Research projects at VV lab:
1. Effects of sleep deprivation on cortical neuronal activity and cognitive performance (Funded by Marie-Curie Career Integration Grant to VV)
Sleep is a basic physiological state of the organism occupying approximately a third of our lives. It is believed that regular sleep is necessary for an optimal performance during waking. In humans, just a few hours of sleep deprivation can affect brain function, leading to tiredness, inability to concentrate, sleepiness and impaired judgment. The function of sleep still remains unknown despite the large progress in the understanding of basic aspects of sleep regulation.
It is well known that the tendency to fall asleep increases with increasing time awake. Moreover, if a night of sleep was skipped or no nap was taken during the day, then subsequent seep is deeper, or in other words, more intense. Sleep intensity is manifested in the size and number of brain waves occurring at slow frequency (1-4 per second). This process is called sleep homeostasis: the intensity of sleep increases in proportion to the duration of prior wakefulness. Increases in sleep slow waves after wakefulness have been documented in mice, rats, hamsters, rabbits, cats and humans. Since slow waves appear to reflect a need for sleep, it is important to establish which aspects of wakefulness are responsible for its increase, and what are the underlying mechanisms. For example, it is known that sleep slow waves occur when brain cells (so called neurones) increase or decrease their spiking activity in synchrony. However, it is unknown how the changes in the activity of neurones after extended wakefulness lead to objective and subjective cognitive decline.
The main question that will be addressed in this project is what happens to our brain and behaviour when we do not get sufficient sleep, and how the changes in behaviour are related to the changes in the brain activity. We will use laboratory mice and rats, which will be subjected to short-term sleep deprivation (four hours), which increases physiological propensity to fall asleep. At the same time we will use behavioural tasks, such as the discrimination between different visual stimuli, as a measure of cognitive function. We will record the activity of individual neurones with tiny electrodes implanted into the brain, during sleep deprivation, behavioural tasks and subsequent sleep. In addition, we will use pharmacological tools to investigate how to re-normalise brain activity and behaviour after sleep loss. This project will provide novel knowledge crucially important for sleep-related issues of public health and safety.
2. Sleep slow wave oscillations: effects of ageing and preceding sleep-wake history (BBSRC Industrial Case Studentship to VV and Eli Lilly)
We spend about 1/3 of our life asleep and we still do not know why. Investigating the dynamics of sleep across time can provide invaluable insights into its underlying mechanisms, and, ultimately, its function. Sleep shows systematic changes across time at two distinct scales. First, when we go to sleep in the evening, sleep is initially deep, but becomes progressively lighter across the night until we finally wake up in the morning. Notably, sleep depth increases further if we stayed awake for several hours beyond our habitual bedtime. Second, sleep is especially deep early in life, approximately until adolescence, and then progressively becomes more and more superficial, fragmented and difficult to maintain. Understanding the mechanisms underlying the change in sleep across a typical night and during our lifespan may provide unique insights into the function of sleep.
The main hallmarks of the electrical brain activity present during sleep are EEG slow waves. Deep sleep after prolonged wakefulness is characterized by an increase in the number and the amplitude of slow waves. Interestingly, sleep slow waves also show age-dependent changes: they are especially prominent in early age before adolescence and then decline steadily throughout the lifespan. The aim of this project is to investigate the cellular counterpart of the EEG slow waves - the slow oscillation - in vivo and in brain slices after sleep deprivation and across ontogeny. This project will provide new insights into the mechanisms underlying age-dependent changes in sleep quality and cognitive function.
The project will address the following specific points:
1) Preceding sleep/wake history. We will begin by investigating the effects of short-term (4-6 h) sleep deprivation on the parameters of the slow oscillation at the level of individual neurons and networks. Our research will allow us to establish cellular markers of preceding history of staying awake or asleep. Specifically, it will allow us to disentangle two alternative possibilities: whether preceding sleep-wake history affects the properties of the slow oscillation at a single-cell level, for example by altering specific ionic conductances, or whether the network properties are primarily affected. An intriguing possibility is that sleep deprivation differentially affects the slow oscillation in the cortical and thalamic neurons.
