A paper published this week in the journal Neuron peers into a region of the brain involved in the state of wakefulness. The findings could help to design treatments for conditions such as insomnia and depression-related sleep disturbances.

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A new study investigates the brain region responsible for wakefulness.

Most of us, at some point in our lives, will battle with our state of wakefulness. Whether we feel too sleepy when we need to be awake, or feel too awake when we are desperate to get some sleep, the struggle is real.

According to the Centers for Disease Control and Prevention (CDC), sleep and wakefulness disorders affect an estimated 50 to 70 million adults in the United States.

Although there have been great advancements in the field of sleep science, the area of the brain responsible for wakefulness has remained elusive.

A research team recently set out to understand how the human brain manages wakefulness in times of need. For instance, a pressing deadline or a baby crying in the middle of the night are both events that allow us to override our desire to sleep.

The scientists wanted to uncover how we manage to reverse tiredness in the face of so-called salient stimuli.

The team was led by Viviana Gradinaru, an assistant professor of biology and biological engineering, and director of the Center for Molecular and Cellular Neuroscience of the Tianqiao and Chrissy Chen Institute for Neuroscience at the California Institute of Technology in Pasadena.

The dorsal raphe nucleus and wakefulness

The team focused their energy on one particular part of the brain. "We decided to examine a region of the brain called the dorsal raphe nucleus, where there are an under-studied group of dopamine neurons called dorsal raphe nucleus neurons, or DRNDA neurons," says Prof. Gradinaru.

They chose this particular region because earlier studies have shown an association between activity in the dorsal raphe nucleus and sleep cycles. This relationship has been known for decades, but recently, a more specific role in wakefulness has been theorized.

Also, as Prof. Gradinaru explains, "People who have damage in this part of their brain have been shown to experience excessive daytime sleepiness, but there was not a good understanding of the exact role of these neurons in the sleep/wake cycle and whether they react to internal or external stimuli to influence arousal."

A mouse model was used in a series of experiments to study the role of dopaminergic neurons within the dorsal raphe nucleus. First, they measured DRNDA activity when animals were presented with salient stimuli, such as the introduction of a potential mate, food, or a sudden unpleasant sensation. During these encounters, the neurons were active.

They then measured DRNDA firing rates during the sleep/wake cycle. According to Ryan Cho, first author of the study, they saw that the "neurons are least active when the animal is sleeping and increase in activity as the animal is waking up."

The next step was to uncover whether this was purely a correlation, or whether the activity itself was causing the changes in sleep/wake states.

Proving causation with optogenetics

In the final phase they used optogenetics, which is a technique that allows scientists to switch specific neurons on and off using pulses of light. When the team stimulated DRNDA neurons at a time when the animal would normally be asleep, the mouse woke up and stayed awake.

Conversely, if the team silenced the DRNDA neurons chemically, the animal was more prone to sleep, even if it were presented with the type of salient stimuli that would normally keep it awake.

"These experiments showed us that DRNDA cells are necessary for full wakefulness in the face of important stimuli in mice."

Prof. Viviana Gradinaru

The next step will be to see if the same type of activity is found in DRNDA neurons in humans. Although they have not been studied in detail, Prof. Gradinaru explains that there seems to be a similar connection. He says, "Their degeneration has been correlated with excessive daytime sleepiness in patients with neurodegenerative disorders such as multiple systems atrophy and Lewy body dementia."

Insomnia and other sleep disturbances are highly prevalent, so any advancements in understanding ways to modify states of wakefulness are a step forward. There is a long road ahead, but these findings might help to focus future research into sleep disturbance.

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