Project III Brain derived neurotrophic factor (BDNF) plays a critical role in vertebrate nervous system development. Recently, a single nucleotide polymorphism (SNP) in the BDNF gene, a valine (Val) to methionine (Met) substitution in the prodomain (BDNFMet t), has been shown to result in impairments in humans in hippocampal dependent memory, decreased hippocampal volume, and susceptibility to neuropsychiatric disorders. Preliminary studies utilizing a novel transgenic knock-in mouse expressing the BDNFwet SNP have led us to hypothesize that the biological consequences of BDNFMet observed in the adult central nervous system are due to reduced BDNF availability during development. In this project, we propose to use the DNFMet knock-in mouse to establish the typical developmental trajectory of the hippocampus (He), prefrontal cortex (PFC), and amygdala (AMG), as a function of BDNF genotype. We will exploit tasks that are nearly identical to those proposed in human studies in Project I, to probe genotypic differences across development (Center Aim 1). In preliminary studies, we have determined that the BDNFMet genotype has significant effects on neuroanatomy of the He, PFC, and AMG, as well as their associated behaviors. In subsequent studies, environmental (stress, enrichment), as well as genetic (BDNF overexpression) interventions will be used to determine the precise impact of changing levels of BDNF across development. These studies will parallel work in Project 2, investigating the impact of early life adversity (orphanage) and subsequent placement into an adoptive home as a factor of genotype.
The Specific Aims of Project III are to 1) determine the biological consequences of the variant BDNFMet on He, PFC, and AMG function across development, 2) determine the interaction between stress and genotype across development in BDNF mice through the assessment of He, PFC, and AMG function, and 3) Determine the effect of BDNF gain of function on He, PFC, and AMG function of the BDNFMet mouse across development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
5P50MH079513-05
Application #
8379158
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
$331,489
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
Pitula, Clio E; Wenner, Jennifer A; Gunnar, Megan R et al. (2017) To trust or not to trust: social decision-making in post-institutionalized, internationally adopted youth. Dev Sci 20:
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
Lee, T T-Y; Hill, M N; Lee, F S (2016) Developmental regulation of fear learning and anxiety behavior by endocannabinoids. Genes Brain Behav 15:108-24
Heller, Aaron S; Cohen, Alexandra O; Dreyfuss, Michael F W et al. (2016) Changes in cortico-subcortical and subcortico-subcortical connectivity impact cognitive control to emotional cues across development. Soc Cogn Affect Neurosci 11:1910-1918
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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