A Neurobiological Perspective on Emerging Mental Illness Research
Marta Pratelli researches the downstream effects of environment and experience on brain health and the risk of developing psychiatric illness. In addition to insights from her own research, in this interview she offers her perspective on the role of collaboration and chance in scientific breakthroughs as well as areas of mental health research, such as epigenetics, that have potential for future outcomes.
This interview is a complement to SfN’s podcast series History of SfN: 50th Anniversary. Guests on the podcast were asked to nominate individuals whose careers are making positive cultural or scientific impacts that will shape the next 50 years of neuroscience. Marta Pratelli was nominated by Nick Spitzer, Atkinson Family Chair Distinguished Professor of Biological Sciences at University of California, San Diego.
In a couple of sentences, how would you describe your research?
I study the ability of specific subgroups of neurons to change the neurotransmitter they express, in response to changes in brain activity (a phenomenon known as neurotransmitter switching). This is a form of plasticity that depends on the environment, and it has an impact on behavior. Sometimes it improves learning ability, memory, or social interaction. At other times it likely contributes to susceptibility to mental illness.
My project right now models schizophrenia in mice to study whether this kind of plasticity may be involved. We’ve identified excitatory glutamatergic neurons in the prelimbic cortex that, when repeatedly exposed to a drug commonly used to mimic psychosis in rodents, start to express the inhibitory neurotransmitter GABA. We’re now testing if this is causally linked to the behavioral alteration that we and others have observed in this type of mouse model, and whether this form of plasticity occurs in other regions of the brain.
Your background is in cellular and molecular neurobiology. How are you applying that to mental health research?
I want to understand the link between experience, alterations in the brain, behavioral outcome, and how we can interfere with that in noninvasive ways.
I want to understand the link between experience, alterations in the brain, behavioral outcome, and how we can interfere with that in noninvasive ways. We know, for example, that in specific mental illnesses such as schizophrenia, there is a genetic component. But there is also a strong environmental component that is crucial for initiating the pathology. This means that environment impacts the brain, leaving behind what could be viewed as “traces” in the neurons. All mental illnesses have an environmental substrate. We are starting to learn a lot about that, and I want to use my expertise to learn more about the traces left by environmental exposure.
Environmental exposure and the experiences you have can change the biology of your brain to make you more resilient. This fascinates me, because one of the problems in our current approach to mental illness is that in some cases, there isn’t an effective cure.
And there are few preventive strategies. There are no drugs you can give on a large scale to people with a predisposition to mental illness to lessen the likelihood of their becoming mentally ill, because of side-effects. Working on prevention at a genetic or pharmacological level is challenging. While I think it’s worth doing, it is also important to learn more about how exposure to a healthy environment and healthy experiences can help.
You’re fascinated by so many aspects of neurobiology and mental health and illness. How do you prioritize questions to pursue?
Every scientist is curious, so a lot of questions will pop up that you want to follow. When that happens, it’s important to ask yourself, “What should we concentrate on? Why are we doing this?"
Focus on how you want to improve a specific situation. For me, that’s to contribute to a better understanding of what brain pathology is and what brain health is.
Sometimes that means you have to focus your time and avoid beautiful designs of experiments if they’re to answer questions that are not applicable in the real environment.
It’s important to ask yourself, “What should we concentrate on? Why are we doing this?"For example, you can spend a lot of time dissecting what drives something or how something happens. These are good questions, but it's important to identify how closely what you want to know is linked to behavior. Once you are sure of that, you can add the details that will allow you to manipulate the phenomenon and to see the impact on the well-being of the whole organism.
What are some historic scientific breakthroughs that have contributed to advances in mental illness research?
Technical discoveries are incredibly important. When you design a novel tool, that opens an entire new way of being able to test and define problems to then solve.
Combining fields is also key. I decided to join a neurobiology lab after taking a course on gene targeting and genetic mouse models. Mario Capecchi, Oliver Smithies, and Martin Evans, Nobel Prize Winners in Physiology or Medicine, had different scientific backgrounds, but through collaboration they were able to modify the mouse genome for the first time. Sometimes the start of a great discovery is serendipitous. Further thought leads to understanding the potential of the discovery and how it can be transformed into a groundbreaking new technology.
More recently, scientists developed the CRISPR technology, which has turned out to have great potential, but also to have burdens from an ethical perspective. CRISPR is an example of how a discovery can lead to completely unpredictable outcomes, with repercussions on multiple aspects of scientific research that push it forward at an unexpected speed.
Indeed, if you look at the history of research that has had impact, you’ll see that sometimes the start of a great discovery is serendipitous. Further thought leads to understanding the potential of the discovery and how it can be transformed into a groundbreaking new technology, resulting in a concrete step forward.
Are there any areas in which you see breakthroughs on the horizon?
I am fascinated by the discovery that epigenetic traces can be passed through generations, like a sort of biological memory. Although demonstrated in multiple studies, the mechanism behind it remains unclear.
I think epigenetics may have potential to be exploited for therapeutic intervention in mental health. While for ethical reasons you cannot manipulate genes in human stem cells, working with epigenetics is far safer, as its consequences will be time-limited in terms of generations and will not directly impact evolution. For example, there is a lot of development of RNA therapeutics to target epigenetics or gene expression of RNA in the brain.
At the same time, we’re seeing that deep brain stimulation is starting to have great potential. It’s still at the beginning, but there may arrive a moment at which we will be able to affect stimulation in less invasive ways. Increasing plasticity will also have a lot of potential if stimulation is correct.
Where do you plan to take your research next?
If you think about it, no mental illness — depression, anxiety — seems to be effectively cured with drugs alone. A combination of drugs and psychotherapy is generally the more successful strategy. This makes me believe that experience is really important to changing the biology and achieving a better response. I want to investigate how therapeutic experiences, such as psychotherapy, impact the brain’s biology. It's difficult to put the two fields together, but I believe that doing it could bring great benefit to both fields.
We are close to having all the tools that could allow us to manipulate the human brain and express or suppress the expression of specific genes. This could work for a few rare and severe illnesses, but it’s currently unthinkable as a treatment for illnesses affecting a large percentage of the population, such as mood disorders and addiction. In the case of illnesses that are expressed on a large scale, developing an understanding of how to ameliorate them or increase resilience to them by exploiting the impact of experience and environment on the brain is far more important.
Studying neurotransmitter switching may have potential because, being driven by activity, at a certain point we may be able to induce or prevent a switch not only with experience, but also with brain stimulation. Even if these types of interventions are only partially effective (reducing the probability of developing a severe addiction, for example), they would, in my opinion, be a great advance.