What causes the interrupted sleep of the elderly? Lateral hypothalamus plays a role in feeding behaviour, learning, sleep

Ageing neurons: The nerve cells that produce hypocretin are no longer active when a person sleeps.  Getty Images Getty Images

A common human wish is to be able to sleep like a baby. Indeed, in adults, the total hours of sleep, and the quality of this sleep declines with age. Older people are especially prone to listless, fragmented sleep. A chronic drop in the quality and quantity of sleep can lead to diminished mental and physical health, and to a reduced lifespan (Mander et al., Neuron, 94, 19 (2017)).

Research has provided many clues to what induces sleep in humans. The pineal gland, at night, releases the hormone melatonin which is involved in regulating the sleep-wake cycle. This has made it a popular supplement for overcoming insomnia, although its effectiveness beyond the short term remains debatable.

However, our ‘awake’ state is much more complex, because nearly the whole brain is involved. This is perhaps why we are perplexed by the often-disrupted sleep of the elderly, where wakefulness repeatedly encroaches upon blissful sleep.

Voluntary movements

It is known that in older people with sleep disturbances, degeneration of nerve cells is seen in brain centres involved in the coordination of voluntary movements. A recent study has added a new dimension to our knowledge (Li et al., Science, 375, 2022). The study points to the hypothalamus, which lies in the centre of the brain and is the size and shape of an almond. An area in this part of the brain, the lateral hypothalamus, plays an outsized role in wakefulness, feeding behaviour, learning and sleep. Emanating from here are a bunch of nerve cells that fan out and project their nerve ending to all the parts of the central nervous system that are associated with the state of arousal. The chemical message released by these neurons is in the form of small proteins, called hypocretins and also known as orexins (The two names come from two groups of scientists who independently discovered these neuropeptides in 1998).

Excitatory signals

Like all neurons, Hcrt/OX neurons have endings called synapses, which may be next to the synapse of another neuron, or next to a muscle cell. Electrical signals pass along the length of neurons until they come to the synapse, where they are fleetingly transformed into chemical signals, which cross over and generate a response in the adjacent neuron. In the language of neuroscience, an excitatory signal will lead to the firing of the next neuron – electrical signals are conducted to a synapse at the other end of that neuron. Inhibitory signals tamp down the firing of an active neuron. Hypocretin tends to be excitatory, stimulating the neurons that it reaches.

Hypocretin stimulates wakefulness, and with it, motivated behaviour such as seeking food or a mate, as well as responsiveness to cold, nausea or pain. Of the 86 billion neurons in the human brain, less than 20,000 produce hypocretin, but their influence is profound. Most of all, hypocretin is important for maintaining prolonged periods of wakefulness. Directly injecting hypocretin into the cerebrospinal fluid (so that it is quickly delivered inside the brain) will keep you wide-awake for several hours. And neurons that produce hypocretin are no longer active when you are asleep.

In experiments, mice deprived of food stay awake and busy for a very long time while they search for food. Mice lacking hypocretin, in which the hypocretin gene has been knocked out, are far less motivated in their hunt.

Fractionation of sleep

What happens to the sleep of the elderly? Li et al. show that with age, changes occur in these hypocretin-producing neurons. They become hyperexcitable, conducting signals and releasing neuropeptides at a very low threshold, at the slightest provocation.

The unwanted activation of inactive hypocretin neurons leads to the fractionation of sleep. Changes in aged neurons thus make it more difficult to inhibit their activity.

There is a rare disorder of the nervous system triggered by the loss of Hcrt/OX neurons. Narcolepsy has strange characteristics – an overwhelming desire to sleep in the daytime, even though the total hours of sleep remain unchanged; a tendency to hallucinate as the sleep-wake phases are blurred; frequent loss of muscle tone – cataplexy – during which muscles become flaccid. Only a handful of cases have been documented in India, mostly men in their thirties (Ray, Indian Journal of Medical Research, 148, 748 (2018)). Patients with this condition have vanishingly low amounts of hypocretin in their cerebrospinal fluids.

Finally, can sufferers of fractured sleep dream of ways to bring better constancy to their sleep? In aged mice, the analgesic Flupirtine, although beset with toxicity issues, appears to raise back the threshold at which hypocretin neurons get excited, thus restoring the structure of sleep.

(The article was written in collaboration with Sushil Chandani who works in molecular modelling. sushilchandani@gmail.com)

dbala@lvpei.org