Altered local cortical interneuron signalling in the sleep-deprived state

One third of the UK's population experience sleep disturbances and the nature of modern society means that the health and economic impact of disrupted sleep is increasing. At the same time, sleep disturbances are observed in every major dis¬order of the brain, both neurological and psychiatric. Sleep disruption therefore represents a common factor in the diagnosis, aetiology, prevention and treatment of these disorders. Despite its ubiquity and importance, however, our understanding of the cellular changes that result from sleep disruption is still lacking. Determining the underlying cellular mechanisms would generate much needed advances in understanding how sleep deprivation affects cognition in healthy and disease states, and would identify intervention strategies for addressing the negative effects of sleep disturbances. A disruption in cognitive abilities is a familiar and well-documented feature of the sleep-deprived condition. Deficits in performance become evident after relatively short periods of extended wakefulness (hours) and affect processes including stimulus responsivity, attention, and memory. Responsivity and attention are particularly sensitive to sleep loss, with performance on tasks negatively correlating with the time spent awake. Attention becomes variable and exhibits 'lapses', resulting in unstable performance that manifests as failures to respond and errors in response. Studies that have monitored brain activity in humans indicate that acute sleep deprivation leads to an overall increase in cortical excitability, but has complex effects on oscillatory activities that reflect how cortical activity is organised in time. Sleep deprivation in humans results in an increase in low frequency oscillatory activity (including so-called delta and low theta bands; 0.5-6 Hz), which occurs across spatially-restricted areas of cortex and has been referred to as 'local sleep'. Sleep deprivation is also associated with increases in higher frequencies (>20 Hz), but decreases in intermediate frequencies such as the alpha band (8-12 Hz), which are associated with attentional processes. We have recently discovered that a lack of sleep is associated with significant changes to chemical transmission in the cortex - the brain region that is responsible for higher cognitive functions and is implicated in multiple neurological and psychiatric conditions. Our previous research revealed that sleep deprivation leads to changes in the ionic basis of inhibitory signaling at connections between cortical nerve cells, which alters the temporal pattern of electrical activity in the major excitatory neurons of the cortex. In this research proposal we will examine the effect of sleep deprivation upon another major type of cortical nerve cell called interneurons, which are responsible for releasing the inhibitory signaling molecule, GABA. We will investigate how periods of sleep deprivation affect different types of interneurons and particularly how these interneurons are themselves inhibited by other nerve cells. This is important because interneurons are key regulators of oscillatory activity in cortex, making them strong candidates for mediating the effects of sleep deprivation. Furthermore, these interneurons have become a focal point for understanding neurological disorders including schizophrenia, bipolar disorder, depression, and epilepsy.