Abstract
Acetylcholine (ACh), released in the hippocampus from fibers originating in the medial septum/diagonal band of Broca (MSDB) complex, is crucial for learning and memory. The CA2 region of the hippocampus has received increasing attention in the context of social memory. However, the contribution of ACh to this process remains unclear. Here, we show that in mice, ACh controls social memory. Specifically, MSDB cholinergic neurons inhibition impairs social novelty discrimination, meaning the propensity of a mouse to interact with a novel rather than a familiar conspecific. This effect is mimicked by a selective antagonist of nicotinic AChRs delivered in CA2. Ex vivo recordings from hippocampal slices provide insight into the underlying mechanism, as activation of nAChRs by nicotine increases the excitatory drive to CA2 principal cells via disinhibition. In line with this observation, optogenetic activation of cholinergic neurons in MSDB increases the firing of CA2 principal cells in vivo. These results point to nAChRs as essential players in social novelty discrimination by controlling inhibition in the CA2 region.
Highlights
Acting in the brain as a neurotransmitter and a neuromodulator, acetylcholine (ACh) controls neuronal circuits involved in attention, learning, and memory
ACh released from cholinergic neurons of the medial septum/diagonal band of Broca (MSDB) is required for social novelty discrimination To evaluate the extent of MSDB cholinergic fibers targeting the hippocampus, we injected an AAV- DIO-C hR2-mCherry virus into the MSDB of 1-month-o ld male mice-expressing Cre recombinase in acetylcholine transferase-positive neurons (ChAT-C re) (Figure 1A). mCherry was expressed in cells bodies of neurons in the MSDB (Figure 1B) and in cholinergic fibers targeting different hippocampal areas (Figure 1C)
Counting of MSDB c-Fos+ nuclei was evaluated in home-caged control (HCC) mice or in animals exposed to social interaction (SI) by performing sociability and social novelty discrimination tasks in the three-c hamber test (Moy et al, 2004)
Summary
Acting in the brain as a neurotransmitter and a neuromodulator, acetylcholine (ACh) controls neuronal circuits involved in attention, learning, and memory (for review see Hasselmo, 2006). ACh, released from cholinergic terminals via both wired and volume transmission, targets nicotinic and muscarinic receptors (nAChRs and mAChRs) differently distributed in subcellular domains and cell types across the hippocampal layers Activation of nAChRs and mAChRs, which relies on local ACh concentration controlled by the hydrolytic action of acetylcholinesterase (Vijayan, 1979), leads to complex effects on neuronal excitability, synaptic plasticity, rhythmic oscillations, brain states, and behavior (for review see Teles-Grilo Ruivo and Mellor, 2013; Dannenberg et al, 2017; Haam and Yakel, 2017)
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