{ "paper": "ejdrup-2026-dopamine", "claims": 25, "panels": { "total": [ "fig1a", "fig1b", "fig1c", "fig1d", "fig1e", "fig1f", "fig1g", "fig1h", "fig1i", "fig1j", "fig1s1a", "fig1s1b", "fig1s1c", "fig1s1d", "fig1s1e", "fig1s1f", "fig1s1g", "fig1s1h", "fig1s2a", "fig1s2b", "fig1s2c", "fig1s2d", "fig1s2e", "fig1s2f", "fig2a", "fig2b", "fig2c", "fig2d", "fig2e", "fig2f", "fig2g", "fig2h", "fig2s1a", "fig2s1b", "fig2s1c", "fig2s1d", "fig2s1e", "fig2s1f", "fig3a", "fig3b", "fig3c", "fig3d", "fig3e", "fig3f", "fig3g", "fig3h", "fig3i", "fig3j", "fig3k", "fig3l", "fig3s1a", "fig3s1b", "fig3s1c", "fig3s1d", "fig3s1e", "fig3s1f", "fig3s1g", "fig3s2a", "fig3s2b", "fig3s2c", "fig3s2d", "fig3s2e", "fig3s2f", "fig4a", "fig4b", "fig4c", "fig4d", "fig4e", "fig4f", "fig4g", "fig4h", "fig4i", "fig4j", "fig4k", "fig4l", "fig4m", "fig4n", "table1", "keyresource", "app2table1", "app2table2" ], "orphan": [ "fig1a", "fig1b", "fig1c", "fig1i", "fig1j", "fig1s1a", "fig1s1b", "fig1s1c", "fig1s1d", "fig1s1e", "fig1s1f", "fig1s1g", "fig1s1h", "fig1s2a", "fig1s2b", "fig1s2c", "fig1s2d", "fig1s2e", "fig1s2f", "fig2f", "fig2h", "fig2s1a", "fig2s1b", "fig2s1c", "fig2s1d", "fig2s1e", "fig2s1f", "fig3a", "fig3d", "fig3h", "fig3i", "fig3j", "fig3k", "fig3l", "fig3s1a", "fig3s1b", "fig3s1c", "fig3s1d", "fig3s1e", "fig3s1f", "fig3s1g", "fig3s2a", "fig3s2b", "fig3s2c", "fig3s2d", "fig3s2e", "fig3s2f", "fig4a", "fig4b", "fig4h", "fig4i", "fig4j", "fig4k", "fig4l", "fig4m", "fig4n", "table1", "keyresource", "app2table1", "app2table2" ], "figure_level": [ "fig2s1" ], "phantom": [], "pct": 25.9 }, "statistics": { "total": 3, "orphan": [], "pct": 100.0 }, "spans": { "segmented": 513, "obligations": 227, "textual": 286, "accounted": 118, "pct": 52.0, "orphans": [ { "uid": "results-002", "section": "results", "text": "DA release sites on axons projecting from the midbrain were randomly simulated as uniformly distributed discrete points in a three-dimensional space ( Figure 1A ).", "stats": [], "panels": [ "fig1a" ] }, { "uid": "results-024", "section": "results", "text": "( A ) Average DA concentration across a 100 x 100 \u00d7 100 \u00b5m volume of simulated DS at pacemaker activity.", "stats": [], "panels": [ "fig1a" ] }, { "uid": "results-025", "section": "results", "text": "( B ) Mean concentration change in response to a single event with 60% release probability (see supplementary notes on electrical stimulation) in all neurons at time zero.", "stats": [], "panels": [ "fig1b" ] }, { "uid": "results-027", "section": "results", "text": "( C ) Modelling of predicted FSCV measurement and representative snapshot of simulation space just after a release event.", "stats": [], "panels": [ "fig1c" ] }, { "uid": "results-035", "section": "results", "text": "Figure 1\u2014figure supplement 1\u2014source code 1. Source code used to generate data in Figure 1\u2014figure supplement 1 .", "stats": [], "panels": [ "fig1s1" ] }, { "uid": "results-036", "section": "results", "text": "Figure 1\u2014figure supplement 2. Simulation size and granularity.", "stats": [], "panels": [ "fig1s2" ] }, { "uid": "results-037", "section": "results", "text": "( A ) Schematic of different simulation sizes.", "stats": [], "panels": [ "fig1s2a" ] }, { "uid": "results-038", "section": "results", "text": "( B ) Concentration percentiles at different simulation diameters.", "stats": [], "panels": [ "fig1s2b" ] }, { "uid": "results-040", "section": "results", "text": "( C ) Schematic of simulation granularity.", "stats": [], "panels": [ "fig1s2c" ] }, { "uid": "results-041", "section": "results", "text": "( D ) Effect of simulation voxel diameter on concentration percentiles.", "stats": [], "panels": [ "fig1s2d" ] }, { "uid": "results-044", "section": "results", "text": "( E ) Absolute difference in [DA] between simulations