Fatima Soliman

A Genetic Variant BDNF Polymorphism Alters Extinction Learning in Both Mouse and Human

Of Mice and Men Just how closely must mouse models replicate the known features of human disorders to be accepted as useful for mechanistic and therapeutic studies? Soliman et al. (p. 863, published online 14 January) compared mice that vary only in their allelic composition at one position within the gene encoding brain-derived neurotrophic factor (BDNF) with humans exhibiting the same range of allelic variation. Individuals (mice and humans) carrying the allele that codes for a methionine-containing variant of BDNF retained a fearful response to a threatening stimulus even after its removal in comparison to those with the valine variant. Furthermore, in both cases, this linkage was mediated by diminished activity in the ventral-medial region of the prefrontal cortex. This deficit in extinction learning may contribute to differential responses to extinction-based therapies for anxiety disorders. A common genetic variation affecting fear learning and extinction operates through the same pathways in mice and men. 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.

BRAIN-DERIVED NEUROTROPHIC FACTOR AS A MODEL SYSTEM FOR EXAMINING GENE BY ENVIRONMENT INTERACTIONS ACROSS DEVELOPMENT

There has been a dramatic rise in gene x environment studies of human behavior over the past decade that have 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.

Variant brain-derived neurotrophic factor Val66Met endophenotypes: implications for posttraumatic stress disorder

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.

Ecological nuances in functional magnetic resonance imaging (fMRI): psychological stressors, posture, and hydrostatics

Brain imaging techniques such as functional magnetic resonance imaging (fMRI) have forged an impressive link between psychology and neuroscience. Whereas most experiments in cognitive psychology require participants to perform while sitting upright in front of display devices, fMRI obliges participants to perform cognitive tasks while lying supine and motionless inside a narrow bore. In addition to introducing psychological and physical stressors, such as loud thumps and head restraints, fMRI procedures also alter brain hydrostatics. The ecological factors associated with current fMRI technology, such as supine posture, may skew cognitive processing and influence hemodynamic and electrophysiological measurements, especially in extreme age groups and pathological populations. Recognizing the central role of fMRI in unraveling the neural mechanisms of cognition, we outline ways to address these limitations.

Transitional and translational studies of risk for anxiety

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.

Imaging genetics and development: Challenges and promises

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.

The use of 18F-FDG PET ratios in the differential diagnosis of common malignant brain tumors.

OBJECTIVE This study examined the use of positron emission tomography (PET) ratios to improve the diagnostic ability of 18F-FDG PET/computed tomography (CT) in the differentiation of enhancing brain metastases, central nervous system lymphomas, and gliomas. MATERIALS AND METHODS Seventy-six patients with malignant brain tumors and available magnetic resonance imaging and PET/CT examinations were included. RESULTS Among standardized uptake value (SUV)-related parameters tested, tumor maximum SUV to ipsilateral cortex maximum SUV ratio (Tmax:WMimax) and maximum SUV (SUVmax) proved to be the two most valuable parameters for differential diagnosis. CONCLUSION In addition to SUVmax, Tmax:WMimax also seems to provide helpful information for the differential diagnosis of lymphomas from other malignant brain tumors.