Intensity of Brain Activity Associated With Sleep Necessity

The intensity of brain activity during the day, controlling for length of time being awake, is linked to sleep necessity through a neuron named galanin, according to a study on zebrafish published last week in the journal Neuron.

Researchers from University College London (UCL) sought to understand what processes in the brain drive homeostatic sleep regulation without factors such as the time of the day. Lead study author Jason Rihel, PhD, UCL Department of Cell and Developmental Biology, described that although we understand 1 of the 2 systems regulating sleep through the circadian system, the other system, homeostatic, which causes people to feel increasingly tired after a long day or a sleepless night, is understudied, noted Rihel.

In the study, zebrafish, who share similarities to humans by sleeping every night, were given a variety of stimulants to trigger an increase in brain activity. The effects of pentylenetetrazol (PTZ), a GABA-A receptor antagonist, was examined as it is “known to potently and dose dependently induce neuronal and behavioral hyperactivity in larval zebrafish,” said the authors.

Six-day post-fertilization larvae exposed to 10 mM PTZ for 1 hour in the morning exhibited increased swimming activity and seizure-like behavior during exposure. After drug removal, known as washout, the zebrafish stopped their increased swimming activity and entered a period called the rebound phase, which is a state of behavioral inactivity.

Researchers examined the correlation of inactive states in zebrafish to actual sleep states by testing whether post-PTZ inactivity fulfilled key behavioral criteria of sleep in non-mammalian species. Inactive states longer than 1 minute are associated as sleep in larval zebrafish. After PTZ exposure, sleep time was significantly increased by an average of 1.7-fold.

Other variables associated with sleep such as subsequent increase in arousal threshold and response to strong, salient stimuli, were observed in zebrafish, as well as the scant possibility of neuronal injury. “These data indicate that inactivity following acute drug-induced neuronal hyperactivity is a sleep-like state comparable to physiological sleep,” said the authors.

After confirming comparability of sleep states, researchers uncovered 1 area in the zebrafish brain called galanin that is central to the effect on sleep pressure. This part of the zebrafish brain is similar to that found in the hypothalamus, an area in the human brain known to be active during sleep. Galanin was visibly active during recovery sleep but was not an active part in regular overnight sleep.

The study authors then assessed whether the impact of galanin in recovery sleep for stimulant administered zebrafish was relevant to actual sleep deprivation through a test where larval zebrafish were kept awake all night on a treadmill-like device to insinuate the necessity to keep swimming. The zebrafish who were kept awake had an extended amount of sleep the next day, and an increase in their galanin activity during recovery sleep. These findings indicate the correlation of galanin activity and sleep necessity, with further potential of distinguishing these neurons as a hallmark of total brain activity.

In finding a gene that plays a central role in homeostatic sleep regulation, the study’s first author Sabine Reichert, PhD, UCL department of cell and developmental biology, emphasized galanin’s potential for increased knowledge of sleep impairing disorders and conditions such as Alzheimer’s disease. “We may have identified a good drug target for sleep disorders, as it may be possible to develop therapies that act on galanin,” said Reichert.

Reference

Reichert S, Arocas OP, Rihel J, et al. The neuropeptide galanin is required for homeostatic rebound sleep following increased neuronal activity. [published online September 16, 2019]. Neuron. doi: 10.1016/j.neuron.2019.08.010.