at 0.1 \u00b5m voxel diameter and 0.5, 1.0, and 2.0 \u00b5m.", "stats": [], "panels": [ "fig1s2e" ] }, { "uid": "results-046", "section": "results", "text": "( F ) Percentage difference in [DA] between simulations at 0.1 \u00b5m voxel diameter and 0.5, 1.0, and 2.0 \u00b5m.", "stats": [], "panels": [ "fig1s2f" ] }, { "uid": "results-047", "section": "results", "text": "Figure 1\u2014figure supplement 2\u2014source code 1. Source code used to generate data in Figure 1\u2014figure supplement 2 .", "stats": [], "panels": [ "fig1s2" ] }, { "uid": "results-068", "section": "results", "text": "Importantly, our model faithfully mirrored DA release seen with fast-scan cyclic voltammetry (FSCV) recordings upon direct stimulation of striatal slices when we corrected for kinetics of the typical FSCV recording setup ( Figure 1\u2014figure supplement 1A, B and Appendix 1 - supplementary text) ( Atcherley et al., 2015 ; Brimblecombe et al., 2019 ; Stuber et al., 2010 ; Xie et al., 2020 ).", "stats": [], "panels": [ "fig1s1" ] }, { "uid": "results-073", "section": "results", "text": "Further, when we calculated the average concentration of a larger area across time, which fibre photometry conceivably does, the results resembled a tonic DA concentration ( Figure 1\u2014figure supplement 1C ).", "stats": [], "panels": [ "fig1s1" ] }, { "uid": "results-075", "section": "results", "text": "Table 1. List of variables used in the simulation of the dorsal striatum.", "stats": [], "panels": [ "table1" ] }, { "uid": "results-076", "section": "results", "text": "Variable Abbreviation Value Reference Firing rate 4 Hz Paladini et al., 2003 Release probability 6% Dreyer et al., 2010 DA molecules per vesicle 3000 Klaus et al., 2019 Diffusion coefficient 763 \u00b5m 2 s -1 Nicholson, 1995 Tortuosity 1.54 Rice and Nicholson, 1991 Vmax 6.0 \u00b5m s -1 See Appendix 2\u2014table 2 Km 210 nM Hovde et al., 2019 Active terminal density - 0.04 \u00b5m -3 Liu et al., 2021 Extracellular volume fraction 0.21 Rice and Nicholson, 1991 Number of neurons in simulation space - 150 Matsuda et al., 2009 To ensure our simulations were performed within a sufficiently large space to yield consistent results, we tested different sizes of the simulated area and found a diameter of 50 \u03bcm to faithfully mimic the results of larger simulations ( Figure 1\u2014figure supplement 2A, B ).", "stats": [], "panels": [ "app2table2", "fig1s2" ] }, { "uid": "results-078", "section": "results", "text": "The finer the spatial grain, the higher the detail close to a release event; however, at a spatial granularity of 1 \u03bcm, [DA] deviated by <2% across most percentiles and only by >1 nM above the 99.5 th percentile ( Figure 1\u2014figure supplement 2C-F ), leading us to use this voxel size for our simulations.", "stats": [], "panels": [ "fig1s2" ] }, { "uid": "results-085", "section": "results", "text": "The relationship between firing rate and the sphere of influence by DA became further evident when plotting maximal concentration of the surrounding space ( Figure 1\u2014figure supplement 1D ) and the volume of space with a DA concentration above 100 nM ( Figure 1\u2014figure supplement 1E ).", "stats": [], "panels": [ "fig1s1" ] }, { "uid": "results-091", "section": "results", "text": "D1 receptors (-Rs) were assumed to have a half maximal effective concentration (EC 50 ) of 1000 nM, and we extrapolated the reverse rate constant ( k off ) to 19.5 s \u20131 based on a linear fit of the recently characterised DA-receptor-based sensors ( Figure 1\u2014figure supplement 1E ; Labouesse and Patriarchi, 2021 ).", "stats": [], "panels": [ "fig1s1" ] }, { "uid": "results-092", "section": "results", "text": "We set the EC 50 of D2Rs to 7 nM and k off to 0.2 s \u20131 based on the DA sensor kinetic fit ( Figure 