Simon Rhiana C, Fleming Weston T, Senthilkumar Pranav, Briones Brandy A, Ishii Kentaro K, Hjort Madelyn M, Martin Madison M, Hashikawa Koichi, Sanders Andrea D, Golden Sam A, Stuber Garret D
Center for the Neurobiology of Addiction, Pain, and Emotion (NAPE), University of Washington, Seattle, WA, 98195, USA.
Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA, 98195, USA.
bioRxiv. 2024 Jan 16:2024.01.15.575766. doi: 10.1101/2024.01.15.575766.
Because opioid withdrawal is an intensely aversive experience, persons with opioid use disorder (OUD) often relapse to avoid it. The lateral septum (LS) is a forebrain structure that is important in aversion processing, and previous studies have linked the lateral septum (LS) to substance use disorders. It is unclear, however, which precise LS cell types might contribute to the maladaptive state of withdrawal. To address this, we used single-nucleus RNA-sequencing to interrogate cell type specific gene expression changes induced by chronic morphine and withdrawal. We discovered that morphine globally disrupted the transcriptional profile of LS cell types, but Neurotensin-expressing neurons (; LS- neurons) were selectively activated by naloxone. Using two-photon calcium imaging and electrophysiology, we next demonstrate that LS- neurons receive enhanced glutamatergic drive in morphine-dependent mice and remain hyperactivated during opioid withdrawal. Finally, we showed that activating and silencing LS- neurons during opioid withdrawal regulates pain coping behaviors and sociability. Together, these results suggest that LS- neurons are a key neural substrate involved in opioid withdrawal and establish the LS as a crucial regulator of adaptive behaviors, specifically pertaining to OUD.
由于阿片类药物戒断是一种极其令人厌恶的体验，患有阿片类药物使用障碍（OUD）的人常常会复吸以避免这种情况。外侧隔核（LS）是前脑结构，在厌恶处理中起重要作用，先前的研究已将外侧隔核（LS）与物质使用障碍联系起来。然而，尚不清楚哪些特定的LS细胞类型可能导致戒断的适应不良状态。为了解决这个问题，我们使用单核RNA测序来研究慢性吗啡和戒断诱导的细胞类型特异性基因表达变化。我们发现吗啡全面破坏了LS细胞类型的转录谱，但表达神经降压素的神经元（；LS-神经元）被纳洛酮选择性激活。接下来，我们使用双光子钙成像和电生理学证明，在吗啡依赖的小鼠中，LS-神经元接受增强的谷氨酸能驱动，并且在阿片类药物戒断期间保持过度激活。最后，我们表明在阿片类药物戒断期间激活和沉默LS-神经元可调节疼痛应对行为和社交能力。总之，这些结果表明LS-神经元是参与阿片类药物戒断的关键神经基质，并将LS确立为适应性行为的关键调节因子，特别是与OUD相关的行为。
