A series of experiments on young and aged mice found that hyperexcitability of a specific type of neurons, called hypocretin neurons, in the lateral hypothalamus regions of the brain is strongly associated with fragmented sleep and sleep instability that develop with age in mice. Based on the results, researchers propose a strategy for medical treatment of similar age-related sleep problems in humans. The study was published in Science.
Sleep problems often develop with age and the decline of cognitive functions. The most common type of sleep problem in elderly populations is sleep fragmentation. Fragmented sleep happens when a person experiences frequent awakenings during the normal sleep cycle. These awakenings can be brief, but can also be longer periods of wakefulness accompanied by difficulty in falling back to sleep.
“A wealth of clinical data indicates that sleep quality decreases with age and sleep fragmentation is a major problem in patients with neurodegenerative disorders,” said the study’s senior author, Luis de Lecea, a professor of psychiatry and behavioral sciences at Stanford University.
One possible explanation for this decline in sleep quality that develops with age is a malfunction of the neuronal circuits that control sleeping and wakefulness. Sleep quality is associated with cognitive functioning and a common mechanism of this cognitive decline is the loss of neurons and neural connections in the brain.
A special type of neurons called hypocretin/orexin neurons in the lateral hypothalamus region of the brain play a pivotal role in sleep-wake control. Their stimulation triggers waking, while the suppression of their activity induces a specific type of sleep.
With the goal of investigating whether alterations in the excitability of hypocretin neurons lead to the destabilization of sleep/wake control during aging, de Lecea and his colleagues conducted a study in which they compared sleep/wake patterns of young (3-5 months) and aged (18-22 months) wild-type mice. Mice were implanted with electroencephalogram-electromyography electrodes and fiber optics. At different points of the study, they were injected with a number of different virus vectors and other agents aimed at producing various study-relevant effects.
Results showed that non-REM (rapid eye movement) sleep, but not REM sleep, was more fragmented in aged mice. Additionally, aged mice were found to have around 38% less hypocretin neurons than young mice. This indicated high vulnerability of these neurons in the aging brain. Additional tests showed that hypocretin neuronal activity that defines sleep-to-wake transition was lower in aged mice and a number of differences were observed in various aspects of neural activity.
Results also showed hyperactivity of these neurons with lower expression of certain genes and neural structures related to them. “There is something wrong with the brake system of the older hypocretin neurons, making it easier for them to fire more frequently and disrupt sleep,” explained Shi-Bin Li, a research scientist in the de Lecea lab and lead author of the study.
When these genes (KCNQ2/3) were disrupted in hypocretin neurons of young mice, young mice also started exhibiting the same type of sleep fragmentation observed in aged mice.
“Our data indicate that emerging hyperexcitability of arousal-promoting hypocretin neurons is strongly associated with fragmented sleep in aged mice, which display a lowered sleep-to-wake transition threshold defined for hypocretin neuronal activity. We have demonstrated that the down-regulation of KCNQ2/3 channels compromising repolarization drives hypocretin neuronal hyperexcitability, which leads to sleep instability during aging,” the authors conclude and add that “pharmacological remedy of sleep continuity through targeting KCNQ2/3 channels in aged mice confers a potential translational therapy strategy for improving sleep quality in aged individuals.”
De Lecea told PsyPost that he was surprised to find “that different neuronal types age differently and some of the changes that occur as we age are very subtle yet they may have serious consequences.”
“In the best case scenario, older patients are diagnosed with primary insomnia after a sleep study but the tools available to clinicians is extremely limited. Our manuscript may set the ground for new treatments targeting potassium channels that affect neuronal excitability in aged patients,” de Lecea added.
This series of experiment sheds light on important neural mechanisms of sleep process changes that happen with age. However, it should be taken into account that all the insights were obtained on mice and neural mechanisms in humans might not be the same.
“We still don’t know how many neuronal cell types are changed during aging and how they change,” de Lecea noted. “We only scratched the surface.”
The study, “Hyperexcitable arousal circuits drive sleep instability during aging”, was authored by Shi-Bin Li†, Valentina Martinez Damonte†, Chong Chen, Gordon X. Wang, Justus M. Kebschull, Hiroshi Yamaguchi, Wen-Jie Bian, Carolin Purmann, Reenal Pattni, Alexander Eckehart Urban, Philippe Mourrain, Julie A. Kauer, Grégory Scherrer, and Luis de Lecea.
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December 26, 2022 at 11:09PM
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Extreme excitability of a specific type of neuron linked to sleep problems in mice, study finds - PsyPost
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