Several years ago, a young adult with bipolar disorder got an eye-opening opportunity. They were participating in a Michigan Medicine study and got the chance to see the difference between the cells in their brain and those of a control subject. Researcher Sue O’Shea, Ph.D., professor emerita of cell and developmental biology and of psychiatry, recalls it as a pivotal moment that brought home an unexpected outcome of her research. After looking through the microscope to observe the cells, the young adult turned to their mother and said, “See, Mom, I told you my brain was different.” The mother walked away crying softly.
“The individual thought that since the cells looked different, the person wasn’t to blame for their condition — that it was as real as a broken limb — that the stigma was less when there was something observable,” O’Shea recalls. The patient was relieved that “finally, there was real evidence of a real disease.”
O’Shea is one of several researchers at Michigan Medicine whose work demonstrates the genetic components of mental illness. Their groundbreaking studies help to remove the feeling of blame that so many struggling with mental health issues feel. And these discoveries invite a host of compelling questions regarding the genetics of temperament and what makes us human: What does it mean if you have a certain type of personality, and can you change it? What amount of sadness adds spice or meaning to our lives and helps us become more creative — yet does not result in debilitating pain? The research results are encouraging for those who struggle with mental health issues and their loved ones, showing that in one sense, our genes predispose how we think, feel, and act — and limit our control. Yet understanding the genetic components has helped scientists find targets for pharmaceutical treatments and test the efficacy of psychotherapy and other interventions, making it possible for individuals to regain some control in alleviating distress.
One researcher who has spent decades exploring these issues is Huda Akil, Ph.D., the Gardner C. Quarton Distinguished University Professor of Neurosciences, who received the National Medal of Science Award, the nation’s highest scientific honor, in October 2023. Akil’s groundbreaking research investigates the genetic, environmental, and developmental factors that shape the risk of mental disorders, including depression and substance use disorder. Early in her career, she discovered the first physiological evidence for the actions of endorphins, the brain’s natural opioids. While continuing to study substance use disorder, she has broadened her interests to the biology of stress and depression, as well as the biological underpinnings of resilience. By uncovering the biological origins of mental illness, she’s helping to dispel the notion that those struggling with mental health issues are inherently weak or flawed, which she says helps to reduce stigma.
The genetics of temperament
Emotions are necessary for survival and “should be embraced,” Akil says. Yet in some people, “emotions can take over in a maladaptive way [and] distort the ability to think, learn, remember, build relationships, or make plans.” One approach to understand emotion scientifically is to uncover the genetics of temperament. Akil points out that some people are more prone to being optimistic and joyous, while others tend to be more anxious, shy, or pessimistic. These tendencies are a normal part of personality traits, but they also predispose you to different types of brain disorders. “If you are a shy, inhibited person, you’re more likely to have depression or anxiety disorder. If you are a risk-taking, impulsive individual, you’re more likely to have confrontational behavior and substance use disorders.”
To better understand the biology of temperament, she’s created a genetic animal model of temperament in rats, breeding them based on how they respond to a novel environment. In a new and mildly stressful situation, some rats are “high responders” — they’re excited, explore activity, and take risks — while others are “low responders” and are more withdrawn, anxious, and prone to becoming stressed. Once the rats are bred together, these characteristics are highly heritable. There are now 95 generations from the two lines of rats that have been separated based on just this one behavior. Akil found that many different behaviors are inherited along with the trait she bred for, including differences in anxiety, impulsivity, and drug use. Her laboratory is uncovering not only the specific genes associated with these temperaments, but also differences in the activity or brain circuits and cell types that shape the behavior of the rats across many dimensions, from taking care of their babies to coping with stress.
Yet her research shows that it’s possible to rewrite some of these tendencies through interventions with the environment, especially during critical periods of development. “You’re not changing their genes, but you can change the activity of the genes in the brain in a way that changes their behavior,” Akil says. “It was very exciting to discover that if you place the anxious, low responder rats in an enriching environment with toys and opportunities for more social interactions, you render them much more resilient and able to withstand social stress — and you change the brain in a lasting way.” This finding offers hope that behaviors that can be distressing can be altered, especially with intervention at a young age, and significant behavioral consequences can be prevented.
“Genes are not your destiny. They are predispositions. The brain has the capability of rewriting its own program to adapt to the world,” Akil says. She emphasizes that psychological resilience to stress is not simply the absence of vulnerability. It can result from countering genetic vulnerability through positive experiences in successfully confronting stress, helping the individual become “more self-assured, confident, and less scared,” and rebalancing negative emotions with positive ones.
Brain mechanics
Akil has collaborated with her husband, psychiatry professor Stanley Watson Jr., M.D., Ph.D., for 50 years, and they directed the Michigan Neuroscience Institute together for 25 years. Watson, who is the Ralph Waldo Gerard Professor of Neurosciences, considers himself “a mechanic of the brain.” He looks at the structures in the brain to understand how they’re regulated and which systems are involved in pain or emotion. Akil says she is drawn to the behavioral and molecular aspects of brain research.
