In diagnosing and treating neuropsychiatric and neurodegenerative diseases like depression, schizophrenia, and Parkinson’s disease, doctors rely on evaluating a patient’s symptoms rather than directly analyzing brain chemistry. Although a variety of tools can study the brain, they are too imprecise, indirect, or invasive to probe the brain at the molecular level. So chemists are developing optical sensors that they hope will one day provide a clearer picture of how symptoms relate to changes in brain chemistry. In this video, host Kerri Jansen explores a trend in sensing dopamine in brain tissue using new synthetic and protein-based probes. University of California, Berkeley’s Markita Landry shares her team’s progress with carbon nanotubes (Sci. Adv. 2019, DOI: 10.1126/sciadv.aaw3108). And Lin Tian from the University of California, Davis gives us a glimpse of tools based on genetically modified proteins (Science 2018, DOI: 10.1126/science.aat4422).
Watch Manny Morone’s visit to Janelia Research Campus here.
“Morning Mandolin” by Chris Haugen
The following is a transcript of this video.
Kerri Jansen: When it comes to many neuropsychiatric and neurodegenerative diseases, like depression, schizophrenia, and Parkinson’s disease, doctors rely mostly on symptoms like behavior to diagnose a patient or tell if a particular treatment is working.
This type of evaluation has helped countless patients. But researchers would like to give psychiatrists additional tools—chemical ones that could peer inside the brain and report back on its inner workings. If we could understand how brain diseases and treatments work on the molecular level, psychiatrists like Jessica Hairston might be able to provide better care to individual patients.
Jessica Hairston: As a psychiatrist we look at people’s behavior and how their behavior changes, and also we look at their thinking by talking with them and relating to them. But the brain chemistry is going to be much more specific than behavior.
Kerri: Doctors currently do have tools to study the brain, like functional MRI and PET scans, but those are geared to coarsely mapping activity in the brain rather than looking at brain chemistry at the level of individual neurons.
There are some tools out there that can measure brain chemistry very sensitively, but they tend to be invasive, which limits their use in humans. Think poking the brain with an electrode.
Scientists want to change this landscape. Chemists are developing sensors that can directly and noninvasively probe chemical signaling between neurons in the brain. Today, they’re testing these sensors in tissue samples and in animals to better understand brain chemistry. Although human use is a distant target, these researchers believe their work can offer more insight into how symptoms correlate to brain chemistry and how drugs work in the brain.
At UC Berkeley, Markita Landry and her team are at the forefront of making synthetic nanosensors to monitor brain chemistry. In particular, they’re interested in using carbon nanotubes to detect dopamine, one of the brain’s chemical messengers that’s implicated in a variety of brain diseases.
Dopamine is one of the chemicals that neurons use to transmit signals to one another. But it doesn’t just move from one neuron to another, like electrons through a wire. It can also spread through the brain, more like a radio signal. And how exactly neurons respond to dopamine is still a mystery—one that’s tough to solve because the responses are lightning fast and they occur in places scientists struggle to see.
Markita Landry: The information that we’re looking at is stored in a place that’s very inaccessible, inside the brain where signaling happens very quickly.
Kerri: To detect dopamine, Markita and her group use nanosensors they built by pairing carbon nanotubes with polymers. When the polymers react with dopamine, they increase the nanotube’s natural fluorescence to signal binding.
Brain tissue interferes with the path of certain types of light. But Markita’s sensors emit fluorescence at wavelengths that should be able to shine through.
So far, the team has tested their nanotube sensors in brain tissue samples. The researchers bathe the samples in fluid containing the sensors so the samples soak them up.
Hot spots of dopamine show up as bursts of light when neurons in the tissue are artificially stimulated to release the chemical.
If Markita and her team want to see how a drug would affect dopamine levels, they can dose their tissue samples with the drug and watch the sensors’ response change. And the team noticed something interesting. When they used a drug designed to change dopamine levels, they found that not every neuron in a sample reacted the same way to the drug. So, on average, brain tissue might respond to the drug the way you would expect, but . . .
Markita Landry: When we look at what individual terminals do or what individual hot spots do, they don’t all necessarily respond that way.
Kerri: If a drug doesn’t affect every neuron equally in every sample, those variations could help explain why different people respond to drugs differently.
Alex Kwan, who studies how neurons work together to produce certain behaviors, says he thinks this kind of tool could help develop more precise alternatives to the drugs that are currently used to treat Parkinson’s disease and schizophrenia.
Alex Kwan: Those are kind of like a sledgehammer type of drug, where they affect all of the receptors or dopamine level somewhat globally in the brain. So I think this kind of sensor can help us understand what dopamine is doing in different brain areas.
Kerri: While Markita’s team is using a synthetic material—carbon nanotubes—for its sensors, other scientists, such as Lin Tian of UC Davis, are manipulating proteins that already exist in the human brain to build sensors.
Using a virus to insert foreign DNA into brain cells, they genetically modify dopamine receptor proteins to glow green when dopamine binds. Because these sensors piggyback on brain biology, getting them into brain tissue is easier than inserting, say, carbon nanotubes.
Lin Tian: You can inject the virus into a specific brain region, and the brain region will actually—it spreads those probes on its own.
Kerri: As you might guess, there are significant technical obstacles and ethical questions that would need to be overcome or answered before genetically modifying proteins in human brains, but at the moment Lin’s group is able to use its sensors in living animals to measure dopamine release.
Lin sees both her genetically encoded sensors and Markita’s carbon nanotube ones as tools in an expanding toolbox for understanding changes in brain chemistry.
And psychiatrist Jessica Hairston is excited to see the developments.
Jessica Hairston: The more that we can learn about the neurochemistry and the neuroscience of it all, I think that it would make things a lot easier for a number of practitioners. It would give us more to work with and hopefully more successful outcomes.
Kerri: For more molecular tools to peer in on biochemistry, check out Manny Morone’s visit to Janelia Research Campus, where scientists are making fluorescent dyes for nerve cell imaging. We’ll post that link in this episode’s description.