Mouse models are useful for studying genes involved in behavior, but whether they are relevant for 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.Genetically modified mice provide useful model systems for testing the role of candidate genes in behavior. The extent to which such genetic manipulations in the mouse and the resulting phenotype can be translated across species, from mouse to human, is less clear. In this report we focused on identifying biologically valid phenotypes across species. We utilized a common single nucleotide polymorphism (SNP) in the brain-derived neurotrophic factor (BDNF) gene that leads to a valine (Val) to methionine (Met) substitution at codon 66 (Val66Met). In an inbred genetic knock-in mouse strain that expresses the variant BDNF allele to recapitulate the specific phenotypic properties of the human polymorphism in vivo, we found the BDNF Val66Met genotype was associated with treatment resistant forms of anxiety-like behavior (1). The objective of this study was to test if the Val66Met genotype could impact extinction learning in our mouse model, and if such findings could be generalized to human populations.BDNF mediates synaptic plasticity associated with learning and memory (2,3) specifically in fear learning and extinction (4,5). BDNF-dependent forms of fear learning have known biological substrates, and lie at the core of a number of clinical disorders (6,7) associated with the variant BDNF (8-10). Fear learning paradigms require the ability to recognize and +To whom correspondence should be addressed. fas2002@med.cornell.edu or bjc2002@med.cornell.edu. remember cues that signal safety or threat and to extinguish these associations when they no longer exist. These abilities are impaired in anxiety disorders such as posttraumatic stress disorder and phobias (11,12). Behavioral treatments for these disorders such as exposure therapy rely on basic principles of extinction learning (13) in which an individual is repeatedly exposed to an event that was previously associated with aversive consequences. Understanding the effect of the BDNF Met allele on these forms of learning can provide insight into the mechanism of risk for anxiety disorders, refine existing treatments, and may lead to genotypebased personalized medicine. NIH Public AccessWe examined the impact of the variant BDNF on classic fear...

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. F ear learning is a highly adaptive, evolutionarily conserved process that allows one to respond appropriately to cues associated with danger. In the case of psychiatric disorders, however, fear may persist long after an environmental threat has passed. This unremitting and often debilitating form of fear is a core component of many anxiety disorders, including posttraumatic stress disorder (PTSD), and involves exaggerated and inappropriate fear responses. Existing treatments, such as exposure therapy, are based on principles of fear extinction, during which cues previously associated with threat are presented in the absence of the initial aversive event until cues are considered safe and fear responses are reduced. Extinction-based exposure therapies have the strongest empirical evidence for benefitting adult patients suffering from PTSD (1), yet a comparative lack of knowledge about the development of fear neural circuitry prohibits similarly successful treatment outcomes in children and adolescents (2). Adolescence, in particular, is a developmental stage when the incidence of anxiety disorders peaks in humans (3-6), and it is estimated that over 75% of adults with fear-related disorders met diagnostic criteria as children and adolescents (7, 8). Because of insufficient or inaccurate diagnoses and a dearth of pediatric and adolescent specialized treatments, fewer than one in five children or adolescents are expected to receive treatment for their anxiety disorders (9), leaving a vast number with inadequate or no treatment (2, 10). The increased frequency of anxiety disorders in pediatric and adolescent populations highlights the importance of understanding neural mechanisms of fear regulation from a developmental perspective, as existing therapies directly rely upon principles of fear-extinction learning. Converging evidence from human and rodent studies suggests that insufficient top-down regulation of subcortical structures (11-14), such as the amygdala, may coincide with diminished prototypical extinction learning (15...

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. ß 2010 Wiley Periodicals, Inc. Dev Psychobiol 52: 225-235, 2010.

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.

Recently, a common single nucleotide polymorphism (SNP) has been identified in the gene encoding brain-derived neurotrophic factor (BDNF). The variant BDNF Met 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 BDNF Met has also been linked to increased anxiety-like behavior. In a translational study, mice and human carriers of the BDNF Met 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.