Final Report Summary - SLEEPNEED (Cortical neuronal mechanisms of behavioural and cognitive deficits after sleep deprivation)
Chronic sleep deprivation and sleep disorders are experienced by millions of people in our society, and sleep loss has profound effects on brain activity and cognitive functions. Surprisingly, little is still known what happens in the brain after sleep deprivation that makes us feel tired and impaired even in simple tasks. Sleep disturbances as well as circadian rhythm disruptions are also typical for many psychiatric and neurological disorders, but the underlying mechanisms remain poorly understood. Notably, ageing and neurological disorders are associated with deficits in synaptic plasticity, cognitive and behavioural deficits. Given strong links between sleep, attention and cognition, it is likely that renormalisation of sleep quality will also improve numerous waking functions.
The objective of SleepNeed project was to investigate neuronal mechanisms underlying behavioural, sensory and cognitive changes incurred after sleep deprivation through a comprehensive suite of neurophysiological techniques and methodologies. We have performed several behavioural, electrophysiological and pharmacological experiments, which revealed a complex picture where waking experiences, brain state, immediate preceding and long-term history affect the activity of cortical networks and individual neurons.
Our achievements can be briefly summarised as follows:
1. We have established the visual discrimination task (VDT) for the first time as a tool to investigate the effects of preceding sleep-wake history on behaviour, learning and brain activity in young and older mice;
2. We performed continuous recordings of cortical neuronal activity in freely moving mice during running wheel activity, and found that stereotypic running is associated with a stable, uniform cortical state, characterised by substantially reduced cortical neuronal activity. The duration of wake bouts dominated by running was increased, while wake-dependent changes in neuronal excitability were attenuated, suggesting that automatic waking behaviours may have a lower metabolic cost, and result in a slower accumulation of homeostatic sleep need;
3. We for the first time have successfully applied a computer modelling approach to estimate the parameters of homeostatic Process S in mice using the elaborated version of the two process model. This opened up novel opportunities for assessing quantitatively sleep homeostasis in mouse mutants with sleep phenotypes (the work currently in progress), and to provide mechanistic and functional understanding understand of the alterations at the molecular and neuronal levels that give rise to specific changes in sleep homeostasis.
4. We for the first time performed successful recordings of cortical local field potential and neuronal activity in one- and two-year old mice, and observed characteristic changes in network activity, such as increased duration of neuronal OFF periods and decreased functional connectivity between local cortical regions. Our new results will help answering the long-standing and controversial question of age-dependent changes in sleep regulation.
5. We performed first investigation of sleep EEG in GluA1-/- mice and discovered a substantial reduction of EEG spindle activity in the mutant animals. To our knowledge, this represents the first mouse model in which a specific behavioural phenotype relevant for psychosis is associated with a corresponding sleep EEG phenotype. Mechanistically, our data suggest a pivotal role of glutamatergic neurotransmission mediating this link.
6. We have for the first time performed continuous cortical LFP/MUA recordings after diazepam injection in freely-moving mice. Benzodiazepines potentiate GABA-ergic neurotransmission and have been shown to substantially decrease EEG slow-wave activity and increase sleep spindles. However, cortical neuronal activity after diazepam has not been performed previously. Unexpectedly, we found only minor changes in overall neuronal activity after diazepam, although neuronal OFF periods were virtually absent.
7. We for the first time performed continuous simultaneous recordings from the motor cortex and the dorsal striatum in freely moving mice, both during a behavioural task (visuo-motor conditional learning and during sleep deprivation). We found that slow-wave activity in the striatum is regulated homeostatically.
During the four year period since the award has been made, the PI has finalised setting up the state-of-the-art Sleep and Behaviour Laboratory (vvlab.org) at the University of Oxford. The PI has made a significant progress in his career development and re-integration, such as:
1. He has been awarded a title of Associate Professor of Neuroscience at the Department of Physiology, Anatomy and Genetics. It is envisaged that his Senior Fellow position will progress in a tenured University Lecturer position in due course.
2. Since the award has been made, the PI has co-authored 20 peer-review publications, including three last-author papers.
3. Three of his current DPhil students have successfully confirmed their DPhil status, and expected to submit thesis in 2017. His current research group is currently comprised of three postdoctoral fellows, and four full time PhD students (primary supervisor), and he is a co-supervisor of other four full time PhD students.