Over the past several years, with funding from the Pritzker Neuropsychiatric Disorders Research Consortium, Watson and Akil have been studying the brains of those in California who died of suicide or had a history of severe mental illness and comparing them with the brains of those who did not suffer from a mental illness. They’ve explored the circuits of the brain to help understand where these illnesses disturb the brain the most. Watson says these ongoing studies involve a large number of scientists across the country, and the results could lead to more targeted treatments.
Watson is particularly proud of his wife’s early Naloxone experiments in the late 1960s and early 1970s. In one experiment, she passed a low current into the brain of an animal. If the current was put in certain places, suddenly the animal no longer sensed pain. Usually, rats don’t like to stand in icy cold water, but animals that were stimulated appeared to be happy to stay in cold water and eat.
“That experiment basically said the electrode was causing something to be released in the brain,” Watson says. He says this research “suddenly handed the world the intellectual permission to go search in the brain and find out what it is.” We now know that “it” was endorphins, and that mammals have endorphin systems responsible for relieving pain. Depending on where you stimulate the brain, you get different effects. Using anatomical methods, he has mapped the location of all of those cells responsible for releasing what we now know as endorphins.
In Akil’s experiment, when she turned off the electrode and the endorphins were not released, the animal sensed the cold water, felt the pain, and jumped out of it. In a subsequent experiment, she was able to “turn off” the endorphins using Naloxone, resulting in the same cold water escape seen initially. This proved that giving Naloxone could block the endogenous opiates (i.e., the endorphins). Through these experiments, Akil was able to define some of the biological underpinnings of opioid use disorder.
Measuring inherent tendencies
“In our modern environment, we are bombarded with stimuli or cues that exert significant influence over our actions,” says Shelly Flagel (Ph.D. 2003). “The extent to which these cues can distract us from our goals is dependent on several factors, including one’s inherent tendencies.” Flagel, who is a professor of psychiatry and a research professor at the Michigan Neuroscience Institute, has used Akil’s animal model to study this phenomenon. “The animal model that Akil uses offers a great opportunity to look at the gene/environment interactions and what’s driving individual differences in behavior,” she says. Flagel’s research builds on this approach, using animal models to study the neural mechanisms that underlie individual differences in response to stimuli in the environment.
Specifically, Flagel places rats into a testing chamber in which a stimulus or cue is paired with the delivery of a food reward. Rats are then categorized based on how they respond to the cue presentation. On one extreme are “sign-trackers,” who approach and interact with the cue, and on the other are “goal-trackers,” who go to the location of reward delivery. For sign-trackers, the cue itself becomes attractive and desirable, even in the absence of a reward. Goal-trackers, on the other hand, treat the cue as a mere predictor of reward. Sign-tracker rats generally seem to lack inhibitory control, are more impulsive, and exhibit an exaggerated fear response. Goal-trackers seem better equipped to control their behavior.
Flagel and her colleagues have applied these findings to human studies as well, working with children ages 9 to 13. In this experiment, kids were presented with two large Lego boxes. One box had a lever that would extend for a few seconds, and the other box had a slot where a reward would pop out immediately after the lever was retracted. The reward was not dependent on participants hitting the lever. Yet, some of the participants behaved very similar to the “sign-tracker” rats and interacted vigorously with the lever every time it popped out. She says her study, published in Scientific Reports in 2023, was the first in children to demonstrate a possible relationship between sign-tracking and behavioral tendencies that suggest a kid might have the potential to develop psychiatric disorders like attention-deficit hyperactivity disorder or obsessive compulsive disorder.
If it’s possible to identify a child or adolescent who has sign-tracking tendencies, their brain potentially could be “rewired” through non-invasive means like cognitive behavioral therapies. “Then, we may be able to help protect them from maladaptive behaviors or the development of psychiatric disorders,” she says. She believes that her work not only helps to reduce stigma, but also shows that there are individual differences and multiple paths to vulnerability or resilience, arguing for more individualized treatments versus a one-size-fits-all approach.
Research on bipolar disorder
O’Shea’s research involves taking skin biopsies from patients diagnosed with bipolar disorder and changing them first into stem cells, then into brain cells such as neurons and glia to study how these brain cells may be altered in disease. While mood disorders such as depression, schizophrenia, and bipolar disorders can be studied in cells from autopsies, stem cells have the additional advantages of allowing investigators to study differences in gene expression, electrical characteristics, and in cell behavior in response to agents which might improve these conditions. Looking at novel gene expression patterns in patients with bipolar disorder compared to neurons from control patients provides an opportunity to identify new, more targeted medications that can activate or down regulate gene expression, “thereby modulating mood.”