1\u2014figure supplement 1F ), which matches a recent binding study (0.197 s \u20131 for binding study vs. 0.204 s \u20131 based on linear fit), indicating the receptor-based sensor fit can be extrapolated to the endogenous receptors ( \u00c5gren et al., 2021 ).", "stats": [], "panels": [ "fig1s1" ] }, { "uid": "results-100", "section": "results", "text": "This made the D2R incapable of temporally separating closely linked bursts of activity and rather summarised the output, whereas the D1R occupancy reset between each individual burst ( Figure 1\u2014figure supplement 1G ).", "stats": [], "panels": [ "fig1s1" ] }, { "uid": "results-102", "section": "results", "text": "Indeed, this finding was robust across an order of magnitude of D2R affinity (2 nm - 20 nM), although the sensitivity to a one-second pause was larger at an affinity of 20 nM ( Figure 1\u2014figure supplement 1H ).", "stats": [], "panels": [ "fig1s1" ] }, { "uid": "results-106", "section": "results", "text": "In line with this, most studies report lower dopaminergic density in the VS than in DS regardless of methodological modality with a median value of ~90% in VS relative to DS ( Appendix 2\u2014table 1 ).", "stats": [], "panels": [ "app2table1" ] }, { "uid": "results-107", "section": "results", "text": "Further, DAT-mediated uptake capacity is reported to be lower in VS with a median capacity at ~30% of DS ( Appendix 2\u2014Tables 1 and 2 ).", "stats": [], "panels": [ "table1" ] }, { "uid": "results-110", "section": "results", "text": "We simulated DA release during pacemaker activity in both DS and VS. DS values were set as previously described (25 \u00b5m 3 per terminal, uptake capacity of 6.0 \u03bcM s \u20131 ), but for VS we reduced the terminal density to 90% (27.8 \u00b5m 3 per terminal) and DAT uptake capacity to 33% (2.0 \u00b5M s \u20131 ) ( Appendix 2\u2014Tables 1 and 2 ).", "stats": [], "panels": [ "table1" ] }, { "uid": "results-133", "section": "results", "text": "( H ) Peak occupancy at different distances from the area bursting, normalised to maximal and minimum occupancy.", "stats": [], "panels": [ "fig2h" ] }, { "uid": "results-143", "section": "results", "text": "( F ) Effect of complete pause in firing in VS for 1 s on both average [DA] and D1R and D2R occupation.", "stats": [], "panels": [ "fig2f" ] }, { "uid": "results-155", "section": "results", "text": "Additionally, the larger DA overflow in VS after a burst caused a higher relative increase in receptor occupancy further away from the area actively bursting than compared to DS ( Figure 2H ).", "stats": [], "panels": [ "fig2h" ] }, { "uid": "results-157", "section": "results", "text": "Changes to uptake capacity greatly affect [DA] in the ventral striatum The values used to model the striatum ( Table 1 ) in the previous simulations were chosen to best mimic the physiological system found in vivo.", "stats": [], "panels": [ "table1" ] }, { "uid": "results-159", "section": "results", "text": "First, we varied the number of varicosities actively releasing DA by setting the varicosity density to one site per 9 \u00b5m 3 ( Doucet et al., 1986 ) and simulating 4 Hz pacemaker activity with the release-capable fraction ranging from 5% to 100% (reported values range from 20% to virtually all) ( Ducrot et al., 2021 ; Liu et al., 2021 ; Liu et al., 2018 ; Pereira et al., 2016 ; Figure 3A ).", "stats": [], "panels": [ "fig3a" ] }, { "uid": "results-166", "section": "results", "text": "( A ) Schematic of the fraction of active release sites.", "stats": [], "panels": [ "fig3a" ] }, { "uid": "results-171", "section": "results", "text": "( D ) Schematic of changing quantal size ( Q ).", "stats": [], "panels": [ "fig3d" ] }, { "uid": "results-175", "section": "results", "text": "( H ) Schematic of changing DAT K m .", "stats": [], "panels": [ "fig3h" ] }, { "uid": "results-179", "section": "results", "text": "Shaded areas are median V max of the two regions (DS and VS) as found in the literature shown in Appendix 2\u2014table 2 \u00b1 50%.", "stats": [], "panels": [ "app2table2" ] }, { "uid": "results-181", "section": "results", "text": "The shaded area indicates median V max for VS found in the literature shown in Appendix 2\u2014table 2 \u00b1 50%.", "stats": [], "panels": [ "app2table2" ] }, { "uid": "results-183", "section": "results", "text": "( A ) Schematic of our definitions of tonic (50 th percentile/median, dashed lines) and peak (99.5 th percentile, solid line) DA for both the dorsal and ventral striatum.", "stats": [], "panels": [ "fig3a" ] }, { "uid": "results-186", "section": "results", "text": "( D ) Ratio between 99.5 th and 50 th percentiles as a measure of focality for both regions.", "stats": [], "panels": [ "fig3d" ] }, { "uid": "results-192", "section": "results", "text": "Figure 3\u2014figure supplement 1\u2014source code 1. Source code used to generate data in Figure 3\u2014figure supplement 1 .", "stats": [], "panels": [ "fig3s1" ] }, { "uid": "results-193", "section": "results", "text": "Figure 3\u2014figure supplement 2. Fold change during inhibition, V max -sensitivity at different release parameters and release-uptake balance.", "stats": [], "panels": [ "fig3s2" ] }, { "uid": "results-194", "section": "results", "text": "( A ) Fold change over baseline (K m of 210 nM) for mean DA concentration in the dorsal (DS) and ventral striatum (VS) with changing DAT K m .", "stats": [], "panels": [ "fig3s2a" ] }, { "uid": "results-195", "section": "results", "text": "( B ) Relative difference between the dorsal and ventral striatum for both phasic and tonic DA at different K m values.", "stats": [], "panels": [ "fig3s2b" ] }, { "uid": "results-196", "section": "results", "text": "( C ) Effect of changing DAT V max on DA concentrations for three different quantal sizes ( Q ).", "stats": [], "panels": [ "fig3s2c" ] }, { "uid": "results-197", "section": "results", "text": "[DA] normalised to highest values within each Q. Shaded area indicates median V max for DS and VS as found in the literature shown in Appendix 2\u2014table 2 with \u00b150%.", "stats": [], "panels": [ "app2table2" ] }, { "uid": "results-198", "section": "results", "text": "( D ) Effect of changing DAT V max on DA concentrations for three different release probabilities (R % ).", "stats": [], "panels": [ "fig3s2d" ] }, { "uid": "results-200", "section": "results", "text": "Shaded area indicates median V max for DS and VS as found in the literature shown in Appendix 2\u2014table 2 with \u00b150%.", "stats": [], "panels": [ "app2table2" ] }, { "uid": "results-201", "section": "results", "text": "( E ) Least-square fit linear regression between release rate and autocorrelation decay rate (\u03c4) ( Ejdrup et al., 2023 ).", "stats": [], "panels": [ "fig3s2e" ] }, { "uid": "results-203", "section": "results", "text": "( F ) Partial regression plot error of the regression in ( f ) and error between DA response to amphetamine as measured by microdialysis and the release rate from Ejdrup et al., 2023 to show that the less release and uptake correlate, the less release rate can explain the microdialysis response, suggesting release and uptake are partially independent of each other.", "stats": [], "panels": [ "fig3s2f" ] }, { "uid": "results-205", "section": "results", "text": "Figure 3\u2014figure supplement 2\u2014source code 1. Source code used to generate data in Figure 3\u2014figure supplement 2A-D .", "stats": [], "panels": [ "fig3s2" ] }, { "uid": "results-206", "section": "results", "text": "The predicted total DA content of a vesicle and the fraction of content released