Temporal dynamics of cholinergic activity in the septo-hippocampal system

Abstract

Cholinergic projection neurons in the medial septum and diagonal band of Broca are the major source of cholinergic modulation of hippocampal circuit functions that support neural coding of location and running speed. Changes in cholinergic modulation are known to correlate with changes in brain states, cognitive functions, and behavior. However, whether cholinergic modulation can change fast enough to serve as a potential speed signal in hippocampal and parahippocampal cortices and whether the temporal dynamics in such a signal depend on the presence of visual cues remain unknown. In this study, we use a fiber-photometric approach to quantify the temporal dynamics of cholinergic activity in freely moving mice as a function of the animal’s movement speed and visual cues. We show that the population activity of cholinergic neurons in the medial septum and diagonal band of Broca changes fast enough to be aligned well with changes in the animal’s running speed and is strongly and linearly correlated to the logarithm of the animal’s running speed. Intriguingly, the cholinergic modulation remains strongly and linearly correlated to the speed of the animal’s neck movements during periods of stationary activity. Furthermore, we show that cholinergic modulation is unaltered during darkness. Lastly, we identify rearing, a stereotypic behavior where the mouse stands on its hindlimbs to scan the environment from an elevated perspective, is associated with higher cholinergic activity than expected from neck movements on the horizontal plane alone. Taken together, these data show that temporal dynamics in the cholinergic modulation of hippocampal circuits are fast enough to provide a potential running speed signal in real-time. Moreover, the data show that cholinergic modulation is primarily a function of the logarithm of the animal’s movement speed, both during locomotion and during stationary activity, with no significant interaction with visual inputs. These data advance our understanding of temporal dynamics in cholinergic modulation of hippocampal circuits and their functions in the context of neural coding of location and running speed.

A Continuous Attractor Model with Realistic Neural and Synaptic Properties Quantitatively Reproduces Grid Cell Physiology

“…However, speed signals could also come from inhibitory INs [ 51 ], and a near real-time accurate speed code by firing rate may require fast-spiking INs [ 52 , 53 ]. Another alternative or complementary source of speed signal could come from the correlation of speed with theta rhythms [ 29 , 53 ] and related cholinergic [ 23 ] or glutamatergic [ 54 , 55 ] input from the medial septum. Expanding this SNN implementation of the CAN to include those additional mechanisms might help shed light on their computational plausibility.…”

Cholinergic modulation shifts the response of CA1 pyramidal cells to depolarizing ramps via TRPM4 channels with potential implications for place field firing

“…On the other hand, hippocampal ACh release in an animal placed in a novel environment has two components, one related to novelty, that disappears in a familiar environment ( Thiel et al, 1998 ), and one related to motor activity, associated with increased exploration ( Giovannini et al, 2001 ). Indeed, a recent fiber photometric study showed that part of the population activity in medial septal cholinergic neurons is correlated with the logarithm of running speed ( Kopsick et al, 2022 ). We are primarily interested in the component of the ACh signal related to novelty because of previous studies demonstrating modulation of place cell firing that was more pronounced during the first day in a novel environment ( Roth et al, 2012 ).…”

Special issue on cholinergic signalling

“…Behavioural exploration in rodents is associated with hindlimb rearing which is thought to be important for memory encoding (Layfield et al, 2023). Cholinergic tone is elevated during novel exploration including during periods of behavioural rearing (Acquas et al, 1996;Giovannini et al, 2001;Kopsick et al, 2022;van Abeelen, 1989). In this issue, Cassity et al (2024) utilized optogenetic inhibition of the medial septum to identify whether cholinergic activity promotes exploratory behaviour or whether it acts in concert with exploration to enhance spatial information encoding.…”