Septal cholinergic input to CA2 hippocampal region controls social novelty discrimination via nicotinic receptor-mediated disinhibition

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.

Medial septum: relevance for social memory

“…Among different brain networks contributing to social memory formation, the medial septum-diagonal band of Broca complex (MS) has recently emerged as a relevant region (Pimpinella et al, 2021 ; Wu et al, 2021 ). The MS has been mainly studied for its bidirectional communication with the hippocampus and its contribution to hippocampal-dependent contextual memory (Hasselmo, 2006 ; Khakpai et al, 2013 ).…”

“…In rodents, social memory has been causally linked to the activity of the dorsal CA2 and the ventral CA1 hippocampal regions (Hitti and Siegelbaum, 2014 ; Okuyama et al, 2016 ). Recent evidence pointed out the requirement of the MS-CA2 pathway for social novelty discrimination and social memory stability (Pimpinella et al, 2021 ; Wu et al, 2021 ). In humans, the activation of neurons in the temporal lobe, including the hippocampus, has been associated to face recognition (Quiroga et al, 2005 ) but the role of MS in this process has not been elucidated yet.…”

“…In adult mice, cholinergic signaling is crucial for social memory as well, as cholinergic neurons activate in response to social stimuli. In addition, the selective silencing of MS cholinergic neurons by tetanus toxin or chemogenetic approaches impairs the recognition of a novel mouse over a familiar one in the three chamber test (Pimpinella et al, 2021 ). These manipulations do not affect the preference for an animal as compared to an object indicating that MS signaling is not required for social interactions (Pimpinella et al, 2021 ; Wu et al, 2021 ; but see Okada et al, 2021 ).…”

“…In addition, the selective silencing of MS cholinergic neurons by tetanus toxin or chemogenetic approaches impairs the recognition of a novel mouse over a familiar one in the three chamber test (Pimpinella et al, 2021 ). These manipulations do not affect the preference for an animal as compared to an object indicating that MS signaling is not required for social interactions (Pimpinella et al, 2021 ; Wu et al, 2021 ; but see Okada et al, 2021 ). Social memory is under the control of ACh released in the CA2 region of the hippocampus as cholinergic axon terminal inhibition or nicotinic ACh receptors (nAChRs) blockade mimic MS cholinergic neuron silencing (Pimpinella et al, 2021 ).…”

“…These manipulations do not affect the preference for an animal as compared to an object indicating that MS signaling is not required for social interactions (Pimpinella et al, 2021 ; Wu et al, 2021 ; but see Okada et al, 2021 ). Social memory is under the control of ACh released in the CA2 region of the hippocampus as cholinergic axon terminal inhibition or nicotinic ACh receptors (nAChRs) blockade mimic MS cholinergic neuron silencing (Pimpinella et al, 2021 ). Here, ACh preferentially targets nAChRs expressed on GABAergic interneurons leading to principal cell disinhibition (Pimpinella et al, 2021 ).…”