Synaptic plasticity during cortical slow wave activity

Lead Research Organisation: University of Oxford
Department Name: Physiology Anatomy and Genetics


When neurons in the brain become excited, they 'fire' electrical impulses, which they rapidly transmit to all their contacts. The points at which neurons contact each other are called synapses, and long-term changes in the strength of these synaptic connections are thought to provide the biological basis of the brain's ability to learn and remember. If synaptic strengths are continuously altered as we go about our daily lives, is there a point at which the flow of electricity through the brain will eventually become congested? One hypothesis is that sleep provides a critical period for retuning synaptic connections, to enable continued and efficient learning.

During sleep, the brain alternates between two different patterns of electrical activity - low-amplitude fast oscillations, associated with rapid eye movements and vivid dreaming, and slow wave oscillations of deep sleep. It is the slow wave oscillations that have been implicated in playing a role in retuning synapses in brain circuits, but the cellular mechanisms have yet to be resolved. The aim of this project to record directly the strength of synaptic connections in cortical circuits, and determine how they change during sleep-related slow wave oscillations. We will use thin slices of brain tissue, which preserve the intrinsic patterns of slow wave oscillations, while allowing unprecedented access to monitor synaptic events using electrical measurements and optical imaging techniques. These experiments will determine how the precise sequences of neuronal firing during slow wave oscillations are translated into increases versus decreases in synaptic strength, and thus provide insights into rules and mechanisms by which slow wave sleep recalibrates neuronal circuits.

Sleep has previously been viewed as an evolutionary adaptation to conserve energy during dark and cold nights, but we now know that the brain is highly active during sleep, suggesting it has a positive function. Nevertheless, the need to sleep is still commonly viewed as a nuisance in our busy schedules, and we take stimulants and sedatives to override our biological clocks. Disturbances in sleep are correlated with problems in physical and mental health, and resolving the function of sleep is a critical step to determining the pathway to healthy aging.

Technical Summary

In slow wave sleep, cortical neurons display oscillations between hyperpolarised Down states and depolarised Up states. The rhythmic bouts of Up state activity have been proposed to provide the conditions for the downscaling synaptic weights built up during awake behaviour, and thus enable synaptic homeostasis in cortical networks. It has also been shown that sequences of neuronal firing observed during behaviour are replayed during slow wave sleep, supporting an alternative function of this sleep stage in memory consolidation and transfer. Our hypothesis is that synapses that participate directly in triggering postsynaptic spikes during Up state will be strengthened, while the majority that do not will be downscaled. To test this, we will record electrically-evoked synaptic events in layer 2/3 pyramidal neurons, in slices of medial entorhinal cortex that display spontaneous Up/Down states. Synaptic efficacy will be monitored in the Down state, and the effect of pairing protocols tested in the Up state. To resolve the dendritic calcium events underlying synaptic plasticity during Up states, we will load layer 2/3 pyramidal neurons with a high-affinity calcium indicator, and simultaneously image activated dendritic shafts and spines using a fast 3D scanning two-photon microscope. To determine whether isolated dendritic plateau potentials provide the salient trigger for synaptic strengthening, we will use the same microscopy system to image voltage changes in these thin dendritic structures. These experiments will provide insights into the functions of slow wave sleep in retuning cortical synapses.

Planned Impact

There are four potential pathways to impact of the proposed research:

1) Improved understanding of the basic biological functions of sleep
The aim of this project is to determine the mechanisms of synaptic plasticity during sleep-related slow wave oscillations in cortical circuits. The outcome of these experiments, disseminated throughout the time course of the project, will offer valuable insights for researchers attempting to understand the mechanisms of synaptic plasticity and the functions of sleep, as well as informing models of neural processing in wider areas of neuroscience research.

2) Establishing a cross-disciplinary research platform
Our collaborative approach will provide immediate expose of physiology researchers to the current developments in optical techniques that can enhance biological and health science, whilst providing researchers in optical engineering with experience in biological experiments to inform equipment design and implementation. Moreover, the Research Co-I will be trained in electrophysiological techniques, which will complement his engineering background, and thus provide essential skills that can be applied to dissecting further basic biological questions.

