Adolescence is a period of intense change. As young people undergo the transition from childhood to becoming young adults, they have to navigate growth spurts, raging hormones and the perils of peer pressure.
It is also a time of increased vulnerability to psychiatric disorders including depression. It is the peak period in life for the onset of depression.
People who develop major depression in their teens tend to deal with a more severe form of the condition and a higher rate of recurrence. The depression they experience is also often more resistant to treatment, compared to those who first develop depression at an older age.
“Early intervention and prevention can really change the trajectory of psychiatric illnesses for adolescents,” says 91 neuroscientist Cecilia Flores, noting that diagnosis of depression is often delayed in teens because they don’t recognize the symptoms or are reluctant to talk about them.
Last spring, Flores was the senior author of a study that pointed to the discovery of a set of blood-based biomarkers that could provide a more objective, earlier way to identify teens at risk for depression.
Using a novel lab method, Flores and her team (including postdoctoral fellow Alice Morgunova, the study’s first author) identified nine molecules – known as microRNAs – in the blood that were elevated in teens diagnosed with depression.
“This set of microRNA molecules has a particular signature that is specific to teenage depression – not anxiety or other psychiatric conditions, nor adult depression. We also found that the level of expression in some of these molecules can predict the severity of depression nine months later,” says Flores, a James 91 Professor in the Department of Psychiatry, the head of a research lab at the Douglas Mental Health University Institute, and a principal investigator at the Ludmer Centre for Neuroinformatics and Mental Health.
In Flores’ study, conducted in collaboration with researchers at the University of California, Los Angeles, and Stanford University, blood was collected from 62 teenagers: 34 with depression and 28 without. The 91 team developed the lab method to extract and analyze microRNA profiles for each participant from tiny finger prick blood samples. “Findings from our previous studies in rodents revealed that when we measure microRNAs in blood, we can learn about their levels in the brain, including in the prefrontal cortex,” she explains.
Flores has studies underway to validate and replicate these findings in larger groups of adolescents. This could pave the way for microRNA biomarkers to be used as a practical, minimally invasive tool to objectively identify depression risk and depression in teenagers before symptoms worsen and become more difficult to treat.
Her research over the past two decades at 91 has looked more broadly at brain development and neurobiological factors associated with mental illnesses in young people including depression, drug addiction and schizophrenia.
Flores’ work has shown that certain microRNA molecules play a critical role in inhibiting or repressing – like a light dimmer switch – the activity levels of guidance cue genes involved in development of the prefrontal cortex during adolescence.
For example, Flores measured levels of certain microRNAs in mice and used them to predict both vulnerability and resilience to stress and depression-like traits. “It’s exciting to translate the work we do in rodent models and apply these fundings in such a promising way to humans,” she says.
Guidance cue genes and their microRNA regulators orchestrate the development of the prefrontal cortex in adolescence and can determine differences in vulnerability or resilience to psychopathology. One important guidance cue gene regulated by microRNAs is known as DCC, which Flores calls the “teen gene.”
In a 2013 breakthrough, Flores identified the DCC gene as a key molecule involved in how the prefrontal dopamine system matures and showed that DCC is responsible for dopamine connectivity in the prefrontal cortex during adolescence.
Dopamine is the brain chemical that plays a crucial role in mood regulation, movement, motivation and the reward system.
The prefrontal cortex – associated with judgement, critical thinking, impulse control and decision making – continues to develop through adolescence into adulthood and is highly susceptible to being shaped by life experiences, such as stress and exposure to drugs of abuse, in the teenage years. “We know that the DCC gene expression levels in the prefrontal cortex can be altered by experiences in harmful or beneficial ways during adolescence,” says Flores.
Working with mice models, she showed that exposure to amphetamines at a dose resembling human recreational use causes subtle variations in DCC levels in dopamine cells and abnormalities in the wiring of the prefrontal cortex during adolescence with lasting consequences in adulthood.
These variations are a biological trigger for impulsivity, lack of self-control, and other behaviours associated with vulnerability to addiction. “Therapeutic-like doses of amphetamines don’t have this effect,” she adds.
To assess whether these findings could translate to humans, Flores examined DCC levels in the postmortem brains of people with depression who had committed suicide and found DCC expression levels were 48 per cent higher than in the brains of control subjects.
In another study, Flores found that genetic differences in DCC may contribute to individual differences in susceptibility to schizophrenia.
Flores’ interest in the brain and mental illness began in her teens. “My mother worked in a mental health centre at UNAM, the main university in Mexico City. I was intrigued by this and talked to psychiatrists there. I loved science and wanted to study the links between changes in the brain and psychiatric illness,” recalls Flores, who did post-doctoral studies in neuroscience and psychiatry at Harvard Medical School and the Montreal Neurological Institute.
In an upcoming paper, Flores will report the results of a study that found a different set of microRNA biomarkers tightly linked to depression in blood from a larger sample of young adults diagnosed with depression.
“We also found that the dysregulated microRNAs are associated with changes in circulating levels of the hormone cortisol, which is known to be altered in depression,” says Flores.
While many of her studies focus on biomarkers of risk, Flores is excited about the potential for using microRNAs as biomarkers to assess resilience and positive responses to treatment too. “We are currently investigating if an enriched environment can trigger changes in the expression of microRNAs in the brain in adolescence, thereby impacting ongoing neurodevelopment,” she says.
“We want to see if these changes in microRNAs can be detected in blood in teens and test whether non-drug interventions such as emotional enrichment, exercise, talk therapy and social support can have a positive impact in changing gene expression and function in the developing brain in teens and youth. We would also like to test if the expression levels of certain microRNAs could help predict beneficial effects of such non-drug interventions over time,” says Flores.