Problems sleeping? You’re not alone; every year, around 40 million Americans experience insomnia, with some cases warranting drug treatment. But new research may pave the way to a more effective treatment option; in a mouse study, researchers found that a brain circuit involved in reward response is also crucial for sleep.
Researchers say targeting reward-related VTA activity in the brain could be promising treatment for sleep problems.
Senior author Luis de Lecea, Ph.D., professor of psychiatry and behavioral sciences at Stanford University School of Medicine in California, and colleagues publish their findings in the journal Nature Neuroscience.
The brain’s reward system is made up of several structures – including the prefrontal cortex, the nucleus accumbens, and the ventral segmental area (VTA) – and it plays a role in desire, pleasure, and motivation.
The reward system is primarily activated by a neurotransmitter called dopamine, which is produced in response to rewarding stimuli – such as food or sex.
As the research team notes, it is perhaps unsurprising that the reward system is linked to the sleep-wake cycle; for example, when we are excited about the day ahead – an emotion fueled by the reward system – it can be difficult to sleep.
However, de Lecea says that no studies had pinpointed the exact brain region where this overlap occurs – until now.
Lead author Ada Eban-Rothschild, Ph.D., of the Department of Psychiatry and Behavioral Sciences at Stanford, notes that amphetamines and other drugs that activate the reward system through dopamine secretion are known to disrupt sleep.
With this in mind, assessing whether dopamine is involved in the sleep-wake cycle seems an obvious area of research.
“But, in part due to existing technical limitations, earlier experimental literature has unearthed little evidence for the connection and, in fact, has suggested that this circuit probably wasn’t so important,” adds Eban-Rothschild.
Activating dopamine cells in the VTA kept mice awake
To further investigate the link between the reward system and the sleep-wake cycle, the researchers bioengineered male mice in a way that allowed them to activate, deactivate, and monitor the dopamine-secreting nerve cells in the rodents’ VTA.
Additionally, the team assessed the overall brain activity and muscle tone of the mice, enabling them to track their sleep-wake states. The rodents’ behavior was also monitored through video recording.
The researchers found that when the mice awoke from sleep, dopamine-secreting nerve cell activity in the VTA increased, and this activity remained high when the rodents were awake.
Sleep, however, had the opposite effect; dopamine nerve cell activity in the VTA reduced when the mice were falling asleep, and this activity stayed low during sleep.
By activating these nerve cells, the team was able to wake the mice from slumber and keep them awake for long periods. This was the case even during a point in the mice’s 24-hour sleep-wake cycle when they would normally be sleeping.
However, control mice – which did not have their dopamine nerve cells activated – built nests in their cages and continued to sleep as normal.
On deactivating these nerve cells during a period in the 24-hour sleep-wake cycle at which the mice would normally be active, the mice fell asleep, and they stayed asleep throughout numerous arousal triggers – such as the introduction of high-fat chow.
VTA activity involved in sleep preparation
As expected, mice that were placed in an unfamiliar cage spent time exploring their new environment.
Among mice that had their dopamine nerve cell activity suppressed in the VTA, however, the team noticed that the rodents spent the first 45 minutes in their new environment making nests, before quickly falling asleep in them.
Interestingly, when these mice were placed in cages with ready-made nests, they climbed in and fell asleep immediately. Control mice placed in cages with nesting materials, however, did not make nests and preferred to run around.
Next, the team compared 1-second video segments of the mice’s behavior in unfamiliar cages with the corresponding recorded brain activity.
The researchers found that the nest-building activity of the mice was linked to reduced activity in the VTA, while increased VTA activity was associated with other behaviors.
VTA-targeting drugs could help treat sleep problems
Overall, the researchers say their results indicate that VTA activity is important in sleep preparation, which could have important implications for humans.
“We knew stimulating the brain’s dopamine-related circuitry would increase goal-directed behaviors such as food- and sex-seeking,” says Eban-Rothschild. “But the new study shows that at least one complex behavior is induced not by stimulating, but by inhibiting, this very circuit. Interestingly, this behavior – nest building – is essential to a mouse’s preparation for sleep.”
“This is the first finding of a sleep-preparation starter site in the brain. It’s likely we humans have one, too.
If we’re disrupting this preparation by, say, reading email or playing videogames, which not only give off light but charge up our emotions and get our VTA dopaminergic circuitry going, it’s easy to see why we’re likely to have trouble falling asleep.”
Luis de Lecea, Ph.D.
The researchers say their results indicate that drugs that target VTA activity in the brain could be promising for the treatment of insomnia and other sleep disorders.
“We have plenty of drugs that counter dopamine,” says de Lecea. “Perhaps giving a person the right dose, at just the right time, of a drug with just the right pharmacokinetic properties so its effect will wear off at the right time would work a lot better than bombarding the brain with benzodiazepines, such as Valium, that knock out the entire brain.”
What is more, he says drugs that target dopamine-secreting cells in the VTA could lead to new treatments for mental health disorders involving sleep-wake problems, such as schizophrenia and bipolar disorder.
“It could be that merely solving the sleep-wake part will clear up a lot of symptoms,” adds de Lecea.
Read about a new computer model that could offer insight into the sleeping brain.