{
 "paper": "ejdrup-2026-dopamine",
 "model": "supplied:runs/ejdrup-2026-dopamine/plain-claim.answer.json",
 "prompt": "extract/prompts/plain-claim.md",
 "claims": [
  {
   "slug": "d1r-tracks-da-50ms-delay",
   "role": "empirical",
   "panel": "fig1H, fig1I",
   "plain": "D1 receptor occupancy trails extracellular dopamine by about 50 milliseconds and rises only during bursts, not tonic firing."
  },
  {
   "slug": "d2r-initialization-unjustified",
   "role": "methodological",
   "panel": "fig1H",
   "plain": "Every simulation starts D2 occupancy at a value the model's own parameters do not predict, with no test of how much it matters."
  },
  {
   "slug": "d2r-insensitive-to-brief-pauses",
   "role": "empirical",
   "panel": "fig1J",
   "plain": "A full one-second pause in firing barely lowers D2 receptor occupancy, across a tenfold range of assumed D2 affinity."
  },
  {
   "slug": "d2r-integrates-over-seconds",
   "role": "empirical",
   "panel": "fig1H",
   "plain": "D2 receptor occupancy takes seconds to fall back after a burst, so it cannot separate closely spaced bursts."
  },
  {
   "slug": "d2r-occupancy-higher-in-vs",
   "role": "empirical",
   "panel": "fig2G",
   "plain": "During pacemaker firing, D2 receptor occupancy is higher in ventral than dorsal striatum, matching the higher tonic dopamine."
  },
  {
   "slug": "dat-clustering-greater-in-vs",
   "role": "empirical",
   "panel": "fig4M, fig4N",
   "plain": "Super-resolution imaging shows the dopamine transporter is more nanoclustered in ventral than in dorsal striatum."
  },
  {
   "slug": "dat-immunostaining-dorsoventral-gradient",
   "role": "empirical",
   "panel": "fig2—supplement 1B, fig2—supplement 1C",
   "plain": "Dopamine transporter protein is more abundant in dorsal than ventral striatum, matching the uptake-rate ratio the model assumes."
  },
  {
   "slug": "dat-nanoclustering-slows-clearance",
   "role": "empirical",
   "panel": "fig4C, fig4D, fig4E, fig4F, fig4G",
   "plain": "Dense transporter nanoclusters clear dopamine about twice as slowly as evenly spread ones, because dopamine runs out around them."
  },
  {
   "slug": "ds-lacks-pervasive-tonic-da",
   "role": "empirical",
   "panel": "fig1D, fig1E, fig1F",
   "plain": "During pacemaker firing, dorsal striatum holds separate dopamine hotspots with much of the volume empty, not a tonic baseline."
  },
  {
   "slug": "ds-vs-vmax-ratio-assumed",
   "role": "scope",
   "panel": "fig2A (implied throughout)",
   "plain": "The three-to-one dorsal-to-ventral ratio of transporter uptake capacity is taken from prior literature, not measured here."
  },
  {
   "slug": "fscv-matches-may-wightman-1989",
   "role": "empirical",
   "panel": "fig2E",
   "plain": "Simulated voltammetry reproduces published recordings where ventral striatum peaks higher than dorsal at every frequency."
  },
  {
   "slug": "hypothesis-d1-d2-temporal-distinction",
   "role": "hypothesis",
   "panel": "hypothesis",
   "plain": "D1 receptors detect brief dopamine bursts while D2 receptors integrate dopamine over seconds, because their kinetics differ."
  },
  {
   "slug": "hypothesis-nanoclustering-regulates-vmax",
   "role": "hypothesis",
   "panel": "hypothesis",
   "plain": "Packing transporters into dense nanoclusters lowers their effective uptake capacity even with total transporter unchanged."
  },
  {
   "slug": "hypothesis-vmax-explains-regional-difference",
   "role": "hypothesis",
   "panel": "hypothesis",
   "plain": "Dorsal hotspots versus ventral tonic coverage follow from the difference in uptake capacity, not from how dopamine is released."
  },
  {
   "slug": "interprets-cragg-rice-vmax-ratio",
   "role": "literature-context",
   "panel": "fig2A (implied parameterization)",
   "plain": "Earlier voltammetry work established that dopamine uptake capacity is roughly three times higher in dorsal than ventral striatum."
  },
  {
   "slug": "interprets-may-wightman-1989-fscv",
   "role": "literature-context",
   "panel": "fig2E (explicit replication comparison)",
   "plain": "May and Wightman found in rat slices that ventral striatum reaches higher evoked dopamine peaks than dorsal at every frequency."
  },
  {
   "slug": "low-burst-no-spillover-high-burst-does",
   "role": "empirical",
   "panel": "fig1G",
   "plain": "Short low-frequency bursts keep dopamine inside the burst zone, while stronger bursts spill it into a far larger volume."
  },
  {
   "slug": "nanoclustering-constant-vmax-constraint",
   "role": "scope",
   "panel": "fig4C, fig4D, fig4E, fig4F",
   "plain": "The nanoclustering simulations hold total uptake capacity fixed, so slower clearance would not follow if clustering added DAT."
  },
  {
   "slug": "nanoclustering-model-varicosity-scale",
   "role": "scope",
   "panel": "fig4C, fig4D, fig4E, fig4F",
   "plain": "The nanoclustering work uses a separate tiny-scale model never coupled back to the tissue-scale model of the other figures."
  },
  {
   "slug": "vmat2-gradient-absent",
   "role": "control",
   "panel": "fig2—supplement 1A, fig2—supplement 1B, fig2—supplement 1C",
   "plain": "VMAT2, which loads dopamine into vesicles, shows no dorsoventral gradient, so release capacity cannot explain the difference."
  },
  {
   "slug": "vmax-modulation-larger-impact-in-vs",
   "role": "empirical",
   "panel": "fig3K",
   "plain": "Ventral striatum, running closer to transporter saturation, shifts its tonic dopamine far more than dorsal when uptake changes."
  },
  {
   "slug": "vmax-only-parameter-driving-regional-difference",
   "role": "empirical",
   "panel": "fig3B, fig3C, fig3E, fig3F, fig3G, fig3K, fig3L",
   "plain": "Of all the parameters swept, only uptake capacity affects dorsal and ventral striatum differently, the rest moving both alike."
  },
  {
   "slug": "vs-low-active-fraction-resembles-ds-distribution",
   "role": "empirical",
   "panel": "fig3B",
   "plain": "Ventral striatum with a twentieth of its terminals active spreads dopamine as widely as dorsal striatum with all of them active."
  },
  {
   "slug": "vs-lowest-percentiles-above-10nm",
   "role": "empirical",
   "panel": "fig2D",
   "plain": "Even the lowest-concentration parts of ventral striatum stay above ten nanomolar dopamine during pacemaker firing."
  },
  {
   "slug": "vs-maintains-pervasive-tonic-da",
   "role": "empirical",
   "panel": "fig2A, fig2B, fig2C",
   "plain": "With its lower uptake capacity, ventral striatum fills the whole simulated volume with diffuse tonic dopamine, not hotspots."
  }
 ]
}