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

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

doi:10.1371/journal.pcbi.1009435

Abstract

In the hippocampus, episodic memories are thought to be encoded by the formation of ensembles of synaptically coupled CA3 pyramidal cells driven by sparse but powerful mossy fiber inputs from dentate gyrus granule cells. The neuromodulators acetylcholine and noradrenaline are separately proposed as saliency signals that dictate memory encoding but it is not known if they represent distinct signals with separate mechanisms. Here, we show experimentally that acetylcholine, and to a lesser extent noradrenaline, suppress feed-forward inhibition and enhance Excitatory-Inhibitory ratio in the mossy fiber pathway but CA3 recurrent network properties are only altered by acetylcholine. We explore the implications of these findings on CA3 ensemble formation using a hierarchy of models. In reconstructions of CA3 pyramidal cells, mossy fiber pathway disinhibition facilitates postsynaptic dendritic depolarization known to be required for synaptic plasticity at CA3-CA3 recurrent synapses. We further show in a spiking neural network model of CA3 how acetylcholine-specific network alterations can drive rapid overlapping ensemble formation. Thus, through these distinct sets of mechanisms, acetylcholine and noradrenaline facilitate the formation of neuronal ensembles in CA3 that encode salient episodic memories in the hippocampus but acetylcholine selectively enhances the density of memory storage.

Highlights

The hippocampus plays a central role in the formation of episodic memories by processing information from the entorhinal cortex sequentially through the dentate gyrus, CA3 and CA1 regions
We further show in a spiking neural network model of CA3 how acetylcholine-specific network alterations can drive rapid overlapping ensemble formation
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

Summary

Introduction

The hippocampus plays a central role in the formation of episodic memories by processing information from the entorhinal cortex sequentially through the dentate gyrus, CA3 and CA1 regions. This process is related to memory retrieval, in which external sources of input will alter the state of the network by activating subsets of neurons and through recurrent dynamics will be driven towards these stable states in which all neurons in the ensemble are reactivated– a process referred to as pattern completion [7,8] Within this framework, memory encoding is believed to be the procedure of altering the network through synaptic plasticity to create or change the position of attractor states [9,10]. Not all memories are stored, indicating that there may be a gate to select which experiences should be encoded, but it is unclear how such a filter might operate

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Conclusion