Project 1A growing body of literature shows that brain-derived neurotrophic factor (BDNF) plays a significant role inthe development of the nervous system, as well as in activity-dependent learning and plasticity. BDNF levelsincrease over development and peak at adolescence, before beginning a steady decline that continues intoadulthood. This pattern of change in BDNF levels suggests that behavioral and neuroanatomical differencesbetween BDNF genotypes may vary across the course of development. This project examines how theuniquely-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 onthe 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 thesebehavioral learning assays in combination with structural and functional magnetic resonance imagingtechniques to examine changes associated with BDNF genotype. We will specifically examine whetherdifferences 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 experiencedover the course of typical development, as opposed to severe early stressors examined in Projects II andIII, serve to potentiate differences between BDNF genotypes (Center Aim 2). This project is directlycomplemented by Project III, which will use similar assays in a BDNF knock-in mouse model of the humanVal66Met mutation to constrain human findings with evidence from histological and cellular levels ofanalysis. Project I will establish the role of BDNF in the typical developmental trajectory of different forms oflearning and will provide a solid foundation on which to base interpretations of BDNF gene-environmentinteractions in a population of adolescents who experienced severe early-life stress in the form ofinstitutional/orphanage rearing (Project II). Both the Analytic and Data Management Core and StatisticalGenetics Core will support data processing and analysis of behavioral, imaging and genetic data.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Specialized Center (P50)
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Special Emphasis Panel (ZMH1-ERB-A (05))
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Weill Medical College of Cornell University
New York
United States
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Herzberg, Max P; Hodel, Amanda S; Cowell, Raquel A et al. (2018) Risk taking, decision-making, and brain volume in youth adopted internationally from institutional care. Neuropsychologia 119:262-270
Meyer, Heidi C; Lee, Francis S; Gee, Dylan G (2018) The Role of the Endocannabinoid System and Genetic Variation in Adolescent Brain Development. Neuropsychopharmacology 43:21-33
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