Behavioral Decoding Reveals Cortical Endocannabinoid Potentiation during Δ⁹-THC Impairment.

bioRxiv : the preprint server for biology Pub Date : 2025-09-28 DOI:10.1101/2025.09.26.678874

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

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Abstract

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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行为解码揭示Δ 9 -THC损伤期间皮质内源性大麻素增强。

Δ 9 -四氢大麻酚（THC）如何损害小鼠的自然行为尚不清楚。我们开发了一个带有机器学习分类器的视频监控行为平台，以揭示自然小鼠行为的离散变化。四氢大麻酚输注到内侧前额叶皮层（mPFC）破坏了损伤反应的行走运动学特征。四氢大麻酚主要增加行走开始前mPFC gaba能活性，改变mPFC兴奋/抑制（E/I）平衡。mPFC gaba能神经元的姿势定义闭环光刺激表明，四氢大麻酚加重了运动损伤的选定参数。令人惊讶的是，四氢大麻酚还诱导了时间锁定、运动诱导的mPFC内源性大麻素（eCB）释放的短暂增强和随后cb1r介导的突触抑制。在这里，我们建立了thc通过eCB释放的动态变化将mPFC E/I平衡改变为激励，从而诱导行为损伤。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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bioRxiv : the preprint server for biology

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