Repository logo
 

Characterising hippocampal replay in the APPNL-G-F mouse model of Alzheimer’s disease


Type

Thesis

Change log

Authors

Shipley, Sarah 

Abstract

Memories which are initially dependent upon the hippocampus can gradually be incorporated into cortical networks, a process known as system-level consolidation. Replay, the rapid recapitulation of neural sequences experienced during behaviour, is thought to be a key mechanism supporting consolidation and predominantly occurs during rest and sleep. More generally replay is also held to play a role in memory retrieval, navigation, and likely planning. Consistent with these multiple roles, replay disruption negatively impacts performance on memory related tasks.

The hippocampus and associated structures are known to be among the first to exhibit signs of pathology in Alzheimer’s disease; a disorder characterized by progressive memory dysfunction. It is therefore pertinent to understand how functional changes in the hippocampus, including those related to replay, relate to the pathological and symptomatic changes that accumulate of the course of the disease. In this thesis I describe the results of two experiments in which the relationship between hippocampal replay and Alzheimer’s disease are investigated.

In the first experiment, I present a characterization of hippocampal replay in the APPNL-G-F knock-in rodent model of Alzheimer’s disease. Place cells were recorded from the CA1 region of the hippocampus as mice performed a radial-arm maze task, and during subsequent sleep. The task was designed to separably identify errors in reference and working memory. APPNL-G-F mice were found to make greater numbers of reference memory errors than control animals. This reduction in memory performance was related to an overall reduction in the rate at which replay occurred, both during sleep and during brief periods of inactivity in the maze. During waking periods, this deficit appeared to result from a reduction in the number of population activity bursts; some of which incorporated bona fide replay sequences. In sleep, this loss was further exacerbated by a reduction in the coherence of replay sequences; fewer of the candidate population bursts carried decodable sequences. It seems plausible that a deeper understanding of how Alzheimer’s pathology produces the deficits in replay described here, may lead to the identification of new therapeutic targets.

In the second experiment, I describe the interaction between cholinergic tone in the hippocampus and replay in both wild-type and APPNL-G-F mice. Acetylcholine levels are reduced in Alzheimer’s disease and acetylcholinesterase inhibitors, which increase the availability of acetylcholine in the brain, form one of the few approved therapeutic treatments. However, acetylcholine has been hypothesised to modulate the balance between encoding and consolidation, with falling cholinergic levels being necessary for replay to occur after new memories are encoded. To assess the role of acetylcholine in replay, I used a viral vector to exclusively express Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in medial septal cholinergic neurons of ChAT-cre mice. DREADDs were activated using systemic injection of an actuator (CNO), stimulating cholinergic release in the hippocampus and other brain regions. CNO was administered immediately prior to sleep, when Alzheimer’s sufferers are typically recommended to take acetylcholinesterase inhibitors. I found that increased cholinergic tone during sleep reduced the rate at which replay sequences occurred in APPNL-G-F mice. However, this changed was not associated with any further reduction in memory performance. Nevertheless, these results do indicate that that timing of therapeutic treatments targeting the cholinergic system should be considered relative to diurnal changes in neuromodulatory levels, and more generally the sleep-wake cycle.

Description

Date

2023-01-21

Advisors

Henson, Richard
Barry, Caswell

Keywords

Alzheimer's disease, Hippocampus, Replay

Qualification

Doctor of Philosophy (PhD)

Awarding Institution

University of Cambridge