O’Shea explained that since bipolar episodes are “tremendously damaging to the family and the individual, the ability to treat mood disorders in a timely, reliable way would be hugely beneficial.” She believes that her research supports a biological underpinning to mental illness that may be important in starting conversations about the bases of these conditions. When observing differences in cells in a lab, “you can see that there are real changes. We see something that’s reproducible and has a scientific basis, not just, ‘Oh, I feel bad,’” she says. “It’s humanizing.” Helping to destigmatize mental illness is one of the most important contributions that science is making to mental health since it provides language to talk about mental illness “and to help understand how these cells’ function has changed, providing hope for those struggling with the disease,” she adds.
AI to quantify negativity bias
Chandra Sripada, M.D., Ph.D. (Residency 2003), the Theophile Raphael Research Professor of Clinical Neurosciences as well as professor of psychiatry at the Medical School and of philosophy at the College of Literature, Science, and the Arts, examines what these neurobiological circuits do. He is looking at ways to quantify the thought process in an individual with depression or high levels of anxiety who is prone to experience events as stressful. His research explores the phenomenon of negativity bias: the differences in individuals in their reaction to the world and the events in their lives. He models the thought process of people by having them verbalize their spontaneous stream of thought with a voice app. He is using Large Language Models, a type of AI he calls a “breakthrough” that is used to quantify the precise nature of thought processes in people with negativity bias. These language models can “tag” each individual thought with precise ratings of what that thought is like along multiple clinically relevant dimensions like negativity and self-focus. The tags are then used to build quantitative models of thought dynamics. The goal is to give individuals tailored techniques to recognize and rationally criticize their distinctive patterns of distorted thought, he says.
Evidence-based hope
Kara Zivin, Ph.D., the Marcia A. Valenstein, M.D. Collegiate Professor of Psychiatry and professor of obstetrics and gynecology, who specializes in mental health services and policy research, says though people now speak more openly about their mental health challenges, stigma remains. The type of research that Akil and her colleagues focus on can provide important insights. “More and varying types of data can prove beneficial when making the case for policies to support those who struggle with mental health conditions,” Zivin says, though she emphasizes that multiple factors influence policy changes. She says the right information can potentially decrease the stigma that often acts as a barrier to change.
Akil says, “If we can impart evidence-based hope to the public, they can learn from our findings about how to think about these mental health related issues, whether depression, addiction, PTSD, suicidality, or chronic pain — all the things that people really struggle with — in a way that is scientifically based, while being humane and non-judgmental.” She is optimistic that a more accepting, supportive younger generation will be receptive to that message. “I have a lot of hope that it will be a kinder kind of culture.”
Growing up with neuroscientists
Brendon Watson, M.D., Ph.D., grew up hearing conversations in the car about peptides and synapses. His parents are Michigan Medicine researchers Huda Akil, Ph.D., and Stanley Watson Jr., M.D., Ph.D.. Those early conversations inspired Watson to follow in their footsteps, and he’s now an assistant professor of psychiatry at Michigan Medicine. Growing up with neuroscientists who believe that factors impacting mental health are underlain by biological changes in the brain, he never questioned that and only later understood that others do. “This idea that our brain is under [our] control is pervasive throughout society,” he says. “[But] people are not at fault for being depressed, anxious, or feeling bad. I think we need to take it seriously, and we need to help people, which is why I do what I do.”
While his mother studies changes in the brain in relation to stress and social interactions, Watson uses a different set of tools to do it. “She focuses on molecular and protein expression and structural changes that happen with stress and depression,” while he explores electrical activity in neural networks to better understand the basic biology of people struggling with depression and anxiety. This is intended to lead to better screening tools for medications.
Watson says that though his mother was a pioneer as a woman in science when there were few, “she was always one of the most respected people in the room ... It’s almost like she didn’t realize there are obstacles.” Akil says she did perceive obstacles, but they seemed manageable in comparison to the challenges that her family members faced in Syria, where she was raised. “I know how much pressure, inhibition, strife, stress, grief, and loss there is in a war-torn country that faces food and water shortages,” she says. “So I just kept marching on. I didn’t come home and complain.”
Predicting college students’ mental health
More than a third of surveyed undergraduates from U.S. and international schools reported experiencing moderate or severe depression in the 2023-2024 academic year, according to a U-M study. The survey showed the same was true for anxiety. Although the numbers were a decrease from previous years, they are still concerning. Huda Akil, Ph.D., the Gardner C. Quarton Distinguished University Professor of Neurosciences, is taking aim at preventing problems before they occur. She has been conducting an innovative study since 2015 that seeks to identify risk factors for depression in college freshmen. “We want to get people on the right path as early as possible,” she says. Her Michigan Freshmen Study examines the biological and psychological markers in a yearly sample of U-M freshmen. The team has developed a predictive algorithm, which allows them to determine who is likely to be depressed or anxious before the students begin their freshman year of college. The team is now working on ways to help these students who are at higher risk before problems surface. “My hope is that we can hand people [some] prevention strategies.” She says AI offers the promise of personalizing the treatment based on each individual’s particular triggers.
