Huang Zhenbo, Chen Ruifeng, Ho Matthew, Xie Xueyi, Gangal Himanshu, Wang Xuehua, Wang Jun
Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, TX, USA.
Sci Adv. 2024 Dec 20;10(51):eadn2446. doi: 10.1126/sciadv.adn2446. Epub 2024 Dec 18.
Striatal cholinergic interneurons (CINs) are key to regulating behavioral flexibility, involving both extinguishing learned actions and adopting new ones. However, the mechanisms driving these processes remain elusive. In this study, we initially demonstrate that chronic alcohol consumption disrupts the burst-pause dynamics of CINs and impairs behavioral flexibility. We next aimed to elucidate the mechanisms by which CIN dynamics control behavioral flexibility. We found that extinction learning enhances acetylcholine (ACh) release and that mimicking this enhancement through optogenetic induction of CIN burst firing accelerates the extinction process. In addition, we demonstrate that disrupting CIN pauses via continuous optogenetic stimulation reversibly impairs the updating of goal-directed behaviors. Overall, we demonstrate that CIN burst firing, which increases ACh release, promotes extinction learning, aiding the extinguishment of learned behaviors. Conversely, CIN firing pauses, which lead to ACh dips, are crucial for reversal learning, facilitating the adaptation of new actions. These findings shed light on how CIN dynamics regulate behavioral flexibility.
纹状体胆碱能中间神经元（CINs）是调节行为灵活性的关键，这涉及消除已学会的行为以及采用新的行为。然而，驱动这些过程的机制仍然不清楚。在本研究中，我们首先证明长期饮酒会破坏CINs的爆发-暂停动态，并损害行为灵活性。接下来，我们旨在阐明CIN动态控制行为灵活性的机制。我们发现消退学习会增强乙酰胆碱（ACh）的释放，并且通过光遗传学诱导CIN爆发性放电来模拟这种增强会加速消退过程。此外，我们证明通过持续的光遗传学刺激破坏CIN暂停会可逆地损害目标导向行为的更新。总体而言，我们证明增加ACh释放的CIN爆发性放电促进消退学习，有助于消除已学会的行为。相反，导致ACh下降的CIN放电暂停对于逆向学习至关重要，有助于新行为的适应。这些发现揭示了CIN动态如何调节行为灵活性。
