Department of Psychiatry, UC San Diego, California 92093
Department of Psychiatry, UC San Diego, California 92093.
eNeuro. 2023 Jun 27;10(6). doi: 10.1523/ENEURO.0019-23.2023. Print 2023 Jun.
Chronic nicotine results in dependence with withdrawal symptoms on discontinuation of use, through desensitization of nicotinic acetylcholine receptors and altered cholinergic neurotransmission. Nicotine withdrawal is associated with increased whole-brain functional connectivity and decreased network modularity; however, the role of cholinergic neurons in those changes is unknown. To identify the contribution of nicotinic receptors and cholinergic regions to changes in the functional network, we analyzed the contribution of the main cholinergic regions to brain-wide activation of the immediate early-gene Fos during withdrawal in male mice and correlated these changes with the expression of nicotinic receptor mRNA throughout the brain. We show that the main functional connectivity modules included the main long-range cholinergic regions, which were highly synchronized with the rest of the brain. However, despite this hyperconnectivity, they were organized into two anticorrelated networks that were separated into basal forebrain-projecting and brainstem-thalamic-projecting cholinergic regions, validating a long-standing hypothesis of the organization of the brain cholinergic systems. Moreover, baseline (without nicotine) expression of , , , and mRNA of each brain region correlated with withdrawal-induced changes in Fos expression. Finally, by mining the Allen Brain mRNA expression database, we were able to identify 1755 gene candidates and three pathways (Sox2-Oct4-Nanog, JAK-STAT, and MeCP2-GABA) that may contribute to nicotine withdrawal-induced Fos expression. These results identify the dual contribution of the basal forebrain and brainstem-thalamic cholinergic systems to whole-brain functional connectivity during withdrawal; and identify nicotinic receptors and novel cellular pathways that may be critical for the transition to nicotine dependence.
慢性尼古丁使用会导致依赖和戒断症状，这是通过烟碱型乙酰胆碱受体脱敏和胆碱能神经传递改变引起的。尼古丁戒断与全脑功能连接增加和网络模块性降低有关；然而，胆碱能神经元在这些变化中的作用尚不清楚。为了确定烟碱受体和胆碱能神经元在功能网络变化中的作用，我们分析了主要胆碱能区域对雄性小鼠戒断期间即时早期基因 Fos 脑广泛激活的贡献，并将这些变化与整个大脑中烟碱受体 mRNA 的表达相关联。我们发现主要的功能连接模块包括主要的长程胆碱能区域，这些区域与大脑的其他区域高度同步。然而，尽管存在这种超连接性，它们被组织成两个反相关的网络，分为基底前脑投射和脑干丘脑投射的胆碱能区域，验证了大脑胆碱能系统组织的一个长期假设。此外，每个脑区的基线（无尼古丁）表达 、 、 、 和 mRNA 与戒断诱导的 Fos 表达变化相关。最后，通过挖掘艾伦大脑 mRNA 表达数据库，我们能够鉴定出 1755 个候选基因和三个可能参与尼古丁戒断诱导 Fos 表达的途径（Sox2-Oct4-Nanog、JAK-STAT 和 MeCP2-GABA）。这些结果确定了基底前脑和脑干丘脑胆碱能系统在戒断期间对全脑功能连接的双重贡献；并确定了烟碱受体和可能对尼古丁依赖过渡至关重要的新的细胞途径。