per fusion event is reported to range from 1,000\u201330,000 molecules ( Garris et al., 1994 ; Pothos et al., 1998 ; Staal et al., 2004 ; Sulzer and Pothos, 2000 ; Figure 3D ).", "stats": [], "panels": [ "fig3d" ] }, { "uid": "results-211", "section": "results", "text": "We observed a largely similar pattern when changing either release probability or firing rate ( Figure 3\u2014figure supplement 1B-G ).", "stats": [], "panels": [ "fig3s1" ] }, { "uid": "results-213", "section": "results", "text": "To mimic competitive inhibition of DAT by, for example cocaine, we ran a simulation across various K m values ( Figure 3H ) showing that increasing K m caused a linear increase in DA levels, consistent with DAT uptake rate responding almost linearly to increases in [DA] below K m ( Figure 3I ).", "stats": [], "panels": [ "fig3h" ] }, { "uid": "results-216", "section": "results", "text": "Further, we observe a convergence on a twofold difference in the absolute values at both tonic and peak levels, which matches reports from earlier FSCV studies ( Figure 3\u2014figure supplement 2B ; Wu et al., 2001 ).", "stats": [], "panels": [ "fig3s2" ] }, { "uid": "results-220", "section": "results", "text": "Further, the impact of changing V max in VS was independent of both Q and R % within values typically reported in the literature ( Figure 3\u2014figure supplement 2C, D ).", "stats": [], "panels": [ "fig3s2" ] }, { "uid": "results-223", "section": "results", "text": "We therefore reanalysed data from our previously published comparison of fibre photometry and microdialysis ( Ejdrup et al., 2023 ) and found evidence of natural variations in the release-uptake balance of the mice ( Figure 3\u2014figure supplement 2E, F ), which may underlie different tonic levels of DA in the striatum between animals.", "stats": [], "panels": [ "fig3s2" ] }, { "uid": "results-228", "section": "results", "text": "We speculated that dense nanoclusters of DAT would produce domains of low [DA] due to uptake overpowering diffusion ( Figure 4A ).", "stats": [], "panels": [ "fig4a" ] }, { "uid": "results-229", "section": "results", "text": "As the uptake rate is concentration dependent, this would reduce uptake efficiency ( Figure 4B ).", "stats": [], "panels": [ "fig4b" ] }, { "uid": "results-248", "section": "results", "text": "( A ) Schematic of dense DA cluster.", "stats": [], "panels": [ "fig4a" ] }, { "uid": "results-250", "section": "results", "text": "( B ) Effective transport rate dependent on local concentration.", "stats": [], "panels": [ "fig4b" ] }, { "uid": "results-260", "section": "results", "text": "( H ) Difference between DA concentration at the centre of clusters (or general surface of varicosity for unclustered) and mean concentration of the full simulation space ( I ) Concentrations across a cross section of a surface with 80 nm diameter clusters.", "stats": [], "panels": [ "fig4h" ] }, { "uid": "discussion-011", "section": "discussion", "text": "But our modelling suggested this is prevented by the significant DA uptake capacity of the DS, as measured by more recent reuptake studies (see Appendix 2\u2014table 2 ).", "stats": [], "panels": [ "app2table2" ] }, { "uid": "captions-021", "section": "captions", "text": "( A ) Average DA concentration across a 100 x 100 \u00d7 100 \u00b5m volume of simulated DS at pacemaker activity.", "stats": [], "panels": [ "fig1a" ] }, { "uid": "captions-022", "section": "captions", "text": "( B ) Mean concentration change in response to a single event with 60% release probability (see supplementary notes on electrical stimulation) in all neurons at time zero.", "stats": [], "panels": [ "fig1b" ] }, { "uid": "captions-024", "section": "captions", "text": "( C ) Modelling of predicted FSCV measurement and representative snapshot of