Synaptic integration and competition in the substantia nigra pars reticulata—An experimental and in silico analysis
Year: 2025
Type: article
Abstract: The substantia nigra pars reticulata (SNr) is a primary output for basal ganglia signaling. It plays an important role in the control of movement, integrating inputs from upstream structures in the basal ganglia, before sending organized projections to a range of targets in the midbrain, brainstem, and thalamus. Here, we present a detailed in silico model of the mouse SNr, including its major afferent inputs. The electrophysiological and morphological properties of SNr neurons are characterized in acute brain slices via whole cell patch-clamp recordings and morphological reconstruction. Using reconstructed morphologies, multicompartmental models of single neurons are instantiated within the NEURON simulation environment and populated with relevant modeled ion channels. Model parameters are optimized via an evolutionary algorithm, such that simulated neurons faithfully reproduce recorded electrophysiological behavior. Using the simulation infrastructure software Snudda , single neuron models are incorporated into a circuit-level model, where the sparse connectivity within the SNr is recreated. We simulate the mouse SNr at scale, featuring realistic volumes and neuronal density. The unique synaptic properties and activity patterns of different afferent sources are captured in silico. Born out of ex vivo data, our model reproduces in vivo firing patterns. Our simulations suggest that paradoxical activity increases in response to experimental inhibition can be explained by lateral connectivity. In addition, our model predicts the functional implications of characteristic short-term synaptic plasticity in the indirect pathway of the basal ganglia. The model can be extended to include additional inputs and be connected with existing models of upstream basal ganglia nuclei to further explore circuit dynamics.
Language: English
Subfield: Cognitive Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Funders: Digital Futures, Michael J. Fox Foundation for Parkinson's Research, Swedish e-Science Research Centre, European Commission, Hjärnfonden, Karolinska Institutet, Knut och Alice Wallenbergs Stiftelse, Vetenskapsrådet, Science for Life Laboratory, Horizon 2020 Framework Programme, HORIZON EUROPE Framework Programme, HORIZON EUROPE Marie Sklodowska-Curie Actions
Awards: The Human Brain Project, G119252271, Virtual Brain Twin for personalised treatment of Psychiatric Disorders, THE SALIENCE CODING OF DOPAMINE NEURONS AND THEIR DOWNSTREAM EFFECTS ON VISUAL ATTENTION, G1740413602, G2060760749, Neuronal networks of the vertebrate motor system - evolutionarily conserved forebrain control strategies., G2225227269, Brain circuits for sensorimotor decision-making in health and disease., G2355540278, G2789362503, G2797231845, G2866793618, G3012102041, G3171461300, G3230126847, EBRAINS 2.0: A Research Infrastructure to Advance Neuroscience and Brain Health, G3635708190, G3660798674, G3936970252, G429341009, Data-driven multiscale modeling and simulation of the striatum, G5942894660, Functional Multitasking by Striatal Networks in Health and Disease., G6091493096, G6133111771, European School of Network Neuroscience, G6523014278, Neuronal networks of the vertebrate motor system - evolutionarily conserved forebrain control strategies., G7629236453, G8301431789, G8441428806, Human Brain Project Specific Grant Agreement 3, G8791494362, G8845930637, NAISS
OpenAlex ID: W7116759622