As children transition to adulthood, they gradually gain independence, often taking risks as they explore the world. But many early experiences, such as alcohol and drug use, can shape their future. Research shows that the earlier a person begins using alcohol and drugs, the more likely they are to develop a substance abuse problem later on.1 The biological and social factors influencing decision-making during adolescence and beyond were the focus of a session titled “The Adolescent Brain in Flux: How Drugs and Social Factors Impact Development” at the Society for Neuroscience conference in October 2024.
Session moderator Beatriz Luna, a developmental neuroscientist at the University of Pittsburgh, opened with a stark warning: “Right now, there is a crisis in adolescent mental health.”
She noted how, over the past few years, there has been a rise in substance use amongst adolescents. According to the National Center for Drug Abuse Statistics, between 2016 and 2020, drug use shot up 61 percent among eighth graders and around 11 percent of overdose deaths are in individuals aged 15 to 24 years. This public health concern coincides with an increase in anxiety and other psychiatric disorders.
Three developmental neuroscientists presented their research on adolescent brain development and the risk factors for substance use and psychiatric conditions during this critical period. Their research, spanning human neuroimaging to rodent models of binge drinking, revealed age- and sex-specific correlations with brain function.
Two of the speakers presented data from large, longitudinal studies in humans. Neuroscientist Qingyu Zhao from Weill Cornell Medical College sourced functional magnetic resonance imaging (fMRI) data and behavioral data from 9,000 adolescents who participated in the Adolescent Brain Cognitive Development Study. He wanted to know whether neural circuitry is linked to behavior in a uniform way among all adolescents. “Current brain mapping research largely strives to find a single, universal pattern that can characterize the entire population,” said Zhao. But as he analyzed the research data, Zhao realized it was not so straightforward. When he looked at a brain circuit involving sensorimotor and salience networks that were associated with cognitive and attention problems, he found that circuit connectivity was greater in boys than in girls. He also identified a functional connection between dorsal attention, sensorimotor, and cingulo-parietal networks which correlated with symptoms of withdrawal and depression. This connection was more pronounced in adolescents who had experienced high levels of adverse childhood experiences, such as abuse and neglect, than in those who had fewer adverse childhood experiences. Zhao concluded that adolescent brains are not homogeneous. Rather, they are affected by factors like specific life events and biological sex. “Our results suggest the need to develop more fine-grained risk assessment, prevention and intervention plans tailored to subpopulations,” he said.
The other study that made use of longitudinal data was that of Ashley Parr, a developmental neurobiologist from the University of Pittsburgh. Parr worked with the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA), which collected MRI and behavioral data, including information on substance use, from more than 800 participants (12 to 31 year olds) as they developed through adolescence and into adulthood.2 Nearly thirty percent of individuals reported that they started using drugs late in adolescence and increased their use through adulthood, while 47 percent reported that they increased substance use in adolescence but decreased usage as they entered adulthood. The remaining individuals reported no substance use.
Parr was curious about these different longitudinal patterns of substance use. “Risk-taking behavior, including substance use, has been linked to the brain's reward system,” she said. “This system is driven by the neurochemical dopamine.” To find out if variations in dopamine existed among the groups, Parr computed tissue iron levels from the MRI data; Iron is involved in dopamine production and serves as an indirect marker of the neurotransmitter.3 She focused on iron in the striatum, a brain region that is flush with dopamine receptors and is activated during reward processing. Parr discovered that the individuals who reported increased substance use in adolescence but decreased usage as they entered adulthood had lower dopamine levels in the striatum compared to the other groups.
To further understand why some individuals might have a greater risk for developing substance use disorders, Parr wanted to learn more about their executive functioning, which is still developing in adolescence, but drives decisions such as whether to use substances. She turned to the behavioral data from the NCANDA study that measured executive functioning, specifically inhibitory control. “That’s your ability to suppress a very quick action in favor of perhaps a long-term goal,” she said. From this data, she gleaned that, of the three groups, the one that had the lowest striatal dopamine levels also performed worse in inhibitory control. Parr speculated. “These individuals might be sensation seeking or risk taking as a compensatory measure.” Her studies suggest that measurements of brain dopamine may allow scientists to implement interventions before substances have ever been used.
Early life interventions might also come about through an understanding of the molecular mechanisms by which substance abuse affects the brain. In her talk, Laurel Seemiller, a neuroscientist in the laboratory of Nikki Crowley at Pennsylvania State University, discussed her research on the long-term effects of binge drinking. “We give adolescent mice intermittent access to a bottle of alcohol throughout their adolescent period, in a way that promotes binge-like alcohol consumption,” said Crowley. “Then we can track them throughout their development, and once they become adults, we can test the biological and behavioral effects of that alcohol exposure.”
To test anxiety-related behavior in the mice, she used an elevated plus maze, an X-shaped, elevated structure that has two closed and two open arms.4 A greater anxiety-like state is associated with avoidance of the open arms. Seemiller observed that male mice that consumed alcohol as adolescents were quicker to enter the open arms of the maze, relative to their female counterparts.
Based on previous studies, Seemiller thought that the behavioral changes she saw following early life alcohol consumption might be related to biological changes in the prefrontal cortex (PFC).5 “This is a region of the brain that is particularly vulnerable to insults during adolescence,” she said. To more closely examine this brain region her team performed patch-clamp electrophysiology in the PFC region of adult mice.6 In analyzing the data from brains of mice that were exposed to alcohol during adolescence, she and Sicher discovered that the excitability of somatostatin (SST) neurons was markedly increased in both sexes over those who had received only water. SST neurons inhibit other neurons in the PFC and are known to be involved in decision-making. Previous studies from Crowley’s lab showed that the delivery of an SST receptor agonist produced different behavioral effects in males and females.7 Therefore, Seemiller hypothesized that prefrontal SST cells function differently between sexes. So, even though alcohol is increasing SST cell-mediated inhibition in males and females, this leads to different behavioral phenotypes.
The animal models allowed Seemiller to make predictions about molecular mechanisms that underlie behavior, and the data of Parr and Zhao showed that large longitudinal studies offer a wide lens of the human population. “It allows you to start to make predictive models and identify what the trajectories are,” said Luna. These studies highlight how studying the adolescent brain could reveal targets for potential therapies that reduce or prevent substance use disorders.
- Grant BF, Dawson DA. Age of onset of drug use and its association with DSM-IV drug abuse and dependence: Results from the National Longitudinal Alcohol Epidemiologic Survey. J Subst Abuse. 1998;10(2):163-173.
- Brown SA, et al. The national consortium on alcohol and neurodevelopment in adolescence (NCANDA): A multisite study of adolescent development and substance use. JSAD, 2015;76(6):895-908.
- Larson B, et al. Maturation of the human striatal dopamine system revealed by PET and quantitative MRI. Nat Commun. 2020;11:846.
- Walf AA and Frye CA. The use of the elevated plus maze as an assay of anxiety-related behaviors in rodents. Nat Protoc. 2007;2:322-328.
- Ochi R, et al. Patterns of functional connectivity alterations induced by alcohol reflect somatostatin interneuron expression in the human cerebral cortex. Sci Rep. 2022;12:7896.
- Sicher AR, et al. Adolescent binge drinking leads to long-lasting changes in cortical microcircuits in mice. Neuropharmacol. 2023; 234:109561.
- Brockway DF, et al. Somatostatin peptide signaling dampens cortical circuits and promotes exploratory behavior. Cell Rep. 2023; 42(8): 112976.