simulation space just after a release event.", "stats": [], "panels": [ "fig1c" ] }, { "uid": "captions-032", "section": "captions", "text": "Figure 1\u2014figure supplement 1\u2014source code 1. Source code used to generate data in Figure 1\u2014figure supplement 1 .", "stats": [], "panels": [ "fig1s1" ] }, { "uid": "captions-033", "section": "captions", "text": "[panels detected: a, b, c, d, e, f, g, h] === Figure 1s2 === Figure 1\u2014figure supplement 2. Simulation size and granularity.", "stats": [], "panels": [ "fig1s2" ] }, { "uid": "captions-034", "section": "captions", "text": "( A ) Schematic of different simulation sizes.", "stats": [], "panels": [ "fig1s1a" ] }, { "uid": "captions-035", "section": "captions", "text": "( B ) Concentration percentiles at different simulation diameters.", "stats": [], "panels": [ "fig1s1b" ] }, { "uid": "captions-037", "section": "captions", "text": "( C ) Schematic of simulation granularity.", "stats": [], "panels": [ "fig1s1c" ] }, { "uid": "captions-038", "section": "captions", "text": "( D ) Effect of simulation voxel diameter on concentration percentiles.", "stats": [], "panels": [ "fig1s1d" ] }, { "uid": "captions-041", "section": "captions", "text": "( E ) Absolute difference in [DA] between simulations at 0.1 \u00b5m voxel diameter and 0.5, 1.0, and 2.0 \u00b5m.", "stats": [], "panels": [ "fig1s1e" ] }, { "uid": "captions-043", "section": "captions", "text": "( F ) Percentage difference in [DA] between simulations at 0.1 \u00b5m voxel diameter and 0.5, 1.0, and 2.0 \u00b5m.", "stats": [], "panels": [ "fig1s1f" ] }, { "uid": "captions-044", "section": "captions", "text": "Figure 1\u2014figure supplement 2\u2014source code 1. Source code used to generate data in Figure 1\u2014figure supplement 2 .", "stats": [], "panels": [ "fig1s2" ] }, { "uid": "captions-046", "section": "captions", "text": "( A ) Representative snapshots of steady state dynamics at 4 Hz tonic firing with parameters mirroring the dorsal (left) and ventral striatum (right).", "stats": [], "panels": [ "fig1s2a" ] }, { "uid": "captions-047", "section": "captions", "text": "( B ) Cross-section of temporal dynamics for data shown in a.", "stats": [], "panels": [ "fig1s2b" ] }, { "uid": "captions-049", "section": "captions", "text": "( C ) Normalised density of DA concentration of simulations in ( a ).", "stats": [], "panels": [ "fig1s2c" ] }, { "uid": "captions-052", "section": "captions", "text": "( D ) Same data as in ( c ), but for concentration percentiles.", "stats": [], "panels": [ "fig1s2d" ] }, { "uid": "captions-054", "section": "captions", "text": "( E ) Convolved model response (Figure S1c) to mimic FSCV measurements mirroring the experimentally tested stimulation paradigm in May and Wightman, 1989 for the dorsal (left) and ventral striatum (right) ( F ) DA release during three burst activity scenarios for all release sites in a 10 x 10 \u00d7 10 \u00b5m cube (black boxes) and spill-over into the surrounding space.", "stats": [], "panels": [ "fig1s2e", "fig1s2f" ] }, { "uid": "captions-060", "section": "captions", "text": "( G ) Top: representative [DA] trace 1 \u00b5m away from a release site during pacemaker and burst activity.", "stats": [], "panels": [ "fig1s2g" ] }, { "uid": "captions-063", "section": "captions", "text": "( H ) Peak occupancy at different distances from the area bursting, normalised to maximal and minimum occupancy.", "stats": [], "panels": [ "fig1s2h" ] }, { "uid": "captions-073", "section": "captions", "text": "( F ) Effect of complete pause in firing in VS for 1 s on both average [DA] and D1R and D2R occupation.", "stats": [], "panels": [ "fig2f" ] }, { "uid": "captions-082", "section": "captions", "text": "( F ) Ratio between peak and tonic concentrations across various quantal sizes in in DS (blue