Tohoku University researchers have shown that astrocytes — star-shaped glial cells that control the brain’s local ionic and metabotropic environment — exhibit an acidic response to REM sleep in mice. They theorize that the acidic response may be the underlying drive for specific information processing and the generation of plasticity during sleep.
They also discovered that the REM response increased in astrocytes in the epileptic brain, meaning that studying changes in the brain environment associated with REM sleep could potentially be used as a biomarker for the severity of epileptogenesis.
The results were detailed in the journal Brain on March 3, 2023.
Neurons are undoubtedly responsible for information processing in the brain. Astrocytes were not considered an essential part of the neuronal information circuitry. However, recent evidence suggests that the state of the mind, such as consciousness, sleep, memory formation, and metaplasticity, can all be controlled through the actions of astrocytes.
To understand the role of astrocytes in brain function, fluorescent sensor proteins were genetically expressed in mouse astrocytes. The researchers implanted an optical fiber into the mice’s lateral hypothalamus, a part of the brain crucial in controlling our sleep or wakefulness and whole-body metabolism.
Excitation light was sent through this fiber and the emitted fluorescence signals were recorded. Using a newly developed method, the researchers dissected the calcium concentration and the pH value of the astrocytes as well as the local changes in the blood volume in the brain from the recorded optical signals.
A marked change in the optical signals associated with REM sleep was observed. A decrease in calcium, a decrease in pH (ie acidification), and an increase in local cerebral blood volume occurred. The researchers found that acidification and changes in blood volume have a strong impact on optical signals; Therefore, many of the earlier studies using fiber photometry may have misinterpreted their recorded data.
The acidification was particularly unexpected since the intracellular cell solution is highly buffered in pH. Strong acidification occurs with ischemia, but pH changes were not thought to occur under physiological conditions. This acidification of astrocytes may drive amplification of synaptic signals and underlie memory formation during REM sleep.
Interestingly, the changes in the local brain environment detected with the optical recordings preceded the signature change in the ensemble’s neuronal electrical activity detected with the electroencephalogram by almost 20 seconds. This suggests that astrocytes and vascular changes control the state of neuronal activity. The transition to REM sleep can also be predicted from these local changes in the brain environment.
“During REM sleep, previous experiences are sorted and remembered or forgotten, and this process is likely to be perceived as dreams,” says Professor Ko Matsui of the Super-network Brain Physiology Lab at Tohoku University, who led the research. “Astrocyte acidification may control the likelihood of plasticity in neural circuits.”
Researchers continued to study how the characteristics of REM sleep change in epilepsy. Repeated stimulation of the mouse hippocampus produces a brain prone to hyperactivity, and this kinding method has been used as a model of epileptogenesis. After kindling, spontaneously occurring REM sleep episodes were recorded. Surprisingly, only very small decreases in astrocytic calcium and local increases in blood volume in the brain occurred during REM sleep, and a strong acid response of astrocytes was recorded.
“Our previous study showed an increased acid response of astrocytes associated with increased epileptic seizures,” said lead study investigator Dr. Yoko Ikoma. “Information is transmitted and processed with electrical signals in neurons. Astrocytic pH can control these neuronal activities in both physiology and disease.”
Monitoring of total pH and local cerebral blood flow is possible in humans with fMRI. Ikoma says these local changes in the brain environment associated with REM sleep could potentially be used to diagnose the severity of epilepsy in human patients. “A therapeutic strategy to control astrocyte pH could potentially be used to prevent exacerbation of epilepsy.”