B. J. Casey

Significance: Anxiety disorders peak during adolescence, a developmental period that is marked by dynamic changes in gene expression, frontolimbic circuitry, and endocannabinoid signaling. This cross-species study identifies parallel gene by development interactions across humans and a knock-in mouse model of the same fatty acid amide hydrolase (FAAH) polymorphism. The impact of FAAH genetic variation on frontolimbic circuitry and anxiety in mice and humans emerges during adolescence as anandamide levels decrease but not before. These findings have important implications for the identification of risk for disease and precise targeting of treatments to the biological state of the developing brain as a function of developmental changes in gene expression and neural circuit maturation.

An individual is typically considered an adult at age 18, although the age of adulthood varies for different legal and social policies. A key question is how cognitive capacities relevant to these policies change with development. The current study used an emotional go/no-go paradigm and functional neuroimaging to assess cognitive control under sustained states of negative and positive arousal in a community sample of one hundred ten 13- to 25-year-olds from New York City and Los Angeles. The results showed diminished cognitive performance under brief and prolonged negative emotional arousal in 18- to 21-year-olds relative to adults over 21. This reduction in performance was paralleled by decreased activity in fronto-parietal circuitry, implicated in cognitive control, and increased sustained activity in the ventromedial prefrontal cortex, involved in emotional processes. The findings suggest a developmental shift in cognitive capacity in emotional situations that coincides with dynamic changes in prefrontal circuitry. These findings may inform age-related social policies.

This paper highlights recent human neuroimaging and cross‐species developmental and genetic studies that examine how fear regulation varies by age and the individual, especially during the period of adolescence, when there is a peak in the prevalence of anxiety disorders. The findings have significant implications for understanding who may be at risk for anxiety disorders and for whom, and when, an exposure‐based therapy may be most effective. We provide proof of concept for targeting treatment to the individual as a function of age and genetics, inferred from mouse and human studies, and suggest optimization of treatment for nonresponders.

Adolescence is a time of intensified emotional experiences, during which anxiety and stress-related disorders peak. The most effective behavioral therapies for treating these disorders share exposure-based techniques as a core component. Exposure-based therapies build on the principles of fear extinction learning and involve desensitizing the individual to cues that trigger anxiety. Yet, recent evidence shows an adolescent-specific diminished capacity to extinguish fear responses, suggesting that adolescents may respond less well to exposure-based therapies than other age groups. Here we demonstrate an alternative method for blocking the recall of fear memories in adolescents, building on principles of memory reconsolidation in adults. During memory reconsolidation, a memory that is recalled becomes labile during which time it can be updated. Prior research has shown that extinction training during memory reconsolidation attenuates the recovery of fear memory in human adults and in rodents. Using this method, we show attenuation of fear memory in adolescent humans. These findings have significant implications for treating one of the most vulnerable populations to anxiety and stress related disorders - adolescents - by optimizing exposure therapy based on principles of memory reconsolidation.

Cross-species studies enable rapid translational discovery and produce the broadest impact when both mechanism and phenotype are consistent across organisms. We developed a knock-in mouse that biologically recapitulates a common human mutation in the gene for fatty acid amide hydrolase (FAAH) (C385A; rs324420), the primary catabolic enzyme for the endocannabinoid anandamide. This common polymorphism impacts the expression and activity of FAAH, thereby increasing anandamide levels. Here, we show that the genetic knock-in mouse and human variant allele carriers exhibit parallel alterations in biochemisty, neurocircuitry and behaviour. Specifically, there is reduced FAAH expression associated with the variant allele that selectively enhances fronto-amygdala connectivity and fear extinction learning, and decreases anxiety-like behaviours. These results suggest a gain of function in fear regulation and may indicate for whom and for what anxiety symptoms FAAH inhibitors or exposure-based therapies will be most efficacious, bridging an important translational gap between the mouse and human.

Adolescence is the transition from childhood to adulthood that begins around the onset of puberty and ends with relative independence from the parent. This developmental period is one when an individual is probably stronger, of higher reasoning capacity, and more resistant to disease than ever before, yet when mortality rates increase by 200%. These untimely deaths are not due to disease but to preventable deaths associated with adolescents putting themselves in harm's way (e.g., accidental fatalities). We present evidence that these alarming health statistics are in part due to diminished self-control—the ability to inhibit inappropriate desires, emotions, and actions in favor of appropriate ones. Findings of adolescent-specific changes in self-control and underlying brain circuitry are considered in terms of how evolutionarily based biological constraints and experiences shape the brain to adapt to the unique intellectual, physical, sexual, and social challenges of adolescence.

The adolescent brain is more “plastic” than it will ever be again, capable of remarkable adaptability in light of the many social, physical, sexual, and intellectual challenges that this developmental phase brings. This is also a peak time for clinical onset of most mental illnesses (see the chart) (1). One in five adolescents have a mental illness that will persist into adulthood (2). Mental illnesses that emerge before adulthood impose a 10-fold higher cost than those that emerge later in life (3). Mental health costs are the highest single source of global economic burden in the world (4).