line) and VS (red line).", "stats": [], "panels": [ "fig2f" ] }, { "uid": "captions-084", "section": "captions", "text": "( H ) Schematic of changing DAT K m .", "stats": [], "panels": [ "fig2h" ] }, { "uid": "captions-088", "section": "captions", "text": "Shaded areas are median V max of the two regions (DS and VS) as found in the literature shown in Appendix 2\u2014table 2 \u00b1 50%.", "stats": [], "panels": [ "app2table2" ] }, { "uid": "captions-090", "section": "captions", "text": "The shaded area indicates median V max for VS found in the literature shown in Appendix 2\u2014table 2 \u00b1 50%.", "stats": [], "panels": [ "app2table2" ] }, { "uid": "captions-092", "section": "captions", "text": "( A ) Schematic of our definitions of tonic (50 th percentile/median, dashed lines) and peak (99.5 th percentile, solid line) DA for both the dorsal and ventral striatum.", "stats": [], "panels": [ "fig3a" ] }, { "uid": "captions-095", "section": "captions", "text": "( D ) Ratio between 99.5 th and 50 th percentiles as a measure of focality for both regions.", "stats": [], "panels": [ "fig3d" ] }, { "uid": "captions-101", "section": "captions", "text": "Figure 3\u2014figure supplement 1\u2014source code 1. Source code used to generate data in Figure 3\u2014figure supplement 1 .", "stats": [], "panels": [ "fig3s1" ] }, { "uid": "captions-102", "section": "captions", "text": "[panels detected: a, b, c, d, e, f, g] === Figure 3s2 === Figure 3\u2014figure supplement 2. Fold change during inhibition, V max -sensitivity at different release parameters and release-uptake balance.", "stats": [], "panels": [ "fig3s2" ] }, { "uid": "captions-103", "section": "captions", "text": "( A ) Fold change over baseline (K m of 210 nM) for mean DA concentration in the dorsal (DS) and ventral striatum (VS) with changing DAT K m .", "stats": [], "panels": [ "fig3s1a" ] }, { "uid": "captions-104", "section": "captions", "text": "( B ) Relative difference between the dorsal and ventral striatum for both phasic and tonic DA at different K m values.", "stats": [], "panels": [ "fig3s1b" ] }, { "uid": "captions-105", "section": "captions", "text": "( C ) Effect of changing DAT V max on DA concentrations for three different quantal sizes ( Q ).", "stats": [], "panels": [ "fig3s1c" ] }, { "uid": "captions-106", "section": "captions", "text": "[DA] normalised to highest values within each Q. Shaded area indicates median V max for DS and VS as found in the literature shown in Appendix 2\u2014table 2 with \u00b150%.", "stats": [], "panels": [ "app2table2" ] }, { "uid": "captions-107", "section": "captions", "text": "( D ) Effect of changing DAT V max on DA concentrations for three different release probabilities (R % ).", "stats": [], "panels": [ "fig3s1d" ] }, { "uid": "captions-109", "section": "captions", "text": "Shaded area indicates median V max for DS and VS as found in the literature shown in Appendix 2\u2014table 2 with \u00b150%.", "stats": [], "panels": [ "app2table2" ] }, { "uid": "captions-110", "section": "captions", "text": "( E ) Least-square fit linear regression between release rate and autocorrelation decay rate (\u03c4) ( Ejdrup et al., 2023 ).", "stats": [], "panels": [ "fig3s1e" ] }, { "uid": "captions-112", "section": "captions", "text": "( F ) Partial regression plot error of the regression in ( f ) and error between DA response to amphetamine as measured by microdialysis and the release rate from Ejdrup et al., 2023 to show that the less release and uptake correlate, the less release rate can explain the microdialysis response, suggesting release and uptake are partially independent of each other.", "stats": [], "panels": [ "fig3s1f" ] }, { "uid": "captions-114", "section": "captions", "text": "Figure 3\u2014figure supplement 2\u2014source code 1. Source