What happens to the brain during sleep

“During wakefulness, our brain is constantly active, particularly the frontal regions responsible for judgment, movement, and action execution. Wakefulness is regulated by many neurotransmitters chemical messengers that enable communication between neurons such as glutamate, GABA, dopamine, acetylcholine, noradrenaline, adrenaline, histamine, and orexin. During sleep, however, the brain’s frontal regions consume very little energy. The neurotransmitters that maintain the state of rest are fewer: GABA and galanin are involved in Non-REM sleep, while acetylcholine is active during REM sleep,” explains Ferini-Strambi.

Sleep consists of 4–5 cycles in which the Non-REM phases (stages 1, 2, and 3) alternate with the REM phase:

• Stage 3 Non-REM is deep sleep, during which activity in the brain’s frontal regions is at its lowest. This stage, which dominates the first part of the night, is essential for restoring much of the energy used during the day and for consolidating declarative memory—that is, memories tied to personal facts like name and date of birth, and autobiographical events.
• REM sleep (Rapid Eye Movement), which is longer in the second half of the night, is the stage in which we dream. It’s important for consolidating procedural memory, which helps us remember how to perform tasks, and emotional memory.

“During deep Non-REM sleep in particular, the brain undergoes a cleanup process that removes waste products generated by neural activity. This ‘brain washing’ is performed by the glymphatic system,” says Ferini-Strambi.

In 2012, Danish neuroscientist Maiken Nedergaard first described the glymphatic system: a tiny space just nanometers wide located between cerebral capillaries and the end-feet of astrocytes a type of glial cell that provides mechanical and nutritional support to neurons.

“At night, this space fills with cerebrospinal fluid, which during the day accumulates waste products from neural activity. The glymphatic system acts like a waste management service: overnight, it drains this fluid full of potentially neurotoxic debris, thereby protecting the brain,” explains Professor Furlan.

Among the waste materials are:

• Beta-amyloid protein, whose accumulation is associated with Alzheimer’s disease
• Cellular debris, including remnants of synapses (the connections between neurons)

Normally, memories are stored in the brain as synaptic connections between neurons. However, the brain cannot retain the full flood of information it receives daily. It selectively strengthens useful connections and eliminates the rest. This synaptic pruning produces cellular debris that the glymphatic system must then remove.

“To learn and retain information long-term, the brain must strike a balance between strengthening and pruning synapses. This balance and the resulting memory consolidation is made possible in part by the glymphatic system’s cleanup activity. Because this system is most active during deep sleep, quality sleep is essential for long-term memory,” adds Furlan.

For the glymphatic system to function effectively, it’s not only important to get enough deep sleep but also to sleep on your side.

“As research, including our own at San Raffaele, has shown, the glymphatic system clears waste more effectively when we sleep on our side, compared to sleeping on our back,” notes Professor Ferini-Strambi.

Today, it’s possible to indirectly observe glymphatic system activation in humans through specific functional MRI protocols, which measure brain activity.

Another indirect method is to measure blood levels of neurofilament light chains, which are proteins from the neuronal cytoskeleton that can enter the glymphatic system as a result of synaptic pruning during memory consolidation.

“Studies have shown that levels of these neurofilaments in the blood are higher in the morning than in the evening. Scientists interpret this rise as evidence of the glymphatic system’s overnight activity in transporting waste proteins out of the brain,” says Furlan.

Another key function of the glymphatic system is to channel waste fluids into the lymphatic vessels located in the dura mater the tough membrane that lines the inside of the skull and protects the brain.

For a long time, scientists believed the brain had no lymphatic vessels. Elsewhere in the body, these vessels remove foreign agents like viral proteins and carry them to lymph nodes, where immune cells neutralize them.

“Shortly after the glymphatic system was discovered, meningeal lymphatic vessels were described in 2015. These vessels presumably collect waste and threats from the brain, carried there by the glymphatic system. Interestingly, the existence of these vessels had already been illustrated in the late 18th century by neuroanatomist and illustrator Paolo Mascagni, but they were only recently recognized for what they are. Because meningeal lymphatic vessels so closely resemble blood vessels in both structure and molecular makeup, the researchers who described them in 2015 had a hard time convincing the scientific community of their discovery,” explains Professor Furlan.

How the glymphatic system, which bathes the brain, interacts with these peripheral lymphatic vessels is still unclear.

“Research is ongoing to better understand the physiology of the glymphatic system in healthy humans. This knowledge will also help us understand what happens when the system becomes obstructed, for example, by the accumulation of beta-amyloid in Alzheimer’s disease. It’s likely that future neurology textbooks will include a chapter on glymphaticopathies, conditions involving dysfunction of the glymphatic system. Much remains to be discovered about its physiology and potential involvement in immune responses,” concludes Furlan.