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

Abstract

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...

Fear Generalization in Humans: Systematic Review and Implications for Anxiety Disorder Research

“…Unlike the Hajcak et al study, however, the results did not reveal significant differences between these groups in terms of the acquisition or generalization of conditioned fear (potentiated startle reflex, SCR, risk ratings). These results are in line with another study failing to show fear acquisition deficits in Met-allele carriers (Soliman et al, 2010), although that study did reveal delayed fear extinction effects. Taken together, the currently available studies show highly variable effects of the BDNF polymorphism on fear acquisition and generalization in humans.…”

Caloric Restriction Enhances Fear Extinction Learning in Mice

“…Mice received three trials of CS tone (30 s, 70 dB, and 5 kHz) coterminating with an US footshock (1 s, 0.7 mA) with 30 s between each CS-US pairing (Soliman et al, 2010). Extinction training occurred 24 and 48 h after conditioning.…”

“…The ability to reassess cues of danger as safe has been associated with lower subjective experiences of anxiety, and inefficient fear extinction learning is present in a number of anxiety disorders (Graham and Milad, 2011). Because fear extinction learning is an active learning process that requires neural plasticity (Kaplan and Moore, 2011;Sotres-Bayon et al, 2007), genetic and pharmacologic factors that increase neural plasticity, can enhance fear extinction learning (Mao et al, 2006;Soliman et al, 2010;Sotres-Bayon et al, 2007).…”

BDNF rs6265 methylation and genotype interact on risk for schizophrenia

“…[8][9][10][11] However, while cell and animal models are consistent in showing a functional effect, studies in humans reveal discrepancies in associating the Met or the Val allele to phenotypes relevant for schizophrenia and different psychiatric disorders. [8][9][10][28][29][30][31][32][33] Interestingly, hypoxia-related events during pre-, peri-and early post-natal life (hOCs) have been reported to interact with BDNF in affecting risk for schizophrenia, independently from rs6265.…”

“…5 In the present work we focus our analysis on another popular gene in behavioral genetics, highly important in neurodevelopment and in system-level neural phenotypes and sensitive to environmental factors, the gene coding for the Brain Derived Neurotrophic Factor (BDNF). BDNF is a highly regulated protein, a crucial factor for the development of the feto-placental unit 6 and of the brain, 7 as well as for neural plasticity, energy metabolism, learning, episodic and working memory (WM) [7][8][9][10][11][12] and cancer. 13 The effects of BDNF on synaptic plasticity and neuron survival strongly suggest a role for this factor in schizophrenia, a neurodevelopmental disorder whose risk is heritable and characterized by physiological prefrontal cortex (PFC) dysfunction during WM, [14][15][16] as well as reduced prefrontal levels of BDNF.…”