People with Alzheimer’s disease have trouble sleeping and awaken frequently, but exactly why this happens is unclear. In the November 3 Science Translational Medicine, researchers led by Jeannie Chin, Baylor College of Medicine, Houston, home in on a problem in the thalamic reticular nucleus (TRN), a brain area that regulates deep sleep. TRN neurons became less active at each worsening Braak stage in people who had AD, and also in a mouse model of amyloidosis. A bit like people, these mice slept in fits and starts, missing out on deep sleep. Jolting this region via an inducible receptor restored the mice's sleep quality, increased their slow-wave sleep, and slowed their plaque deposition. The authors suggest that if a way can be found to boost the TRN's activity, it might be therapeutic in AD.
- The thalamic reticular nucleus maintains sleep, regulates slow-wave activity.
- In people, neuron activity in this region dims with higher Braak stages.
- Could TRN activity be enhanced to treat Alzheimer's?
“This study is exciting because it directly shows that manipulating a specific sleep-related brain circuit can restore sleep and reduce Aβ plaques,” Laura Lewis of Boston University wrote to Alzforum. Luigi de Gennaro, University of Rome, Italy, agreed. “This work suggests a causal role of the TRN in mediating sleep and AD risk,” he wrote (full comment below).
Previously, Chin and colleagues noticed that J20 mice slept intermittently, and that their thalamic reticular nuclei were less active than those of control mice (Hazra et al., 2016). The TRN consists of a thin sheet of mostly inhibitory GABA-ergic neurons that surround the thalamus and block sensory input to enable undisturbed snoozing (Steriade and Timofeev, 2003; Fogerson and Huguenard, 2016; Lewis et al., 2015). “The TRN plays a critical role in coordinating network oscillations during sleep that are thought to be important for its beneficial effects on memory,” Lewis wrote.
Did activity dwindle in this region in people too? First author Rohan Jagirdar immunostained TRN tissue from 10 people who had had AD, three people who had had mild cognitive impairment, and 15 age-matched controls from the NIH NeuroBioBank. Compared to controls, neurons in diseased tissue expressed less FosB/∆FosB, a marker thought to reflect a history of neuronal activity. This marker tracked with Braak stage (see image below).
Similarly, the researchers detected less FosB/ΔFosB in TRN tissue from J20 mice and two other sleep-disturbed models of amyloidosis, APP/PS1 and Tg2576, compared to controls. This suggested that impaired TRN activity may be a shared feature among AD and amyloidosis.
To see if the inactive TRN neurons affect sleep, the scientists video-monitored the mice's sleep and wake times in their cages. They implanted electrodes into the mice's frontal lobes and neck muscles to record electroencephalographs and electromyographs, respectively, as they slept. This was done with J20s only.
Compared to controls, 2-month-old J20 mice woke up twice as often, slept an hour less, and spent less time in slow-wave sleep. Synchronous firing of neurons during SWS helps convert short- to long-term memories and drain waste products from the brain (Jun 2015 news; Nov 2019 news). By 6 months, the mice awoke even more often, as amyloid plaques also developed.
Could making the TRN more active correct abnormal sleep? To address this question, the scientists used the “designer receptor exclusively activated by designer drug” (DREADD) method. In short, they injected a virus carrying a synthetic excitatory receptor into the TRN of 2-month-old mice, then implanted electrodes to measure EEG/EMG. To activate the receptor and jolt the TRN, the researchers fed the mice clozapine N-oxide (CNO; Roth, 2017). Mice manipulated in this way awoke less often, got more SWS, and had restored TRN neuron activity compared to animals given saline (see image below).
A DREADDed TRN. After injection of a virus encoding a CNO-inducible receptor labeled with mCherry dye (red), TRN tissue from mice given CNO (right) have more cells expressing FosB/ΔFosB (green) than mice given saline (left). [Courtesy of Jagirdar et al., Science Translational Medicine, 2021.]
To test if long-term TRN activation could reduce plaque load, Jagirdar injected 6-month-old mice with either CNO or saline before they fell asleep; they did this every day for a month and recorded EEG/EMG sleep data every five days. Treated mice slept more normally, expressed twice as much FosB/ΔFosB, and had 40 percent fewer plaques (see image below). “Daily, transient improvements in sleep are sufficient to produce measurable effects on AD-related pathology,” the authors conclude.
C NO Plaques. After a month of daily treatment, mice given CNO (right) had fewer plaques in the hippocampus and cortex than mice given saline (left). [Courtesy of Jagirdar et al., Science Translational Medicine, 2021.]
The scientists do not yet understand what exactly is silencing TRN neurons. They detected no plaques in the AD TRN tissue or tissue from 15-month-old J20 mice—or postmortem human TRN tissue. Chin’s lab is working to determine if the problem is intrinsic, such as low neuron excitability, or if an upstream input is impaired, causing the TRN to receive dimming signals. Chin noted that the deep cortical layers intimately interact with the TRN, so plaques there may clog communication.
These sleep studies were done in one model. Erik Musiek, Washington University, St. Louis, commented on the importance of studying sleep patterns and TRN activity in other amyloidosis models, as well. “These phenotypes can vary substantially between mouse lines, and the J20 mice have a neuronal hyperexcitability phenotype not seen in some other models,” he wrote to Alzforum. Lea Grinberg, University of California, San Francisco, pointed out that sleep processes differ between mice and humans, so this work may not be directly translatable. For example, Bryce Mander, University of California, Irvine, noted that the TRN primarily generates another type of brain wave called spindles during slumber. “I would have liked to see them explore what TRN disruption and stimulation does to sleep spindle expression,” he wrote (full comments below).
How could the TRN be stimulated in people? Chin and colleagues at the MD Anderson Neurodegeneration Consortium, Houston, are identifying differentially expressed genes in this region in J20 mice in search of potential targets, and are screening drugs against them. “Ideally, we envision a pill someone takes right before bed,” Chin said.
In the meantime, Chin does not think currently available sleep aid would help in the same way. Along with over-the-counter options, the orexin antagonist suvorexant is approved to treat insomnia in AD (Feb 2020 news; Oct 2014 news). Alas, Chin stressed the need to boost SWS specifically, as this is when the brain robustly clears debris. “I’m not sure the available products actually increase SWS,” she noted.
Chin plans to analyze postmortem TRN tissue from people with Parkinson’s disease or Down’s syndrome, which also come with sleep disturbances, to see if decreased TRN activity is common across multiple neurodegenerative conditions.
This paper is part of a special journal issue featuring articles on sleep, from how it influences brain waste clearance and blood flow to how neural patterns during slumber guide memory consolidation.—Chelsea Weidman Burke
Research Models Citations
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