ESI Lecture by Chiara Cirelli

The Burden of Wake and the Reasons for Sleep

Sleep is universal, tightly regulated, and many cognitive functions are impaired if we do not sleep. But why? Any hypothesis about the essential function of sleep must take into account that when asleep we are essentially offline: sensory disconnection must be crucial for whatever function sleep serves. If not, natural selection would likely have found a way to perform the same function while awake, avoiding the danger of being unable to monitor the environment.

Over the past 20 years, we have developed and tested a comprehensive hypothesis about the core function of sleep: The Synaptic Homeostasis Hypothesis (SHY). SHY states that sleep is the price we pay for brain plasticity. During wakefulness the excitatory synapses that allow neurons to communicate with each other undergo net potentiation as a result of learning, an ongoing process that happens all the time while we are awake, constantly adapting to an ever-changing environment. The plasticity of the brain is essential for survival but is also a costly process, because stronger synapses increase the demand for energy and cellular supplies, lead to decreases in signal-to-noise ratios, and saturate the ability to learn. According to SHY during sleep, while our brain is offline, neural circuits can be reactivated, renormalizing synaptic strength. This renormalization favors memory consolidation and the integration of new with old memories, and eliminates the synapses that contribute more to the “noise” than to the “signal.” Just as crucially, synaptic renormalization during sleep restores the homeostasis of energy and cellular supplies, including many proteins and lipids that are part of the synapses, with beneficial effects at both the systems and cellular level.

I will discuss the rationale underlying this hypothesis and summarize electrophysiological, molecular and ultrastructural studies in flies, rodents and humans that confirmed SHY’s main predictions, including the recent observation, obtained in mice using serial block face scanning electron microscopy, that most cortical synapses grow after wake and shrink after sleep.