulation platform is open-source, dynamic, and can be used to test novel hypotheses.Paper II demonstrated the existence of monosynaptic glutamatergic input from the primary (M1) and secondary (M2) motor cortices to GABAergic neurons in the SNr. Viral-targeted optogenetic activation of cortical axon terminals in acute brain slices evoked glutamate-mediated excitatory postsynaptic potentials in subpopulations of SNr neurons. M1 and M2 were found to target electrophysiologically and spatially distinct SNr subpopulations. Chemogenetic inhibition of the distinct cortical-recipient subpopulations in vivo produced contrasting effects on locomotor behaviour, suggesting functionally divergent roles for the targeted neurons. These findings extend the canonical model of cortico-basal ganglia connectivity and highlight the SNr as a site of direct cortical influence on basal ganglia output.Papers III and IV review principles of basal ganglia structure and physiology, with specific emphasis on the modularisation of basal ganglia circuits, and the organisation of projections to motor centres.Together these studies expand collective comprehension of the organisation of SNr afferents and, ultimately, how these connections control basal ganglia output. Understanding how different signals propagate through cortico-basal ganglia circuits and are integrated in the output stages is central to interpreting both healthy brain function and pathological disruptions.List of scientific papersI. Synaptic integration and competition in the substantia nigra pars reticulata-An experimental and in silico analysis. Thompson W. S., Hjorth J.J.J., Kozlov A., Thunberg W., Silberberg G., Hellgren-Kotaleski J., Grillner S. Proceedings of the National Academy of Sciences. 2025. https://doi.org/10.1073/pnas.2528602122II. Motor cortex directly excites the substantia nigra pars reticulata, the basal ganglia output nucleus. Thompson W. S., Wekwejt P., Grillner S., Silberberg G. Nature Communications. 2026. https://doi.org/10.1038/s41467-026-74569-wIII. The Basal Ganglia Downstream Control of Action - An Evolutionarily Conserved Strategy. Frost-Nylen J., Thompson W. S., Robertson B., Grillner S. Current Neuropharmacology. 2023. https://doi.org/10.2174/1570159X21666230810141746IV. Basal ganglia reign through downstream control of motor centers in midbrain and brain stem while updating cortex with efference copy information. Grillner S., Thompson W. S. Neuron. 2021. https://doi.org/10.1016/j.neuron.2021.04.015