The only evidence-based behavioral treatment for anxiety and stress-related disorders involves desensitization techniques that rely on principles of extinction learning. However, 40% of patients do not respond to this treatment. Efforts have focused on individual differences in treatment response, but have not examined when, during development, such treatments may be most effective. We examined fear-extinction learning across development in mice and humans. Parallel behavioral studies revealed attenuated extinction learning during adolescence. Probing neural circuitry in mice revealed altered synaptic plasticity of prefrontal cortical regions implicated in suppression of fear responses across development. The results suggest a lack of synaptic plasticity in the prefrontal regions, during adolescence, is associated with blunted regulation of fear extinction. These findings provide insight into optimizing treatment outcomes for when, during development, exposure therapies may be most effective.

Adolescence reflects a period of increased rates of anxiety, depression, and suicide. Yet most teens emerge from this period with a healthy, positive outcome. In this article, we identify biological factors that may increase risk for some individuals during this developmental period by: (1) examining changes in neural circuitry underlying core phenotypic features of anxiety as healthy individuals transition into and out of adolescence; (2) examining genetic factors that may enhance the risk for psychopathology in one individual over another using translation from mouse models to human neuroimaging and behavior; and (3) examining the effects of early experiences on core phenotypic features of anxiety using human neuroimaging and behavioral approaches. Each of these approaches alone provides only limited information on genetic and environmental influences on complex human behavior across development. Together, they reflect an emerging field of translational developmental neuroscience in forming important bridges between animal models of neurodevelopmental and neuropsychiatric disorders. Depression and Anxiety, 2011. © 2011 Wiley‐Liss, Inc.

Excitement with the publication of the human genome has served as catalyst for scientists to uncover the functions of specific genes. The main avenues for understanding gene function have been in behavioral genetics on one end and on the other end, molecular mouse models. Attempts to bridge these approaches have used brain imaging to conveniently link anatomical abnormalities seen in knockout/transgenic mouse models and abnormal patterns of brain activity seen in humans. Although a convenient approach, this article provides examples of challenges for imaging genetics, its application to developmental questions, and promises for future directions. Attempts to link genes, brain, and behavior using behavioral genetics, imaging genetics, and mouse models of behavior are described. Each of these approaches alone, provide limited information on gene function in complex human behavior, but together, they are forming bridges between animal models and human psychiatric disorders. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.

Recently, a common single nucleotide polymorphism (SNP) has been identified in the gene encoding brain‐derived neurotrophic factor (BDNF). The variant BDNFMet has been shown to have decreased activity‐dependent BDNF secretion from neurons and to lead to impairments in specific forms of learning and altered susceptibility to stress. A mouse model containing BDNFMet has also been linked to increased anxiety‐like behavior. In a translational study, mice and human carriers of the BDNFMet allele were compared in their ability to extinguish a learned fear memory. Both showed slower suppression of the learned fear response. In humans, the neural correlates of this behavior were validated using fMRI. As anxiety and fear extinction lie at the core of symptoms and therapeutic approaches to posttraumatic stress disorder (PTSD), we propose that BDNF genotype and neuroimaging may be useful as biomarkers to provide guidance for more customized therapeutic directions. The aim of this paper is to review the available knowledge on the BDNF Val66Met SNP, with emphasis on anxiety‐ and fear‐related endophenotypes and its potential implications for PTSD.

The characterization of adolescence as a time of "storm and stress" remains an open debate. Intense and frequent negative affect during this period has been hypothesized to explain the increased rates of affective disorders, suicide, and accidental death during this time of life. Yet some teens emerge from adolescence with minimal turmoil. We provide a neurobiological model of adolescence that proposes an imbalance in the development of subcortical limbic (e.g., amygdala) relative to prefrontal cortical regions as a potential mechanism for heightened emotionality during this period. Empirical support for this model is provided from recent behavioral and human imaging studies on the development of emotion regulation. We then provide examples of environmental factors that may exacerbate imbalances in amygdala-ventrofrontal function increasing risk for anxiety related behaviors. Finally we present data from human and mouse studies to illustrate how genetic factors may enhance or diminish this risk. Together, these studies provide a converging methods approach for understanding the highly variable stress and turmoil experienced in adolescence.

Mouse models are useful for studying genes involved in behavior, but whether they are relevant to human behavior is unclear. Here, we identified parallel phenotypes in mice and humans resulting from a common single-nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene, which is involved in anxiety-related behavior. An inbred genetic knock-in mouse strain expressing the variant BDNF recapitulated the phenotypic effects of the human polymorphism. Both were impaired in extinguishing a conditioned fear response, which was paralleled by atypical frontoamygdala activity in humans. Thus, this variant BDNF allele may play a role in anxiety disorders showing impaired learning of cues that signal safety versus threat and in the efficacy of treatments that rely on extinction mechanisms, such as exposure therapy.

There has been a dramatic rise in gene x environment studies of human behavior over the past decade that has moved the field beyond simple nature versus nurture debates. These studies offer promise in accounting for more variability in behavioral and biological phenotypes than studies that focus on genetic or experiential factors alone. They also provide clues into mechanisms of modifying genetic risk or resilience in neurodevelopmental disorders. Yet, it is rare that these studies consider how these interactions change over the course of development. In this paper, we describe research that focuses on the impact of a polymorphism in a brain-derived neurotrophic factor (BDNF) gene, known to be involved in learning and development. Specifically we present findings that assess the effects of genotypic and environmental loadings on neuroanatomic and behavioral phenotypes across development. The findings illustrate the use of a genetic mouse model that mimics the human polymorphism, to constrain the interpretation of gene-environment interactions across development in humans.