Measuring Brain Chemistry

Posted on June 14th, 2018 by Dr. Francis Collins

Serotonin is one of the chemical messengers that nerve cells in the brain use to communicate. Modifying serotonin levels is one way that antidepressant and anti-anxiety medications are thought to work and help people feel better. But the precise nature of serotonin’s role in the brain is largely unknown.

That’s why Anne Andrews set out in the mid-1990s as a fellow at NIH’s National Institute of Mental Health to explore changes in serotonin levels in the brains of anxious mice. But she quickly realized it wasn’t possible. The tools available for measuring serotonin—and most other neurochemicals in the brain—couldn’t offer the needed precision to conduct her studies.

Instead of giving up, Andrews did something about it. In the late 1990s, she began formulating an idea for a neural probe to make direct and precise measurements of brain chemistry. Her progress was initially slow, partly because the probe she envisioned was technologically ahead of its time. Now at the University of California, Los Angeles (UCLA) more than 15 years later, she’s nearly there. Buoyed by recent scientific breakthroughs, the right team to get the job done, and the support of a 2017 NIH Director’s Transformative Research Award, Andrews expects to have the first fully functional devices ready within the next two years.

Neurotransmitters are often present in extremely low concentrations in the spaces outside of neurons, where communication takes place. That has made designing a neural probe sensitive enough to detect them with the needed specificity a huge challenge. Andrews’ team—including Milan Stojanović, Columbia University, New York City, along with UCLA’s Paul Weiss, Harold Monbouquette, and Yang Yang—found a solution in molecules known as aptamers. They are single stranded nucleic acids that are selected for their unique ability to bind a chemical structure of interest.

Andrews’ team now has aptamers that recognize a number of essential nerve messengers, including serotonin and dopamine, with many more in development. Andrews reports that these aptamers are selective and sensitive enough to differentiate between chemicals that are very similar in structure.

One recent breakthrough was coupling these aptamers to semiconductor materials in field-effect transistors, the same basic elements in today’s common electronic devices such as cell phones and laptops. Because aptamers are small and electrically charged, Andrews found that when aptamers bind to neurotransmitters, even in brain fluid that contains many ions, electronic signals could be detected at the transistors.

The next challenge is to couple aptamer-transistor sensors with small implantable devices with the goal to achieve fully electronic neurochemical sensors small enough for use in tiny mouse brains. Andrews is seeking to develop a device that’s about the width of a human hair. If all goes well, the length of the probes and the types of individual sensors will also be fully customizable to target any area of the brain and any neurotransmitter.

While Andrews is designing the device primarily for laboratory use, she suspects her new tool might ultimately have medical applications. For example, she envisions doctors using the sensors alongside neurostimulators implanted into the brain for treating psychiatric illnesses, including severe depression and post-traumatic stress disorder. Doctors today struggle to determine where best to place such devices in each patient’s brain for the maximum benefit. There’s also limited information about how deep brain stimulation works to influence brain chemistry in patients. Andrews’ neurochemical sensors have potential to provide insight on both counts.

Ultimately, the sensors will be readily adaptable and available for measuring any neurotransmitter for essentially any research application. As remarkable as that is, Andrews still doesn’t consider herself a tool developer at heart. What she’s most looking forward to is working with her mice and capturing those measures of brain serotonin with the precision that she first sought all those years ago—and to learn what serotonin levels reveal about the brain chemistry behind anxiety.

Links:

Anne Andrews Lab (UCLA)

Anne M. Andrews’ Personal Story of Discovery (American Chemical Society)

Milan Stojanovic (Columbia University, New York City)

Paul Weiss (UCLA)

Harold Monbouquette (UCLA)

Yang Yang (UCLA)

Andrews Project Information (NIH RePORTER)

NIH Director’s Transformative Research Program (Common Fund)

NIH Support: National Institute on Drug Abuse; Common Fund