code used to generate data in Figure 3\u2014figure supplement 2A-D .", "stats": [], "panels": [ "fig3s2" ] }, { "uid": "captions-116", "section": "captions", "text": "( A ) Schematic of dense DA cluster.", "stats": [], "panels": [ "fig3s2a" ] }, { "uid": "captions-118", "section": "captions", "text": "( B ) Effective transport rate dependent on local concentration.", "stats": [], "panels": [ "fig3s2b" ] }, { "uid": "captions-119", "section": "captions", "text": "( C ) Top view of unfolded DA varicosity.", "stats": [], "panels": [ "fig3s2c" ] }, { "uid": "captions-122", "section": "captions", "text": "( D ) Cross-section showing DA concentration in space surrounding varicosity unfolded in c.", "stats": [], "panels": [ "fig3s2d" ] }, { "uid": "captions-125", "section": "captions", "text": "( E ) Top view from ( c ), but colour coded for DA concentration immediately above membrane surface at different DAT cluster sizes.", "stats": [], "panels": [ "fig3s2e" ] }, { "uid": "captions-126", "section": "captions", "text": "( F ) Changes in [DA] from 15 nM unclustered (Un.) steady state with constant release after changing to four different cluster size scenarios (\u00f8=diameter).", "stats": [], "panels": [ "fig3s2f" ] }, { "uid": "captions-127", "section": "captions", "text": "( G ) Clearance of 100 nM [DA] for different DAT cluster sizes.", "stats": [], "panels": [ "fig3s2g" ] }, { "uid": "captions-128", "section": "captions", "text": "( H ) Difference between DA concentration at the centre of clusters (or general surface of varicosity for unclustered) and mean concentration of the full simulation space ( I ) Concentrations across a cross section of a surface with 80 nm diameter clusters.", "stats": [], "panels": [ "fig3s2h" ] }, { "uid": "tables-001", "section": "tables", "text": "Table 1. List of variables used in the simulation of the dorsal striatum.", "stats": [], "panels": [ "table1" ] }, { "uid": "tables-002", "section": "tables", "text": "Variable Abbreviation Value Reference Firing rate 4 Hz Paladini et al., 2003 Release probability 6% Dreyer et al., 2010 DA molecules per vesicle 3000 Klaus et al., 2019 Diffusion coefficient 763 \u00b5m 2 s -1 Nicholson, 1995 Tortuosity 1.54 Rice and Nicholson, 1991 Vmax 6.0 \u00b5m s -1 See Appendix 2\u2014table 2 Km 210 nM Hovde et al., 2019 Active terminal density - 0.04 \u00b5m -3 Liu et al., 2021 Extracellular volume fraction 0.21 Rice and Nicholson, 1991 Number of neurons in simulation space - 150 Matsuda et al., 2009 Key resources table Reagent type (species) or resource Designation Source or reference Identifiers Additional information Software, algorithm Python https://www.python.org v3.9.7 Software, algorithm Spyder IDE https://www.spyder-ide.org v5.1.5 Software, algorithm Model code https://github.com/GetherLab/striatal-dopamine-modelling Developed for this work Strain, strain background ( Mus musculus ) C57Bl/6 J Details provided in S\u00f8rensen et al., 2021 Data used are from S\u00f8rensen et al., 2021 Antibody anti-DAT Nt (rat monoclonal) Sigma-Aldrich MAB369 RRID: AB_2190413 IF (1:200) S\u00f8rensen et al., 2021 Antibody Anti-VMAT2 (rabbit polyclonal) Kind gift from Dr Gary W. Miller, Columbia University S\u00f8rensen et al., 2021 IF (1:4000) S\u00f8rensen et al., 2021 Appendix 2\u2014table 1. Overview of reports on dopaminergic density and release in the striatum.", "stats": [], "panels": [ "app2table2", "app2table1", "keyresource" ] }, { "uid": "tables-012", "section": "tables", "text": "Mouse Salvatore et al., 2005 FSCV - [DA] p 91 % 57 52 nM Rat May and Wightman, 1989 FSCV - [DA] p 76 % 89.3 67.5 nM Rat Garris and Wightman, 1994 Median 90 % - - - - - Appendix 2\u2014table 2. Overview of reported V max values for DA uptake in the striatum.", "stats": [], "panels": [ "app2table2" ] } ] } }