Impaired spatial learning and suppression of sharp wave ripples by cholinergic activation at the goal location
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
Article and author information
Author details
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
© 2021, Jarzebowski et al.
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.
Metrics
-
- 2,622
- views
-
- 347
- downloads
-
- 20
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Neuroscience
Reward-rate maximization is a prominent normative principle in behavioral ecology, neuroscience, economics, and AI. Here, we identify, compare, and analyze equations to maximize reward rate when assessing whether to initiate a pursuit. In deriving expressions for the value of a pursuit, we show that time’s cost consists of both apportionment and opportunity cost. Reformulating value as a discounting function, we show precisely how a reward-rate-optimal agent’s discounting function (1) combines hyperbolic and linear components reflecting apportionment and opportunity costs, and (2) is dependent not only on the considered pursuit’s properties but also on time spent and rewards obtained outside the pursuit. This analysis reveals how purported signs of suboptimal behavior (hyperbolic discounting, and the Delay, Magnitude, and Sign effects) are in fact consistent with reward-rate maximization. To better account for observed decision-making errors in humans and animals, we then analyze the impact of misestimating reward-rate-maximizing parameters and find that suboptimal decisions likely stem from errors in assessing time’s apportionment—specifically, underweighting time spent outside versus inside a pursuit—which we term the ‘Malapportionment Hypothesis’. This understanding of the true pattern of temporal decision-making errors is essential to deducing the learning algorithms and representational architectures actually used by humans and animals.
-
- Neuroscience
The basic excitatory neurons of the cerebral cortex, the pyramidal cells, are the most important signal integrators for the local circuit. They have quite characteristic morphological and electrophysiological properties that are known to be largely constant with age in the young and adult cortex. However, the brain undergoes several dynamic changes throughout life, such as in the phases of early development and cognitive decline in the aging brain. We set out to search for intrinsic cellular changes in supragranular pyramidal cells across a broad age range: from birth to 85 y of age and we found differences in several biophysical properties between defined age groups. During the first year of life, subthreshold and suprathreshold electrophysiological properties changed in a way that shows that pyramidal cells become less excitable with maturation, but also become temporarily more precise. According to our findings, the morphological features of the three-dimensional reconstructions from different life stages showed consistent morphological properties and systematic dendritic spine analysis of an infantile and an old pyramidal cell showed clear significant differences in the distribution of spine shapes. Overall, the changes that occur during development and aging may have lasting effects on the properties of pyramidal cells in the cerebral cortex. Understanding these changes is important to unravel the complex mechanisms underlying brain development, cognition, and age-related neurodegenerative diseases.