Anthony English, David Marcus, Khushi Yadav, Yassin Elkhouly, Allan Levy, Victoria Corbit, Maddie Ask, Anika Scedberg, Jordan Poces-Ball, Fleur Uittenbogaard, Rayna Simons, Ilana Witten, Larry Zweifel, Benjamin Land, Nephi Stella, Michael R Bruchas
{"title":"行为解码揭示Δ 9 -THC损伤期间皮质内源性大麻素增强。","authors":"Anthony English, David Marcus, Khushi Yadav, Yassin Elkhouly, Allan Levy, Victoria Corbit, Maddie Ask, Anika Scedberg, Jordan Poces-Ball, Fleur Uittenbogaard, Rayna Simons, Ilana Witten, Larry Zweifel, Benjamin Land, Nephi Stella, Michael R Bruchas","doi":"10.1101/2025.09.26.678874","DOIUrl":null,"url":null,"abstract":"<p><p>How Δ<sup>9</sup>-tetrahydrocannabinol (THC) impairs natural behaviors in mice remains unknown. We developed a video-monitored behavioral platform with machine learning classifiers to unravel discrete changes in natural mouse behaviors. THC infusion into the medial prefrontal cortex (mPFC) disrupted walking kinematic features characteristic of impairment responses. THC predominantly increased mPFC GABAergic activity preceding walk initiation shifting the mPFC excitatory/inhibitory (E/I) balance. Pose-defined closed loop photo-stimulation of mPFC GABAergic neurons demonstrated that THC exacerbates selected parameters of motor impairment. Surprisingly, THC also induced a time locked, movement-induced, transient potentiation of mPFC endocannabinoid (eCB) release and ensuing CB<sub>1</sub>R-mediated synaptic inhibition. Here we establish that THC-modifies mPFC E/I balance to excitation via dynamic changes in eCB release which acts to induce behavioral impairment.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12485844/pdf/","citationCount":"0","resultStr":"{\"title\":\"Behavioral Decoding Reveals Cortical Endocannabinoid Potentiation during Δ<sup>9</sup>-THC Impairment.\",\"authors\":\"Anthony English, David Marcus, Khushi Yadav, Yassin Elkhouly, Allan Levy, Victoria Corbit, Maddie Ask, Anika Scedberg, Jordan Poces-Ball, Fleur Uittenbogaard, Rayna Simons, Ilana Witten, Larry Zweifel, Benjamin Land, Nephi Stella, Michael R Bruchas\",\"doi\":\"10.1101/2025.09.26.678874\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>How Δ<sup>9</sup>-tetrahydrocannabinol (THC) impairs natural behaviors in mice remains unknown. We developed a video-monitored behavioral platform with machine learning classifiers to unravel discrete changes in natural mouse behaviors. THC infusion into the medial prefrontal cortex (mPFC) disrupted walking kinematic features characteristic of impairment responses. THC predominantly increased mPFC GABAergic activity preceding walk initiation shifting the mPFC excitatory/inhibitory (E/I) balance. Pose-defined closed loop photo-stimulation of mPFC GABAergic neurons demonstrated that THC exacerbates selected parameters of motor impairment. Surprisingly, THC also induced a time locked, movement-induced, transient potentiation of mPFC endocannabinoid (eCB) release and ensuing CB<sub>1</sub>R-mediated synaptic inhibition. Here we establish that THC-modifies mPFC E/I balance to excitation via dynamic changes in eCB release which acts to induce behavioral impairment.</p>\",\"PeriodicalId\":519960,\"journal\":{\"name\":\"bioRxiv : the preprint server for biology\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2025-09-28\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12485844/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"bioRxiv : the preprint server for biology\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1101/2025.09.26.678874\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"bioRxiv : the preprint server for biology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1101/2025.09.26.678874","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
Behavioral Decoding Reveals Cortical Endocannabinoid Potentiation during Δ9-THC Impairment.
How Δ9-tetrahydrocannabinol (THC) impairs natural behaviors in mice remains unknown. We developed a video-monitored behavioral platform with machine learning classifiers to unravel discrete changes in natural mouse behaviors. THC infusion into the medial prefrontal cortex (mPFC) disrupted walking kinematic features characteristic of impairment responses. THC predominantly increased mPFC GABAergic activity preceding walk initiation shifting the mPFC excitatory/inhibitory (E/I) balance. Pose-defined closed loop photo-stimulation of mPFC GABAergic neurons demonstrated that THC exacerbates selected parameters of motor impairment. Surprisingly, THC also induced a time locked, movement-induced, transient potentiation of mPFC endocannabinoid (eCB) release and ensuing CB1R-mediated synaptic inhibition. Here we establish that THC-modifies mPFC E/I balance to excitation via dynamic changes in eCB release which acts to induce behavioral impairment.
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