3) Technology Transfer
The application of a newly developed remote focusing two-photon microscope to address the fundamental cellular functions of sleep, will highlight the potential of remote focusing as an enabling technology. Disseminating the results of the research will identify remote focusing microscopy as a valuable tool to deliver key insights into broader fields of biomedical research, thereby creating a wider market for the technology as a commercial instrument.

3) Public health
Sleep is increasingly sacrificed in the face demands from work and society. Through our public engagement, we hope to use our results to argue that sleep has a critical function for plasticity in the brain, and to ensure a public understanding that sleep is a free resource to promote human health.


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Description During deep sleep, neurons display synchronised slow oscillations between periods of high activity (Up states) and periods of quiescence (Down states). It has been suggested that these slow wave oscillations play a role in retuning the strength of connections between neurons (synapses) following awake experience, and that this process is important for memory consolidation.
We have used thin slices of brain tissue, which preserve the intrinsic patterns of slow wave oscillations, to test directly how this activity modulates synaptic strength. We have found:
i) Synapses that are activated during Up states are preferentially weakened.
ii) The precise temporal correlation between presynaptic activation and postsynaptic spiking during Up states, enables synapses to be maintained or strengthened.
iii) Up states influence the amplitude and kinetics of postsynaptic calcium influx, which determines the nature of plasticity.
These findings suggest that slow wave sleep has a homeostatic role in down-scaling the overall strength of synaptic connections, but can also support active consolidation of memory traces.
Exploitation Route The aim of this project is to determine the mechanisms of synaptic plasticity during sleep-related slow wave oscillations in in the medial entorhinal cortex. We will take this forward in future projects in two directions:
i) Examining how slow wave sleep modulates synaptic strength in vivo
ii) Examining the role of dendritic mitochondria in regulating slow wave sleep plasticity.
Addressing these current and future questions requires advances in remote-focusing multiphoton microscopy, which will be of use to researchers across multiple disciplines.
The findings of these projects will benefit other researchers attempting to understand the mechanisms of synaptic plasticity, the functions of sleep, and how sleep disturbances impact human health.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

Description Our research project explores the role of slow wave sleep in oscillations in regulating plasticity in the brain. Sleep is increasingly sacrificed in the face demands from work and society, and becomes fragmented with age. Understanding the basic functions of sleep will be critical for informing public policy on the health and education, from school times for teenagers to sleep management in the elderly. We have presented our data at conferences, and publsihed the findings in high-quality journals. We continue to seek to highlight the research to non-academic communities, and plan to maximize the public impact of our research through our partnership with Prof Foster's Sleep and Circadian Neuroscience Institute. The project is going as planned, but, at present, we are not able to claim an impact beyond academia.
Description OXION 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution Edward Mann is a member of the Wellcome Trust funded Oxford Ion Channels and Disease Initiative. Our group provides training and expertise in electrophysiological recordings from neurons in culture and acute brain slices. We also collaborate with other groups in OXION to study (i) the role of glutamate receptors in synaptic plasticity and memory and (ii) neuro-cardiac interactions.
Collaborator Contribution OXION provides facilities for optical microscopy and in vivo electrophysiology for collaborations within the partnership.
Impact OXION is a multi-disciplinary partnership, that involves groups studying genetics, structural biology, cellular physiology and behaviour. We have had 4 joint rotation project students and 4 joint DPhil students join the laboratory through this partnership.
Start Year 2006
Description SCNi 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution The Sleep and Circadian Neuroscience Institute (SCNi) was funded by a Wellcome Trust Strategic Award to Professor Russel Foster, and is dedicated to understanding the neuroscience of sleep and how disruption of sleep impacts mental health. We are a collaborator on the award, providing expertise in synaptic physiology for examining the mechanistic links between sleep and neuropsychiatric disease. The project is currently at the stage of behavioural phenotyping of mouse models, and we have not yet performed in vitro experiments. We have regulator theme update meetings to discuss progress, in addition to the annual SCNi meeting.
Collaborator Contribution Professor Foster runs the SCNi, and coordinates the research programme across multiple themes.
Impact The collaboration is mulch-disciplinary, examining the links between sleep and neuropsychiatric disease using a combination of genetics, animal behavioral experiments, and human phenotyping.
Start Year 2012