Purvines William, Gangal Himanshu, Xie Xueyi, Ramos Joseph, Wang Xuehua, Miranda Rajesh, Wang Jun
Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas 77807, United States.
Texas A&M Institute for Neuroscience, Texas A&M University, College Station, Texas 77843, United States.
bioRxiv. 2025 May 31:2025.05.27.656351. doi: 10.1101/2025.05.27.656351.
Fetal Alcohol Spectrum Disorder (FASD), caused by prenatal alcohol exposure (PAE), is characterized by significant cognitive impairments, including reduced cognitive flexibility. Despite the critical role of cholinergic interneurons (CINs) in the dorsomedial striatum (DMS) for cognitive and behavioral flexibility, their contribution to neurobehavioral deficits in FASD remains unclear. To address this gap, this research explored the impact of PAE on CIN populations and activity, cognitive flexibility, and compulsive drinking behaviors in adult offspring. Using ChAT-Cre;Ai14-tdTomato mice combined with ChAT staining, we found substantial reductions in CIN number within the striatum of adult PAE offspring. Functional assessments revealed that PAE markedly decreased CIN firing activity and reduced acetylcholine (ACh) release in the DMS, as measured by electrophysiology recordings and live-tissue confocal imaging using a genetically encoded ACh sensor. Behaviorally, PAE-exposed offspring exhibited a significant deficit in adapting to reversed action-outcome contingencies despite intact initial learning capabilities. Moreover, PAE-exposed mice exhibited compulsive alcohol drinking behavior, characterized by elevated consumption and preference for quinine-adulterated alcohol. These findings collectively highlight the critical role of impaired cholinergic signaling in the cognitive and behavioral deficits observed following PAE. Understanding this cholinergic dysfunction provides valuable insights necessary for developing targeted interventions aimed at mitigating cognitive and behavioral consequences associated with FASD.
胎儿酒精谱系障碍（FASD）由产前酒精暴露（PAE）引起，其特征为严重的认知障碍，包括认知灵活性降低。尽管背内侧纹状体（DMS）中的胆碱能中间神经元（CINs）对认知和行为灵活性起着关键作用，但其在FASD神经行为缺陷中的作用仍不清楚。为了填补这一空白，本研究探讨了PAE对成年后代CIN群体和活性、认知灵活性以及强迫性饮酒行为的影响。使用ChAT-Cre;Ai14-tdTomato小鼠并结合ChAT染色，我们发现成年PAE后代纹状体内的CIN数量大幅减少。功能评估显示，通过电生理记录和使用基因编码的乙酰胆碱（ACh）传感器的活组织共聚焦成像测量，PAE显著降低了DMS中CIN的放电活动并减少了ACh释放。在行为方面，尽管初始学习能力完好，但暴露于PAE的后代在适应反向动作-结果偶联方面表现出明显缺陷。此外，暴露于PAE的小鼠表现出强迫性饮酒行为，其特征是饮酒量增加以及对掺有奎宁的酒精的偏好。这些发现共同凸显了胆碱能信号受损在PAE后观察到的认知和行为缺陷中的关键作用。了解这种胆碱能功能障碍为开发旨在减轻与FASD相关的认知和行为后果的靶向干预措施提供了有价值的见解。
