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

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.

Organization and Plasticity of Inhibition in Hippocampal Recurrent Circuits

“…Complementarily, a common excitatory input to these cell types that is activated during immobility could explain their sustained immobility activation. Although such an input remains to be found, neuromodulatory afferents are attractive candidates (Atherton et al, 2015; Kaufman et al, 2020; Prince et al, 2021), as they have been shown to regulate interneuron dynamics during locomotion/immobility in the neocortex (Fu et al, 2014). Of particular interest, serotonergic afferents from the median raphe have been shown to selectively target CCK and CB cells in CA1 (Freund et al, 1990; Varga et al, 2009), and certain serotonin receptor subtypes are depolarizing and restricted to CGE- derived interneurons (5-HT3AR).…”

“…Indeed, subsets of medial septal GABAergic cells have been shown to selectively target AACs and CCKs in CA3 (Joshi et al, 2017), and some medial septal GABAergic cells have been shown to be activated during hippocampal SWRs (Viney et al, 2013). However, many subcortical areas have been shown to be modulated before SWRs (Logothetis et al, 2012), some of which have known afferents to the hippocampus (Atherton et al, 2015; Prince et al, 2021). This also includes subsets of raphe cells (Varga et al, 2009) that decrease their firing rate approximately one second before SWRs (Wang et al, 2015).…”

Tooth Loss Suppresses Hippocampal Neurogenesis and Leads to Cognitive Dysfunction in Juvenile Sprague–Dawley Rats

“…The hippocampus is crucial for memory storage and conversion ( Mujawar et al, 2021 ; Prince et al, 2021 ). It contains the CA1–4 region, which is mainly composed of pyramidal neurons.…”