Sleep homeostasis and synaptic plasticity

Sleep pressure – the internal drive to sleep – is proposed to be regulated by the interaction of circadian and homeostatic processes. In this two-process model, circadian mechanisms synchronize sleep drive to the day-night cycle while homeostatic sleep pressure responds to wake experience, increasing in parallel with wakefulness and dissipating again during sleep. The homeostatic regulation of sleep remains shrouded in mystery. One of the most exciting recent hypotheses concerning the function of sleep homeostasis is the “synaptic homeostasis” hypothesis. The basic idea is as follows: everyday behavior and learning produce a net increase in synaptic weights in the brain, meaning that the chemical connections between neurons are strengthened. One function of sleep is therefore to downscale or “normalize” all synapses in the brain, while maintaining the relative synaptic strength differences that have accrued through learning. But how is wake experience translated into sleep drive? Where in the brain does this occur? Is there a discrete sleep drive circuit (a homeostat) that operates in concert with the circadian circuitry or does sleep drive accumulate everywhere in the brain? This proposal aims to tackle these questions by studying where in the fly brain wake experience accumulates and how wake- and sleep promoting brain regions change their activity after sleep deprivation. This will result in a map of the inputs and outputs of the sleep homeostatic circuitry. The innovation in this proposal lies first in the application of a wide range of cutting edge approaches including the use of a novel technique to identify newly formed synapses in specific compartments of the fly brain (Aim 1B). In addition, we combine these techniques with well-established genetic and behavioral assays including both assessments of sleep, arousal thresholds and sleep homeostasis (Aim 1A, C), providing a multi-tiered approach (gene/neuron/ circuit/behavior) to integrate molecular and cellular results with behavior. Taking advantage of the facility of genetics in Drosophila, we are examining the functional role circuits in sleep homeostasis in this model system. Once we understand how sleep homeostasis is regulated in a small model organism, these findings can generate hypotheses on how sleep homeostasis is regulated in more complex organisms, paving the way to understanding and treating sleep disorders in patients.