Article Figures & Data
Figures
- Figure 1.
Functional and spatial characterization of DA signaling in the healthy human striatum. A, Diagram of dopaminergic innervation and signaling in the human striatum. B, Diagram of dopaminergic regulation of D1- and D2-SPNs, parts of the direct and indirect pathway, respectively. C, Trace showing DA signaling and the underlying dopaminergic neuronal firing pattern. D, Illustration of overlapping dopaminergic axonal arbors belonging to the same CAC. E, Visualization of dopaminergic axonal arbors in the striatum; each arbor center is marked with a circle. For visibility, only 10% of arbors are shown. Red sphere shows the area subsumed by an arbor from one neuron. Notice that all arbors belong to the same CAC, represented by them all having the same color. F, Heatmap of the distribution of overlapping arbors in the two-dimensional plane denoted in E. G, Distribution of the number of overlapping arbors for each individual arbor. H, Distribution of the smallest distance to the nearest neighboring arbor center for each arbor. Inset, Smallest distance to nearest neighboring arbor center for the most isolated arbors found using Voronoi tessellation. DA, dopamine; SNc, substantia nigra pars compacta; D1, D1-class dopamine receptor; D2, D2-class dopamine receptor; SPN, spiny projection neuron; CACs, contiguous arbor classes. See also Extended Data 1 and Extended Data Figure 1-1.
- Figure 2.
Different denervation patterns break down the dopaminergic network with distinct evolutions. A–C, Diagrams of network mechanism for RD, PLD, and SID. The color of each dopaminergic neuron (circle) corresponds to probability of death. In C, dotted lines denote overlap of arbors. D, Visualization of the dopaminergic axonal arbor network following RD, PLD, and SID. Colors correspond to separate CACs. E, Distributions of the number of overlapping arbors for each individual arbor. F, Distributions of the number of arbors in each CAC. G, Distributions of the smallest distance to the nearest neighboring arbor center for each arbor. Dotted line denotes threshold for classifying isolated areas. In E–G, denervation is 80%. H, Fraction of remaining arbors as a function of time. I, Fraction of arbors belonging to the largest CAC as a function of denervation. J, Fraction of striatal space with smallest distance to nearest arbor larger than 0.1 mm (isolated area) as a function of denervation. In H–J, full line is mean, and shading is SD. RD, random denervation; PLD, prion-like denervation; SID, stress-induced denervation; CACs, contiguous arbor classes; AU, arbitrary unit. See also Extended Data Figure 2-1.
- Figure 3.
Dopaminergic denervation affects cAMP signaling and excitability of striatal SPNs. A, Diagram of how DA stimulates and inhibits the production of cAMP in D1- and D2-SPNs, respectively. B, Traces showing cAMP in D1- and D2-SPNs as a function of DA signaling. C, Maximal cAMP concentration in D1- and D2-SPNs during dopaminergic phasic firing and firing pauses, respectively, as a function of the number of dopaminergic terminals. D–K, Membrane potential dynamics of D1- and D2-SPNs in response to synaptic barrages (D, H), cAMP stimulation (E, I), synaptic barrages in combination with cAMP stimulation in the healthy state (F, J), or synaptic barrages in combination with cAMP stimulation in the 75% denervated state (G, K). Raster plots show the firing rate across time for 100 simulated neurons in each condition. DA, dopamine; D1, D1-class dopamine receptor; D2, D2-class dopamine receptor; SPN, spiny projection neuron; SNc, substantia nigra pars compacta. See also Extended Data Figure 3-1.
- Figure 4.
Distinct denervation patterns differentially affect global striatal SPN firing activity. A, B, Maximal firing activity of D1- and D2-SPNs across space in the healthy and 75% denervated striatum for the three denervation patterns. C, D, Spatial mean and SD of maximal firing activity in D1- and D2-SPNs as a function of denervation. RD, random denervation; PLD, prion-like denervation; SID, stress-induced denervation; D1, D1-class dopamine receptor; D2, D2-class dopamine receptor; SPN, spiny projection neuron.
- Figure 5.
