Brain circuits linked to alertness

Scientists revealed the types of neurons supporting alertness using a molecular method called MultiMAP in transparent larval zebrafish. Multiple types of neurons communicate by secreting the chemical messengers serotonin (red), dopamine and noradrenalin (yellow) and acetylcholine (cyan).

How alert, or vigilant, you are during your day can affect your ability to carry out daily tasks. Many things can alter how alert you feel, such as how much sleep or caffeine you’ve had. Being overly alert or not alert enough can also be a sign of certain mental health conditions, like anxiety, mania, or depression.

Scientists have learned a lot about how the brain regulates being asleep or awake in general. But less is known about how the brain regulates changes in alertness throughout the day.

To investigate which brain cells (neurons) regulate alertness, a team led by Drs. Karl Deisseroth and Matthew Lovett-Barron at Stanford University analyzed the activity of brain cells in zebrafish and mice while measuring their reaction times. The research was supported in part by NIH’s National Institute of Mental Health (NIMH) and National Institute on Drug Abuse (NIDA). Results were published online in Cell on November 2, 2017.

The team created a technique called MultiMAP (Multiplexed-alignment of Molecular and Activity Phenotypes) to track and identify the neurons and circuits activated during a particular brain state. Using this technique, researchers tracked the activity of tens of thousands of zebrafish brain cells while the fish were presented with a stimulus mimicking an approaching predator. They gauged alertness by measuring how long it took the fish to swish their tails in response to the threatening stimulus.

A molecular analysis identified several different cell types that were activated when the fish were most alert and responsive. These included neurons that release chemical messengers that alter the activity of other brain cells. Confirming the results of previous studies, they identified norepinephrine-secreting neurons as being active in alertness. In addition, their technique enabled them to identify other cell types not previously shown to be involved in alertness, including acetylcholine-, serotonin-, dopamine-, and peptide-secreting neurons.

The researchers looked for these sets of brain cells in the mouse brain. They found that there were similar cell types and circuits regulating alertness in mice. Activation of specific circuits using optogenetics, which uses light to activate or inhibit specific neurons, made the mice more alert or reduced their reaction times.

“Vigilance gone awry marks states such as mania and those seen in post-traumatic stress disorder and depression,” says NIMH Director Dr. Joshua Gordon. “Gaining familiarity with the molecular players in a behavior—as this new tool promises—may someday lead to clinical interventions targeting dysfunctional brain states.”