Separable actions of acetylcholine and noradrenaline on neuronal ensemble formation in hippocampal CA3 circuits

Luke Y. Prince, Travis Bacon, Rachel Humphries, Krasimira Tsaneva-Atanasova, Claudia Clopath, Jack R. Mellor

Abstract: Author summary How the brain decides which experiences to encode to memory and which to discard is a fundamental question in neuroscience. The neuromodulators acetylcholine and noradrenaline are believed to separately play a central role in determining what is encoded but the mechanisms by which they act are mostly unknown and there have been no direct comparisons made between these two critical neuromodulators. In this study, we investigate the effects of acetylcholine and noradrenaline on a key circuit responsible for the encoding of memories, namely, the dentate gyrus–CA3 microcircuit in the hippocampus. Using slice electrophysiology, we measure the effects of acetylcholine and noradrenaline on key synaptic and cellular nodes within this neuronal network. We then explore the network level implications of these findings on neuronal ensemble formation using a hierarchy of computational models. Based on the observed physiological effects of acetylcholine and noradrenaline, our models predict that acetylcholine facilitates efficient formation of ensembles within CA3 with a high degree of overlap whereas noradrenaline has more limited effects and no impact on the efficiency or overlap of ensemble formation.