{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T21:25:50Z","timestamp":1768512350823,"version":"3.49.0"},"posted":{"date-parts":[[2024,5,31]]},"group-title":"Neuroscience","reference-count":84,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,5,30]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  The globus pallidus externus (GPe) is a central component of the basal ganglia circuit, receiving strong input from the indirect pathway and regulating a variety of functions, including locomotor output and habit formation. We recently showed that it also acts as a gatekeeper of cocaine-induced behavioral plasticity, as inhibition of parvalbumin-positive cells in the GPe (GPe\n                  <jats:sup>PV<\/jats:sup>\n                  ) prevents the development of cocaine-induced reward and sensitization. However, the molecular and circuit mechanisms underlying this function are unknown. Here we show that GPe\n                  <jats:sup>PV<\/jats:sup>\n                  cells control cocaine reward and sensitization by inhibiting GABAergic neurons in the substantia nigra pars reticulata (SNr\n                  <jats:sup>GABA<\/jats:sup>\n                  ), and ultimately, selectively modulating the activity of ventral tegmental area dopamine (VTA\n                  <jats:sup>DA<\/jats:sup>\n                  ) cells projecting to the lateral shell of the nucleus accumbens (NAcLat). A major input to GPe\n                  <jats:sup>PV<\/jats:sup>\n                  cells is the indirect pathway of the dorsomedial striatum (DMS\n                  <jats:sup>D<\/jats:sup>\n                  <jats:sup>2<\/jats:sup>\n                  ), which receives DAergic innervation from collaterals of VTA\n                  <jats:sup>DA<\/jats:sup>\n                  \u2192NAcLat cells, making this a closed-loop circuit. Cocaine likely facilitates reward and sensitization not directly through actions in the GPe, but rather in the upstream DMS, where the cocaine-induced elevation of DA triggers a depression in DMS\n                  <jats:sup>D<\/jats:sup>\n                  <jats:sup>2<\/jats:sup>\n                  cell activity. This cocaine-induced elevation in DA levels can be blocked by inhibition of GPe\n                  <jats:sup>PV<\/jats:sup>\n                  cells, closing the loop. Interestingly, the level of GPe\n                  <jats:sup>PV<\/jats:sup>\n                  cell activity prior to cocaine administration is correlated with the extent of reward and sensitization that animals experience in response to future administration of cocaine, indicating that GPe\n                  <jats:sup>PV<\/jats:sup>\n                  cell activity is a key predictor of future behavioral responses to cocaine. Single nucleus RNA-sequencing of GPe cells indicated that genes encoding voltage-gated potassium channels KCNQ3 and KCNQ5 that control intrinsic cellular excitability are downregulated in GPe\n                  <jats:sup>PV<\/jats:sup>\n                  cells following a single cocaine exposure, contributing to the elevation in GPe\n                  <jats:sup>PV<\/jats:sup>\n                  cell excitability. Acutely activating channels containing KCNQ3 and\/or KCNQ5 using the small molecule carnosic acid, a key psychoactive component of\n                  <jats:italic>Salvia rosmarinus<\/jats:italic>\n                  (rosemary) extract, reduced GPe\n                  <jats:sup>PV<\/jats:sup>\n                  cell excitability and also impaired cocaine reward, sensitization, and volitional cocaine intake, indicating its potential as a therapeutic to counteract psychostimulant use disorder. Our findings illuminate the molecular and circuit mechanisms by which the GPe orchestrates brain-wide changes in response to cocaine that are required for reward, sensitization, and self-administration behaviors.\n                <\/jats:p>","DOI":"10.1101\/2024.05.29.596557","type":"posted-content","created":{"date-parts":[[2024,5,31]],"date-time":"2024-05-31T07:30:43Z","timestamp":1717140643000},"source":"Crossref","is-referenced-by-count":1,"title":["Molecular and circuit determinants in the globus pallidus mediating control of cocaine-induced behavioral plasticity"],"prefix":"10.64898","author":[{"given":"Guilian","family":"Tian","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katrina","family":"Bartas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"May","family":"Hui","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lingxuan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jose J.","family":"Vasquez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ghalia","family":"Azouz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pieter","family":"Derdeyn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R\u00edan 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