Gedankien Tamara, Kriegel Jennifer, Zabeh Erfan, McDonagh David, Lega Bradley, Jacobs Joshua
Department of Biomedical Engineering, Columbia University, New York, NY, 10027, USA.
Department of Neurological Surgery, University of Texas Southwestern, Dallas, TX, 75390, USA.
bioRxiv. 2025 May 12:2025.05.12.653487. doi: 10.1101/2025.05.12.653487.
Cholinergic dysfunction is a hallmark of Alzheimer's disease and other memory disorders. Yet, the neurophysiological mechanisms linking cholinergic signaling to memory remain poorly understood. In this study, we administered scopolamine, a muscarinic cholinergic antagonist, to neurosurgical patients with intracranial electrodes as they performed an associative recognition memory task. When scopolamine was present at encoding, we observed disruptions to hippocampal slow theta oscillations (2-4 Hz), with selective impairments to recollection-based memory. However, when scopolamine was present during retrieval alone, we observed disruptions to slow theta without impaired memory performance. These disruptions included dose-dependent reductions in theta power, theta phase reset, and encoding-retrieval pattern reinstatement. Together, our results challenge the notion that theta oscillations are necessary for memory retrieval, and instead suggest that theta universally reflects an encoding-related neural state. These findings motivate updates to current models of acetylcholine's role in memory and may inform future therapies targeting rhythmic biomarkers of memory dysfunction.
胆碱能功能障碍是阿尔茨海默病和其他记忆障碍的一个标志。然而，将胆碱能信号与记忆联系起来的神经生理机制仍知之甚少。在本研究中，我们在神经外科患者进行联想识别记忆任务时，给他们静脉注射了毒蕈碱胆碱能拮抗剂东莨菪碱。当在编码时存在东莨菪碱时，我们观察到海马体慢θ振荡（2-4赫兹）受到干扰，基于回忆的记忆出现选择性损伤。然而，当仅在检索时存在东莨菪碱时，我们观察到慢θ受到干扰，但记忆表现并未受损。这些干扰包括θ功率的剂量依赖性降低、θ相位重置以及编码-检索模式恢复。总之，我们的结果挑战了θ振荡对记忆检索必不可少的观点，相反表明θ普遍反映了与编码相关的神经状态。这些发现促使对当前乙酰胆碱在记忆中作用的模型进行更新，并可能为未来针对记忆功能障碍节律性生物标志物的治疗提供信息。
