Sleep Homeostasis and Synaptic Plasticity
Abstract
After a busy day we are sleepy. Yet, how the brain translates this accumulated wake experience into sleep drive and eventually forces us to fall asleep remains a mystery. In this proposal, we aim to identify the neural circuitry that regulates this homeostatic sleep drive by mapping where in the brain sleep need is encoded and where it is translated into sleep drive. Sleep plays an increasingly important role in our society, especially now that our regular sleep-wake rhythms are more often disturbed by travel or work-related demands. Sleep-inducing pills are among the most widely prescribed medicines, and persistent loss of sleep can have severe consequences for the sleep-deprived person, as sleep disorders are associated with a wide range of medical and psychiatric conditions as well as diabetes, traumatic brain injury, and Alzheimer s disease. Loss of sleep also endangers the immediate surroundings of a sleep-deprived person, as sleep deprivation increases the risk of accidents on the road and in the workplace. Thus, improving sleep quantity or quality may alleviate or prevent certain types of mental illness as well as decrease sleep deprivation-related accidents in society. 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? To answer these questions, we need to study a brain that is highly accessible while still being similar enough to man to be a valuable model organism. The fruit fly Drosophila melanogaster is the best candidate, as it comes with a wide variety of genetic tools that allow precise control of gene expression and neuronal activity in discrete parts of the brain. At the same time, neuronal biochemistry is very similar -- flies and man respond in a similar manner to wake- and sleep-promoting drugs. 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. Given the role of sleep loss in predisposing individuals to neurobehavioral dysfunction and
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610169
Entities
People
- Ravi Allada
Organizations
- Northwestern University
- United States Army