Li Anfei, Jing Deqiang, Dellarco Danielle V, Hall Baila S, Yang Ruirong, Heilberg Ross T, Huang Chienchun, Liston Conor, Casey B J, Lee Francis S
Sackler Institute for Developmental Psychobiology, Weill Cornell Medicine, New York, NY, USA.
Department of Psychiatry, Weill Cornell Medicine, New York, NY, USA.
Mol Psychiatry. 2021 Mar;26(3):955-973. doi: 10.1038/s41380-019-0422-4. Epub 2019 Apr 16.
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.
社交缺陷在许多精神疾病中很常见。然而，由于用于操纵人类大脑回路活动的工具不足，以及在啮齿动物中模拟社交行为的范式不具有特异性，我们对介导社交行为的分子和回路机制的理解仍然相对有限。利用人类功能性神经成像和啮齿动物纤维光度测量法，我们确定了一条调节社交接近行为并影响社交焦虑易感性的内侧前额叶皮质-杏仁核基底外侧核投射通路。在携带功能丧失型BDNF单核苷酸多态性（Val66Met）的人类和基因敲入小鼠中，该回路的功能发生了改变，导致人类和小鼠出现社交行为变化。我们进一步表明，由于BDNF生物利用度不足，特别是在青春期前后这段时间，BDNF Met携带者中该回路的发育受到破坏。这些发现确定了社交焦虑可能源于眶额-杏仁核投射成熟改变的一种机制，并确定了一个基于BDNF的干预措施可能具有治疗潜力的发育窗口。
