Department of Neurobiology, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA, USA.
Neuropsychopharmacology. 2022 Feb;47(3):641-651. doi: 10.1038/s41386-021-01107-1. Epub 2021 Jul 29.
A critical brain area implicated in nicotine dependence is the interpeduncular nucleus (IPN) located in the ventral midbrain and consisting primarily of GABAergic neurons. Previous studies indicate that IPN GABAergic neurons contribute to expression of somatic symptoms of nicotine withdrawal; however, whether IPN neurons are dynamically regulated during withdrawal in vivo and how this may contribute to both somatic and affective withdrawal behavior is unknown. To bridge this gap in knowledge, we expressed GCaMP in IPN GABAergic neurons and used in vivo fiber photometry to record changes in fluorescence, as a proxy for neuronal activity, in male mice during nicotine withdrawal. Mecamylamine-precipitated withdrawal significantly increased activity of IPN GABAergic neurons in nicotine-dependent, but not nicotine-naive mice. Analysis of GCaMP signals time-locked with somatic symptoms including grooming and scratching revealed reduced IPN GABAergic activity during these behaviors, specifically in mice undergoing withdrawal. In the elevated plus maze, used to measure anxiety-like behavior, an affective withdrawal symptom, IPN GABAergic neuron activity was increased during open-arm versus closed-arm exploration in nicotine-withdrawn, but not non-withdrawn mice. Optogenetic silencing IPN GABAergic neurons during withdrawal significantly reduced withdrawal-induced increases in somatic behavior and increased open-arm exploration. Together, our data indicate that IPN GABAergic neurons are dynamically regulated during nicotine withdrawal, leading to increased anxiety-like symptoms and somatic behavior, which inherently decrease IPN GABAergic neuron activity as a withdrawal-coping mechanism. These results provide a neuronal basis underlying the role of the IPN in the expression of somatic and affective behaviors of nicotine withdrawal.
一个与尼古丁依赖有关的关键大脑区域是位于中脑腹侧的脚间核（IPN），主要由 GABA 能神经元组成。先前的研究表明，IPN 的 GABA 能神经元有助于尼古丁戒断的躯体症状的表达；然而，在体内戒断期间，IPN 神经元是否会被动态调节，以及这如何导致躯体和情感戒断行为，目前尚不清楚。为了弥补这一知识空白，我们在 IPN 的 GABA 能神经元中表达了 GCaMP，并使用活体光纤光度法记录雄性小鼠在尼古丁戒断期间，荧光变化作为神经元活动的替代指标。美加明诱发的戒断显著增加了依赖尼古丁但不依赖尼古丁的小鼠的 IPN GABA 能神经元的活性。对包括梳理和抓挠在内的躯体症状与 GCaMP 信号进行时间锁定的分析表明，在这些行为期间，特别是在经历戒断的小鼠中，IPN 的 GABA 能神经元活性降低。在高架十字迷宫中，用于测量焦虑样行为，即一种情感戒断症状，在尼古丁戒断的小鼠中，与封闭臂探索相比，开放臂探索时 IPN GABA 能神经元的活性增加，而非戒断的小鼠则没有。在戒断期间光遗传沉默 IPN 的 GABA 能神经元，显著减少了戒断引起的躯体行为增加，并增加了开放臂探索。总的来说，我们的数据表明，在尼古丁戒断期间，IPN 的 GABA 能神经元会被动态调节，导致焦虑样症状和躯体行为增加，这是一种作为戒断应对机制的固有降低 IPN GABA 能神经元活性的机制。这些结果为 IPN 在表达尼古丁戒断的躯体和情感行为中的作用提供了神经基础。
