Article Figures & Data
Figures
- Figure 1.
Schematic view of denervation processes in rodent striatum and summary of idealized biophysical models. A–D, Gradual denervation leads to a complex innervation landscape. Gray scale, Denervation; black, intact; white, completely denervated. Red dashed lines show the boundary for fully depleted areas. A, A single neuron is lost (gray scale exaggerated for illustration). The miniature green cube illustrates the simulation volume of E (not to scale). B, Multiple neurons are lost, but voids are absent. The miniature green cube illustrates the simulation volume of F (not to scale). C, Void nucleated at critical neuron loss (arrow). D, Late-stage PD: few neurons left, voids dominate. E, Micrometer-scale simulation volume for intact striatum. F, Ninety percent depleted (simulation volumes around 20 μm diameter). G, Continuum model of DA void; the typical void radius is from 100 to 500 μm.
- Figure 2.
Effect of partial denervation on tonic and phasic DA signaling. A, C, E, Example time series of DA signals from tonic and phasic firing with different innervation density. Blue, Intact; green, 50% denervated; red, 98% denervated; black, 75% denervated and simulated l-dopa therapy. B, D, F, Summary of tonic and phasic DA signals as a function of denervation. Solid blue line, Averages from tonic firing patterns; top dashed blue line, peak level during phasic signals; bottom dashed blue line, minimum level during phasic signals; solid and dashed black line, same, but for simulation of l-dopa therapy. A, Lines indicate DA levels; black raster plots indicate spikes of 15 DA neurons with common tonic (t < 6 s) and phasic (t > 6 s) firing patterns. B, Summary of tonic and phasic DA. The light blue shade indicates ±SD of DA from tonic cell firing. Inset, DA levels at high denervation. The green line shows the effect of 10 times increased nonspecific uptake. C, Tonic and phasic activation of low-affinity D1 receptors. D, Summary of low-affinity D1 receptors (only top dashed line shown). E, Tonic and phasic activation of D2 receptors. F, Summary of high-affinity D2 receptors (only bottom dashed line shown). Colored symbols in B, D, and F indicate conditions shown in A, C, and E.
- Figure 3.
Production of SM by phasic DA signaling and adaptation. A, DA levels for tonic (t < 120 s) and phasic (t > 120 s) DA firing pattern for different degrees of denervation (blue, 0% intact). B, Uncompensated cumulative production of SMs by D1-regulated cascade (blue, intact; green, 75% denervated; red, 97% denervated). C, Same for D2 receptors. D, Blue, ND1 (the sensitivity of the D1-mediated signals for high denervation; blue); black, mean increase in ND1 under l-dopa; green dashed, ND1 = 1. Shades indicate ±SD from n = 4 simulations. E, Same for ND2.
- Figure 4.
Postsynaptic compensation leads to false signals, partly alleviated by l-dopa. A, ΔSMD1, the rate of SM production in D1-regulated cascades, by tonic (t < 120 s) and phasic (t > 120s) DA firing patterns at different degrees of denervation. B, Same for ΔSMD2. C, Rate of SM production in D1-regulated cascades under simulation of l-dopa therapy. Black, Adapted to l-dopa; red, before adaptation. D, Same for D2. E, Relative increase in residual tonic ΔSMD1 as function of denervation. Blue, Unmedicated; black, adapted to l-dopa; red, before adaptation to l-dopa (inset only). The black dashed line level of ΔSMD1 by phasic firing in the intact. Shades indicate ±SD (n = 4 simulations). F, Relative increase in residual ΔSMD2 by tonic firing. Same colors as in E. Dashed line indicates level of ΔSMD2 by phasic firing in the intact.
- Figure 5.
Effect of uptake inhibition on tonic and phasic DA signals in intact (A, D, G) and denervated striatum (B, E, H). Columns 1 and 2: dark red, no uptake inhibition (0 mg/kg); bright red, equivalent of 6 mg/kg, i.p., cocaine; orange, equivalent of 15 mg/kg, i.p., cocaine. For t < 2 s, tonic firing; for t > 2 s, phasic firing. Column 3, Summary of uptake inhibition with a different degree of denervation. Dashed lines indicate peak (C, F, top) and minimum (C, I, bottom) during phasic firing. Blue, Intact; green, 50% denervated; red, 85% denervated. Solid blue lines indicate effect of uptake inhibition for levels during tonic firing for same the degree of denervation (3 lines are nearly coinciding). Markers indicate doses shown in columns 1 and 2. A, Effect of uptake inhibition on DA levels in the intact. B, Same as A, but with 50% denervation. C, Summary of DA levels. D, Effect of uptake inhibition on D1 activation in the intact. E, Same as D, but with 50% denervation. F, Summary of D1 activation. G, Effect of uptake inhibition on D2 activation in the intact. H, Same as G, but with 50% denervation. I, Summary of D2 activation.
- Figure 6.
Effect of voids on steady-state DA levels. A, Time scale for reaching 50% of steady-state value as a function of void size. B, Steady-state DA concentration as a function of distance to the void center. Cyan, Rvoid = 100 μm; violet, Rvoid = 200 μm; pink, Rvoid = 400 μm. Inset, DA concentration around the void edge. The black dashed line indicates the 10 nm level. C, DA concentration in center concentration as a function of void size. Blue, Control; black, simulation of l-dopa therapy. D, Volume with a critically low DA level as a function of void size. Blue, Control; black, simulation of l-dopa therapy.
