Fragmented Sleep in Aging Traced to Over-Sensitive Neurons

By Christine Soares

March 16, 2022

(Reuters Health) - A type of neuron in the hypothalamus that regulates transitions between sleep and wakefulness becomes "hyperexcitable" with age, lowering the threshold that triggers it to fire and rouse the rest of the brain, a study in mice shows.

In older animals, hypocretin neurons - which secrete neuropeptides, known as hypocretins or orexins, that promote wakefulness - were diminished in number and often in a partly active state, requiring less stimulation to fire, researchers found in a series of experiments.

They traced the older neurons' hyperexcitability to downregulation of a voltage-gated potassium-channel in the cell membrane. The channel's function could be supplemented pharmaceutically to restore normal sleep continuity and quality, according to the report in Science.

"I hope that our work will result in more tools that physicians could use to improve sleep and wakefulness in different populations," said senior study author Dr. Luis de Lecea, a professor of psychiatry and behavioral sciences at Stanford University, in California. "Unfortunately, elderly patients are treated with the same hypnotics (as) the general population and clearly they have different needs."

The hypocretin system of the hypothalamus, first described in 1998 by Dr. de Lecea while at the Scripps Research Institute, is universal in mammals. It coordinates brain signals that indicate when arousal is needed, and provides that wake-up call through release of neuropeptides that Dr. de Lecea dubbed hypocretins.

"Hcrt neurons sense many variables including metabolic, circadian and limbic states to provide a coherent output that results in state transitions," Dr. de Lecea explained in an email. They are "a master switch that determines whether and when the brain will wake up." The current study, Dr. de Lecea said, shows "a subtle alteration of the switch" in the brains of aged mice that "makes it more likely that the brain will be turned on."

The role of the peptides released by Hcrt neurons has been investigated in a wide range of disorders, including sleep problems, depression and addiction. The second research group to independently identify the peptides called them orexins and found their receptors regulate feeding behavior.

The importance of Hcrt neurons to sleep quality is illustrated in type-1 narcolepsy, where severe loss of the cells causes unstable sleep, wakefulness, and eventually cataplexy, professors Laura Jacobson and Daniel Hoyer of the Florey Institute of Neuroscience and Mental Health in Parkville, Australia, note in an accompanying commentary.

Previously, there were no data indicating that Hcrt activity would be affected by aging, Dr. de Lecea noted. But an observation of reduced amplitude when the neurons fired in older mice led the group to explore whether malfunctioning Hcrt neurons could be involved in the fragmented sleep and unwanted waking that becomes common in older age.

In aged (18-22 months) and young (3-5 months) mice, the researchers immediately saw differences in Hcrt neuron numbers, with the aged mice showing about 38% fewer cells overall. During sleep, the neurons of aged mice were also firing more often, disrupting sleep continuity. Recordings from the neurons showed they were hyperexcitable, with a smaller difference between their resting membrane potential and firing threshold, and smaller amplitude-attenuation between firings.

The functional impairment of membrane repolarization in older mice was traced to membrane KCNQ2/3 channels and physical loss of KCNQ2. The researchers also saw compensatory mechanisms in older cells, including increased production of the hypocretin precursor molecule.

Replicating the changes seen in the older neurons in the brains of young animals caused the same cell-firing and sleep-fragmentation patterns, including reduction of REM and non-rapid eye movement (NREM) sleep. "Treating" older mice with the KCNQ2/3-selective activator flupirtine repolarized the resting membrane potential of neurons, suppressed spontaneous firing, and consolidated sleep stability, the researchers found.

It's not clear why age-related changes to Hcrt neurons happen, but cell loss might be one trigger, Dr. de Lecea said. "The short answer is that we don't know what comes first but it's easy to speculate that the alterations we see in the remaining hcrt neurons (i.e. decrease in kcnq channels) try to make up for the hcrt cell loss."

The benefits of protecting or restoring youthful functioning to aging Hcrt neurons could extend beyond sleep, Dr. de Lecea added. "Hcrt neurons are important regulators of homeostasis so preserving them will be beneficial for alertness, motivation and to maintain appropriate responses to the environment."

Multiple pharma companies are interested in developing "new small molecules with kcnq2-3 enhancing activity," he said.

Existing drugs that target those channels, like flupirtine, used in the experiments, and retigabine, an anti-epileptic, likely have too many adverse effects for long-term use.

"Restoring the old hypocretin neurons to their normal younger state sounds interesting but is a long shot," Hoyer told Reuters Health in an email. "Whether a selective neuronal K channel opener will work in sleep in the elderly without other side effects remains to be seen in the clinic," he added.

Still, the new study reveals an age-dependent mechanism underlying sleep disruption "and thus reopens the search for new, targeted strategies to combat sleep disturbances in older people," Jacobson and Hoyer note in their commentary.

Flupirtine stabilized NREM sleep as well as the performance of aged mice on memory tests in the study, they point out. An experimental dual-orexin receptor antagonist (DORA), MK6096, also restored NREM sleep in the aged mice. "NREM sleep is associated with learning and memory consolidation and is the most disrupted sleep state with age," they write.

Compared with classical hypnotics, DORA drugs offer the potential benefits of enhanced sleep quality, Jacobson and Hoyer write. Together with the "evidence of improved recognition memory with flupirtine in aged mice, selective targeting of hypocretinergic mechanisms may prove superior in reaping the rewards of pharmacologically-enhanced sleep in older people in both health and disease," they conclude.

SOURCE: https://bit.ly/3COo7d1 and https://bit.ly/3JdQjZh Science, February 25, 2022.

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