Impaired spatial learning and suppression of sharp wave ripples by cholinergic activation at the goal location

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Abstract

The hippocampus plays a central role in long-term memory formation, and different hippocampal network states are thought to have different functions in this process. These network states are controlled by neuromodulatory inputs, including the cholinergic input from the medial septum. Here, we used optogenetic stimulation of septal cholinergic neurons to understand how cholinergic activity affects different stages of spatial memory formation in a reward-based navigation task in mice. We found that optogenetic stimulation of septal cholinergic neurons (1) impaired memory formation when activated at goal location but not during navigation; (2) reduced sharp wave-ripple (SWR) incidence at goal location; and (3) reduced SWR incidence and enhanced theta-gamma oscillations during sleep. These results underscore the importance of appropriate timing of cholinergic input in long-term memory formation, which might help explain the limited success of cholinesterase inhibitor drugs in treating memory impairment in Alzheimer's disease.

Data availability

Code used for the analysis and to generate the figures can be accessed on the authors' GitHub site: https://github.com/przemyslawj/ach-effect-on-hpc. Raw data are available on: https://drive.google.com/drive/folders/19PJazJRdXD3b8cieFVJorL8h8qLmjeh6

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Przemyslaw Jarzebowski

Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-6333-222X
Clara S Tang

Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Ole Paulsen

Department of Physiology, Development and Neuroscience, Physiological Laboratory, University of Cambridge, Cambridge, United Kingdom

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-2258-5455
Y Audrey Hay

Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom

For correspondence
ah831@cam.ac.uk

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-7765-5222

Funding

Biotechnology and Biological Sciences Research Council (BB/N019008/1)

Ole Paulsen

Biotechnology and Biological Sciences Research Council (BB/P019560/1)

Ole Paulsen

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal experiments were performed under the Animals (Scientific Procedures) Act 1986 Amendment Regulations 2012 following ethical review by the University of Cambridge Animal Welfare and Ethical Review Body (AWERB) under personal and project licenses held by the authors.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.