CHOLINERGIC MODULATION OF CELLULAR RESONANCE IN NON-HUMAN PRIMATE HIPPOCAMPUS

Abstract

Acetylcholine modulates the network physiology of the hippocampus, a crucial brain structure that supports cognition and memory formation in mammals 1-3. 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 4-10. Acetylcholine facilitates the hippocampus entering a theta oscillatory regime and modulates the temporal organization of activity within theta oscillations 11,12. 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 13-16. The phasic nature of primate theta oscillations and their susceptibility to muscarinic antagonists 17, 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 18,19. 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.