Sleep plays a critical role in maintaining metabolic homeostasis in the adult brain. Using real-time assessments of tetramethylammonium diffusion and two-photon imaging in live mice, the study shows that sleep or anesthesia increase the interstitial space by 60%, leading to enhanced convective exchange of cerebrospinal fluid (CSF) with interstitial fluid (ISF). This convective exchange increases the clearance of β-amyloid (Aβ) during sleep, suggesting that the restorative function of sleep is due to the removal of potentially neurotoxic waste products that accumulate during wakefulness. Sleep deprivation impairs brain function, reduces learning, and increases the risk of seizures. In humans, severe sleep disorders can lead to dementia and death. The brain lacks a conventional lymphatic system, but cerebrospinal fluid (CSF) circulates through the brain, exchanging with interstitial fluid (ISF) and removing interstitial proteins, including Aβ. This convective exchange is organized around the cerebral vasculature, with CSF influx around arteries and ISF exiting along veins. This system is called the glymphatic system, named for its dependence on astrocytic aquaporin-4 (AQP4) water channels and its function similar to peripheral lymphatic removal of interstitial metabolic byproducts. Deletion of AQP4 channels reduces Aβ clearance by 65%, indicating that convective movement of ISF is a major contributor to the removal of interstitial waste. Aβ concentration is higher in awake than in sleeping rodents and humans, suggesting that wakefulness is associated with increased Aβ production. The study tested the hypothesis that Aβ clearance is increased during sleep and that the sleep-wake cycle regulates glymphatic clearance. Using in vivo two-photon imaging, the study compared CSF influx into the cortex of awake, anesthetized, and sleeping mice. The results showed that sleep significantly increases CSF influx, while arousal reduces it. The interstitial space volume is smaller during wakefulness, which increases resistance to convective fluid movement and suppresses CSF influx. Anesthesia increases the interstitial space volume, leading to increased CSF influx. The study also found that sleep improves the clearance of Aβ, with Aβ cleared twofold faster in sleeping mice compared to awake mice. In addition, an inert tracer, 14C-inulin, was cleared more efficiently in sleeping and anesthetized mice compared to awake mice. The study suggests that adrenergic signaling in the awake state modifies cell volume and thus the size of the interstitial space. Adrenergic receptor antagonists increased CSF tracer influx, making it more comparable with influx observed during sleep or anesthesia. The findings indicate that adrenergic signaling plays an important role in modulating not only cortical neuronal activity but also the volume of the interstitial space. The study concludes that the restorative function of sleepSleep plays a critical role in maintaining metabolic homeostasis in the adult brain. Using real-time assessments of tetramethylammonium diffusion and two-photon imaging in live mice, the study shows that sleep or anesthesia increase the interstitial space by 60%, leading to enhanced convective exchange of cerebrospinal fluid (CSF) with interstitial fluid (ISF). This convective exchange increases the clearance of β-amyloid (Aβ) during sleep, suggesting that the restorative function of sleep is due to the removal of potentially neurotoxic waste products that accumulate during wakefulness. Sleep deprivation impairs brain function, reduces learning, and increases the risk of seizures. In humans, severe sleep disorders can lead to dementia and death. The brain lacks a conventional lymphatic system, but cerebrospinal fluid (CSF) circulates through the brain, exchanging with interstitial fluid (ISF) and removing interstitial proteins, including Aβ. This convective exchange is organized around the cerebral vasculature, with CSF influx around arteries and ISF exiting along veins. This system is called the glymphatic system, named for its dependence on astrocytic aquaporin-4 (AQP4) water channels and its function similar to peripheral lymphatic removal of interstitial metabolic byproducts. Deletion of AQP4 channels reduces Aβ clearance by 65%, indicating that convective movement of ISF is a major contributor to the removal of interstitial waste. Aβ concentration is higher in awake than in sleeping rodents and humans, suggesting that wakefulness is associated with increased Aβ production. The study tested the hypothesis that Aβ clearance is increased during sleep and that the sleep-wake cycle regulates glymphatic clearance. Using in vivo two-photon imaging, the study compared CSF influx into the cortex of awake, anesthetized, and sleeping mice. The results showed that sleep significantly increases CSF influx, while arousal reduces it. The interstitial space volume is smaller during wakefulness, which increases resistance to convective fluid movement and suppresses CSF influx. Anesthesia increases the interstitial space volume, leading to increased CSF influx. The study also found that sleep improves the clearance of Aβ, with Aβ cleared twofold faster in sleeping mice compared to awake mice. In addition, an inert tracer, 14C-inulin, was cleared more efficiently in sleeping and anesthetized mice compared to awake mice. The study suggests that adrenergic signaling in the awake state modifies cell volume and thus the size of the interstitial space. Adrenergic receptor antagonists increased CSF tracer influx, making it more comparable with influx observed during sleep or anesthesia. The findings indicate that adrenergic signaling plays an important role in modulating not only cortical neuronal activity but also the volume of the interstitial space. The study concludes that the restorative function of sleep