Modulating medial septal cholinergic activity reduces medial entorhinal theta frequency without affecting speed or grid coding

Francis Carpenter,Caswell Barry,Neil Burgess

doi:10.1038/s41598-017-15100-6

Abstract

Medial septal inputs to the hippocampal system are crucial for aspects of temporal and spatial processing, such as theta oscillations and grid cell firing. However, the precise contributions of the medial septum’s cholinergic neurones to these functions remain unknown. Here, we recorded neuronal firing and local field potentials from the medial entorhinal cortex of freely foraging mice, while modulating the excitability of medial septal cholinergic neurones. Alteration of cholinergic activity produced a reduction in the frequency of theta oscillations, without affecting the slope of the non-linear theta frequency vs running speed relationship observed. Modifying septal cholinergic tone in this way also led mice to exhibit behaviours associated with novelty or anxiety. However, grid cell firing patterns were unaffected, concordant with an absence of change in the slopes of the theta frequency and firing rate speed signals thought to be used by grid cells.

Highlights

The medial septal nucleus (MS) of the basal forebrain contains a mixture of GABAergic, glutamatergic, and cholinergic neurones, each with projections to the hippocampus and entorhinal cortex[1,2,3,4]
Immunohistochemical staining for Choline Acetyltransferase (ChAT) and mCherry confirmed that expression of hM3Dq was limited to the MS (Fig. 1B), while confocal imaging indicated a tight overlap in expression of ChAT and mCherry (Fig. 1C)
Cell counting revealed that mCherry was expressed in the majority of ChAT + neurones of the MS (Supp Fig. 1D; mean ± SEM proportion of ChAT + neurones co-labelled for mCherry = 0.57 ± 0.039), while almost all mCherry + neurones were ChAT + (Supp Fig. 1E; mean ± SEM proportion of mCherry + neurones co-labelled for ChAT = 0.95 ± 0.0032), indicating that hM3Dq was expressed almost exclusively in cholinergic neurones

Summary

Introduction

The medial septal nucleus (MS) of the basal forebrain contains a mixture of GABAergic, glutamatergic, and cholinergic neurones, each with projections to the hippocampus and entorhinal cortex[1,2,3,4]. In suggesting that an animal’s running speed is encoded in the firing rates of septal and entorhinal neurones, which, when combined with directional information, can be used to shift the grid cell representation of self-location[19,20] At present it is unknown which of these speed signals are used to update grid firing, and what the precise functional contribution of the MS to grid cell processing is. The absence of change in the slopes of these putative speed signals was consistent with a lack of change in grid cell firing patterns These results provide evidence for an involvement of MS cholinergic neurones in the determination of the frequency of theta oscillations, but not in the determination of theta-frequency and firing-rate speed signals, preventing conclusions being drawn regarding which is central to the updating of the grid cell code for self-location. Modulation of septal cholinergic activity led mice to display a pattern of behaviours consistent with anxiety or the detection of novelty

Methods

Results

Conclusion