Project 1 A growing body of literature shows that brain-derived neurotrophic factor (BDNF) plays a significant role in the development of the nervous system, as well as in activity-dependent learning and plasticity. BDNF levels increase over development and peak at adolescence, before beginning a steady decline that continues into adulthood. This pattern of change in BDNF levels suggests that behavioral and neuroanatomical differences between BDNF genotypes may vary across the course of development. This project examines how the uniquely-human BDNF Val66Met polymorphism mediates contextual, cued and reversal learning (extinction). Preliminary imaging studies confirm that the forms of learning under investigation are in part dependent on the hippocampus (Amso et al., 2005), amygdala (Hare et al., 2005) and ventromedial prefrontal cortex (including orbitofrontal cortex). These regions have been shown to be sensitive to environmental factors (stress) and may be compromised in children with clinical disorders (Thomas et al., 2001). We will use these behavioral learning assays in combination with structural and functional magnetic resonance imaging techniques to examine changes associated with BDNF genotype. We will specifically examine whether differences between genotypes change with age as a function of variations in BDNF levels overdevelopment (Center Aim 1). We will also determine whether mild to moderate environmental risk factors experienced over the course of typical development, as opposed to severe early stressors examined in Projects II and III, serve to potentiate differences between BDNF genotypes (Center Aim 2). This project is directly complemented by Project III, which will use similar assays in a BDNF knock-in mouse model of the human Val66Met mutation to constrain human findings with evidence from histological and cellular levels of analysis. Project I will establish the role of BDNF in the typical developmental trajectory of different forms of learning and will provide a solid foundation on which to base interpretations of BDNF gene-environment interactions in a population of adolescents who experienced severe early-life stress in the form of institutional/orphanage rearing (Project II). Both the Analytic and Data Management Core and Statistical Genetics Core will support data processing and analysis of behavioral, imaging and genetic data.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
5P50MH079513-05
Application #
8379154
Study Section
Special Emphasis Panel (ZMH1-ERB-A)
Project Start
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
5
Fiscal Year
2012
Total Cost
$335,279
Indirect Cost
$93,872
Name
Weill Medical College of Cornell University
Department
Type
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
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Dincheva, Iva; Yang, Jianmin; Li, Anfei et al. (2017) Effect of Early-Life Fluoxetine on Anxiety-Like Behaviors in BDNF Val66Met Mice. Am J Psychiatry 174:1203-1213
Jing, Deqiang; Lee, Francis S; Ninan, Ipe (2017) The BDNF Val66Met polymorphism enhances glutamatergic transmission but diminishes activity-dependent synaptic plasticity in the dorsolateral striatum. Neuropharmacology 112:84-93
Zhou, Yan; Huang, Ted; Lee, Francis et al. (2016) Involvement of Endocannabinoids in Alcohol ""Binge"" Drinking: Studies of Mice with Human Fatty Acid Amide Hydrolase Genetic Variation and After CB1 Receptor Antagonists. Alcohol Clin Exp Res 40:467-73
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Proenca, Catia C; Song, Minseok; Lee, Francis S (2016) Differential effects of BDNF and neurotrophin 4 (NT4) on endocytic sorting of TrkB receptors. J Neurochem 138:397-406
Glatt, Charles E; Lee, Francis S (2016) Common Polymorphisms in the Age of Research Domain Criteria (RDoC): Integration and Translation. Biol Psychiatry 79:25-31
Pattwell, Siobhan S; Liston, Conor; Jing, Deqiang et al. (2016) Dynamic changes in neural circuitry during adolescence are associated with persistent attenuation of fear memories. Nat Commun 7:11475
Dincheva, Iva; Lynch, Niccola B; Lee, Francis S (2016) The Role of BDNF in the Development of Fear Learning. Depress Anxiety 33:907-916

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