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Role of BDNF in the development of an OFC-amygdala circuit regulating sociability in mouse and human

Abstract

Social deficits are common in many psychiatric disorders. However, due to inadequate tools for manipulating circuit activity in humans and unspecific paradigms for modeling social behaviors in rodents, our understanding of the molecular and circuit mechanisms mediating social behaviors remains relatively limited. Using human functional neuroimaging and rodent fiber photometry, we identified a mOFC-BLA projection that modulates social approach behavior and influences susceptibility to social anxiety. In humans and knock-in mice with a loss of function BDNF SNP (Val66Met), the functionality of this circuit was altered, resulting in social behavioral changes in human and mice. We further showed that the development of this circuit is disrupted in BDNF Met carriers due to insufficient BDNF bioavailability, specifically during a peri-adolescent timeframe. These findings define one mechanism by which social anxiety may stem from altered maturation of orbitofronto-amygdala projections and identify a developmental window in which BDNF-based interventions may have therapeutic potential.

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Data availability

All the relevant data that support the findings of this study are available from the corresponding author upon reasonable request. Data from PING data set is available publicly online (pingstudy.ucsd.edu).

Code availability

The custom written code files for fiber photometry data processing and human imaging analyses are available upon request.

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Acknowledgements

This work was supported in part by National Institutes of Health (NIH) grants NS052819 (to FSL), 5UL1TR000457 (to FSL), P50MH079513 (to BJC), R01DA018879 (to BJC), RC2DA029475 (to BJC), and MSTP training grant GM07739 (to AL), a generous gift by the Mortimer D. Sackler, M.D. family, the Brain and Behavior Research Foundation (to BJC and FSL), the New York-Presbyterian Youth Anxiety Center (to FSL), the Pritzker Neuropsychiatric, Disorders Research Consortium (to FSL), and the DeWitt-Wallace Fund of the New York Community Trust (to FSL). The authors would like to thank the staff at the Biomedical Imaging Core and Citigroup Biomedical Imaging Center at Weill Cornell Medical College for their assistance in data collection.

Author contributions

AL, BJC, and FSL conceived and designed the study. AL performed most of the experiments, analyzed the data, and wrote the manuscript. DJ and RY performed tract-tracing experiments. DVD recruited human subjects. BSH assisted with rodent social tasks and fiber photometry. RTH and CH assisted with animal handling, surgery, and husbandry. CL, BJC and FSL supervised the analysis of data and wrote the manuscript. All authors discussed the results and commented on the manuscript.

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Li, A., Jing, D., Dellarco, D.V. et al. Role of BDNF in the development of an OFC-amygdala circuit regulating sociability in mouse and human. Mol Psychiatry 26, 955–973 (2021). https://doi.org/10.1038/s41380-019-0422-4

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