4. Since the award has been made, the PI has received several competitive grants, including New Investigator Grant from the Medical Research Council and funding from the BBSRC, Royal Society Research Grant, OUP John Fell Fund, European Space Agency and Oxford-Brain@McGill-ZNZ Partnership in the Neurosciences Funding.
5. The PI has been invited frequently to present at major international meetings and institutional seminars, including several keynote lectures.
The objective of SleepNeed project was to investigate neuronal mechanisms underlying behavioural, sensory and cognitive changes incurred after sleep deprivation through a comprehensive suite of neurophysiological techniques and methodologies. We have performed several behavioural, electrophysiological and pharmacological experiments, which revealed a complex picture where waking experiences, brain state, immediate preceding and long-term history affect the activity of cortical networks and individual neurons.
Our achievements can be briefly summarised as follows:
1. We have established the visual discrimination task (VDT) for the first time as a tool to investigate the effects of preceding sleep-wake history on behaviour, learning and brain activity in young and older mice;
2. We performed continuous recordings of cortical neuronal activity in freely moving mice during running wheel activity, and found that stereotypic running is associated with a stable, uniform cortical state, characterised by substantially reduced cortical neuronal activity. The duration of wake bouts dominated by running was increased, while wake-dependent changes in neuronal excitability were attenuated, suggesting that automatic waking behaviours may have a lower metabolic cost, and result in a slower accumulation of homeostatic sleep need;
3. We for the first time have successfully applied a computer modelling approach to estimate the parameters of homeostatic Process S in mice using the elaborated version of the two process model. This opened up novel opportunities for assessing quantitatively sleep homeostasis in mouse mutants with sleep phenotypes (the work currently in progress), and to provide mechanistic and functional understanding understand of the alterations at the molecular and neuronal levels that give rise to specific changes in sleep homeostasis.
4. We for the first time performed successful recordings of cortical local field potential and neuronal activity in one- and two-year old mice, and observed characteristic changes in network activity, such as increased duration of neuronal OFF periods and decreased functional connectivity between local cortical regions. Our new results will help answering the long-standing and controversial question of age-dependent changes in sleep regulation.
5. We performed first investigation of sleep EEG in GluA1-/- mice and discovered a substantial reduction of EEG spindle activity in the mutant animals. To our knowledge, this represents the first mouse model in which a specific behavioural phenotype relevant for psychosis is associated with a corresponding sleep EEG phenotype. Mechanistically, our data suggest a pivotal role of glutamatergic neurotransmission mediating this link.
6. We have for the first time performed continuous cortical LFP/MUA recordings after diazepam injection in freely-moving mice. Benzodiazepines potentiate GABA-ergic neurotransmission and have been shown to substantially decrease EEG slow-wave activity and increase sleep spindles. However, cortical neuronal activity after diazepam has not been performed previously. Unexpectedly, we found only minor changes in overall neuronal activity after diazepam, although neuronal OFF periods were virtually absent.
7. We for the first time performed continuous simultaneous recordings from the motor cortex and the dorsal striatum in freely moving mice, both during a behavioural task (visuo-motor conditional learning and during sleep deprivation). We found that slow-wave activity in the striatum is regulated homeostatically.
During the four year period since the award has been made, the PI has finalised setting up the state-of-the-art Sleep and Behaviour Laboratory (vvlab.org) at the University of Oxford. The PI has made a significant progress in his career development and re-integration, such as:
1. He has been awarded a title of Associate Professor of Neuroscience at the Department of Physiology, Anatomy and Genetics. It is envisaged that his Senior Fellow position will progress in a tenured University Lecturer position in due course.
2. Since the award has been made, the PI has co-authored 20 peer-review publications, including three last-author papers.
3. Three of his current DPhil students have successfully confirmed their DPhil status, and expected to submit thesis in 2017. His current research group is currently comprised of three postdoctoral fellows, and four full time PhD students (primary supervisor), and he is a co-supervisor of other four full time PhD students.
4. Since the award has been made, the PI has received several competitive grants, including New Investigator Grant from the Medical Research Council and funding from the BBSRC, Royal Society Research Grant, OUP John Fell Fund, European Space Agency and Oxford-Brain@McGill-ZNZ Partnership in the Neurosciences Funding.
5. The PI has been invited frequently to present at major international meetings and institutional seminars, including several keynote lectures.