A dual presynaptic compensation strategy preserves DA signaling in the denervated striatum. A, Diagrams of mechanisms of the ERC, DUC, and DEC models. B, Traces showing cAMP in D1- and D2-SPNs as a function of DA signaling at 80% denervation in the compensation models. C, D, Spatial mean and SD of maximal firing activity in D1- and D2-SPNs as a function of denervation pattern and compensation model. E, Spatial mean of maximal firing activity in D1- and D2-SPNs as a function of denervation and compensation model in the randomly denervated striatum. ERC, enhanced release compensation; DUC, decreased uptake compensation; DEC, dual enhanced compensation; NC, no compensation; DA, dopamine; D1, D1-class dopamine receptor; D2, D2-class dopamine receptor; SPN, spiny projection neuron; RD, random denervation; PLD, prion-like denervation; SID, stress-induced denervation. See also Extended Data Figures 5-1, 5-2.
Extended Data
Extended Data 1
Extended Data Equations. Mathematical models and algorithms. Folder containing a detailed description of all mathematical derivations and formulations, biophysical models, and algorithms employed for the study. Download Extended Data 1, ZIP file.
Extended Data Figure 1-1
Model parameters. Table summarizing the biophysical parameter values used for the respective computational models. Download Figure 1-1, TIF file.
Extended Data Figure 2-1
Spatial denervation evolutions are robust to changes in key parameters. A, Effects of varying the volume of axonal arbors (radius: 0.45, 0.5, or 0.55 mm) uniformly across the arbor population in the three denervation models. Upper, Fraction of arbors belonging to the largest CAC as a function of denervation. Lower, Fraction of striatal space with smallest distance to nearest arbor larger than 0.1 mm (isolated area) as a function of denervation. B, Same as in A, but with the volume of arbors following a δ function
Extended Data Figure 3-1
Distinct denervation patterns differentially affect local and global striatal SPN firing activity in the Izhikevich model. A, Membrane potential of D1-SPN (left) and D2-SPN (right) in the healthy and 75% denervated striatum in response to DA signaling, modelled using the Izhikevich model. B, C, Maximal firing activity of D1- and D2-SPNs across space in the healthy and 75% denervated striatum for the three denervation patterns: RD, PLD, and SID. D, E, Spatial mean and SD of maximum firing activity in D1- and D2-SPNs as a function of denervation. SPN, spiny projection neuron; D1, D1-class dopamine receptor; D2, D2-class dopamine receptor; DA, dopamine. Download Figure 3-1, TIF file.
Extended Data Figure 5-1
Three distinct postsynaptic mechanisms fail to preserve DA signaling in the denervated striatum. A–C, Diagrams of the modelled postsynaptic compensatory mechanisms: increased D2 expression (A), enhanced D1 and D2 sensitivity (B), and suppressed cAMP degradation in D1- and D2-SPNs mediated by, for example, a PDE inhibitor (PDE-I; C). D–F, Example traces showing cAMP in D1- and D2-SPNs as a function of DA signaling at 0% and 80% denervation in the different postsynaptic compensation models. DA, dopamine; D2, D2-class dopamine receptor; D1, D1-class dopamine receptor; SPN, spiny projection neuron; PDE, phosphodiesterase. Download Figure 5-1, TIF file.
Extended Data Figure 5-2
A dual presynaptic compensation strategy preserves SPN firing activity in the Izhikevich model in spite of severe denervation. A, B, Spatial mean and SD of maximum firing activity in D1- and D2-SPNs as a function of denervation pattern (RD, PLD, and SID) and compensation model (ERC, DUC, and DEC). C, Spatial mean of maximum firing activity in D1- and D2-SPNs as a function of denervation and compensation model in the randomly denervated striatum. SPN, spiny projection neuron; D1, D1-class dopamine receptor; D2, D2-class dopamine receptor; RD, random denervation; PLD, prion-like denervation; SID, stress-induced denervation; ERC, enhanced release compensation; DUC, decreased uptake compensation; DEC, dual enhanced compensation. Download Figure 5-2, TIF file.
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