Gambrill Abigail, Rueckemann Jon W, Barria Andres
Department of Neurobiology and Biophysics, University of Washington School of Medicine, Seattle, WA 98195-7290, USA.
Authors contributed equally to this work.
bioRxiv. 2025 Jan 11:2025.01.10.632495. doi: 10.1101/2025.01.10.632495.
Acetylcholine modulates the network physiology of the hippocampus, a crucial brain structure that supports cognition and memory formation in mammals . In this and adjacent regions, synchronized neuronal activity within theta-band oscillations (4-10Hz) is correlated with attentive processing that leads to successful memory encoding . Acetylcholine facilitates the hippocampus entering a theta oscillatory regime and modulates the temporal organization of activity within theta oscillations . Unlike rodents that exhibit constant theta oscillations during movement and exploration, primates only manifest theta oscillations in transient bouts during periods of acute attention-despite conserved hippocampal anatomy . The phasic nature of primate theta oscillations and their susceptibility to muscarinic antagonists , suggest that acetylcholine afferents acutely modulate local circuitry, resulting in a temporary shift in hippocampal rhythmic dynamics. However, we lack a mechanistic understanding that links cellular physiology to emergent theta-rhythmic network dynamics. We explored the hypothesis that acetylcholine induces a distinct modulation of cellular properties to facilitate synchronization within the theta band in non-human primate neurons. Here we show that non-human primate neurons from the CA1 region of monkey hippocampus are not homogeneous in their voltage response to inputs of varying frequencies, a phenomenon known as cellular resonance . We classified these neurons as 'resonant' or 'non-resonant'. Under the influence of carbachol, these two classes of neurons become indistinguishable in their resonance, suggesting that acetylcholine transiently creates a homogeneous susceptibility to inputs within the theta range. This change is mediated by metabotropic acetylcholine receptors that enhance sag potentials, indicating that acetylcholine acts on principal neurons to modulate Hyperpolarization-activated Cyclic Nucleotide-gated channels. Our results reveal a mechanism through which acetylcholine can rapidly modulate intrinsic properties of primate hippocampal neurons to facilitate synchronization within theta-rhythmic circuits, providing insight into the unique features of primate hippocampal physiology.
乙酰胆碱调节海马体的网络生理活动，海马体是哺乳动物中支持认知和记忆形成的关键脑结构。在该区域及相邻区域，θ波段振荡（4-10赫兹）内的同步神经元活动与导致成功记忆编码的注意力处理相关。乙酰胆碱有助于海马体进入θ振荡状态，并调节θ振荡内活动的时间组织。与啮齿动物在运动和探索过程中表现出持续的θ振荡不同，灵长类动物仅在急性注意力集中期间的短暂发作中表现出θ振荡，尽管海马体解剖结构保守。灵长类动物θ振荡的相位性质及其对毒蕈碱拮抗剂的敏感性表明，乙酰胆碱传入神经会急性调节局部回路，导致海马体节律动力学的暂时转变。然而，我们缺乏将细胞生理学与出现的θ节律网络动力学联系起来的机制理解。我们探讨了乙酰胆碱诱导细胞特性发生独特调节以促进非人类灵长类神经元在θ波段内同步的假说。在这里，我们表明，来自猴海马体CA1区域的非人类灵长类神经元对不同频率输入的电压反应并不均匀，这种现象称为细胞共振。我们将这些神经元分为“共振型”或“非共振型”。在卡巴胆碱的影响下，这两类神经元在共振方面变得难以区分，这表明乙酰胆碱会暂时使对θ范围内输入的敏感性变得均匀。这种变化由增强下陷电位的代谢型乙酰胆碱受体介导，表明乙酰胆碱作用于主神经元以调节超极化激活的环核苷酸门控通道。我们的结果揭示了一种机制，通过该机制乙酰胆碱可以快速调节灵长类海马体神经元的内在特性，以促进θ节律回路内的同步，从而深入了解灵长类海马体生理学的独特特征。