2) Development/Ageing. We will then investigate the development of the cortical and thalamic slow oscillation across ontogeny from early postnatal stages until old age. We hypothesize that spatio-temporal properties of the slow oscillation are not stable across age, but show systematic changes, that correlate with the overall quality of sleep. For example, it is well known that the amplitude of EEG slow waves is highest in early age and starts decreasing around adolescence. At the same time, sleep in middle-aged and older people is characterized by early awakening, difficulties in maintaining continuous sleep, and an increase in the number of arousals during the night. We will for the first time address the issue of whether the properties of the slow oscillation change with age, and whether these changes can account for the age-dependent changes in sleep. An intriguing possibility is that ageing differentially affects the properties of the slow oscillation at the level of single neurons and on a large scale of cortical networks.
The innovative aspect of this project consists of integrating several state-of-the-art approaches from single-cell neurophysiology to behaviour in the quest of understanding the effects of sleep deprivation and ageing on the brain and performance. This project will yield novel insights into the neuronal underpinnings of impaired cognition resulting from insufficient sleep and provide new and crucial knowledge that is important for both basic neuroscience and for sleep-related issues of public health and safety.
3. Investigating the neurophysiological basis of sleep quality (MRC New Investigator Award)
We spend about one third of our life asleep, yet we still do not know why sleep is necessary. The importance of sleep becomes especially apparent in primary sleep disorders such as insomnia, as well as in many other diseases associated with poor sleep. When we do not get sufficient sleep our mood worsens, we make more errors, we have a hard time focusing our attention and make poor judgments. Moreover, poor sleep is often a root cause of major accidents such as Chernobyl, Clapham Junction rail crash, the Challenger, Exxon Valdez oil spill and other tragedies, where sleep loss affected misjudgements probably happened. The UK Health and Safety Executive (HSE) makes the point that fatigue can lead to errors and accidents, ill-health and injury, and reduced productivity and has also been implicated in 20% of accidents on major UK roads and is said to cost the UK £115 - £240 million per year in terms of work accidents alone.
If we go to the doctor with a complaint about sleep problems or associated cognitive deficits while we are awake, we are usually asked to convey our subjective account in some form of an “analogue” scale that may result in an inaccurate assessment. Indeed, while “sleep quality” is a concept widely used in clinical practice, it is defined only vaguely and often only in qualitative terms. Existing quantitative measures of sleep quality, such as a total duration of sleep, measured with polysomnography, while useful in some cases, may often appear not adequate as there is a large variation of sleep parameters from patient to patient and these measures do not correlate well with the patient’s experience. Inaccurate assessment of sleep quality may lead to errors in diagnostics, and inadequate or inefficient treatment.
The aim of the current project is to provide an in-depth investigation of the factors that determine sleep quality, focusing for the first time on the electrical activity of many individual cells in the brain. The research strategy we intend to adopt for the current project is based on the recently established concept of “local sleep”, according to which some parts of the brain can be “asleep” while other are “awake” at the same time. This pattern of activity may be very useful, because it would allow some parts of the brain to take rest while others continue to work, but in some cases it may be very disruptive for brain function. For example, under certain conditions, some areas of our brain may be unable to "fall asleep" and remain in a "local wakefulness" state, resulting in us experiencing a very bad nights sleep even though from a behavioural perspective or when the brain waves are measured at the level of the scalp, it seems as if we have been asleep all night. The inability to obtain restorative sleep during the night, may, in turn, lead to an intrusion of brief episodes of "local sleep" during the day, resulting in overall poor wake quality, as manifested in attention lapses and many other cognitive deficits.
Therefore our hypothesis is that sleep quality, both in terms of how refreshed we feel in the morning and how well we perform during the day, depends precisely on how much local sleep and local wake occurred in our brain during the night. Testing this hypothesis will be crucial for improving the recognition and treatment of sleep disorders of various origins.
Research projects at VV lab: