New insights on brain-derived neurotrophic factor epigenetics: from depression to memory extinction

Ann N Y Acad Sci. 2021 Jan;1484(1):9-31. doi: 10.1111/nyas.14458. Epub 2020 Aug 17.


Advances in characterizing molecular profiles provide valuable insights and opportunities for deciphering the neuropathology of depression. Although abnormal brain-derived neurotrophic factor (BDNF) expression in depression has gained much support from preclinical and clinical research, how it mediates behavioral alterations in the depressed state remains largely obscure. Environmental factors contribute significantly to the onset of depression and produce robust epigenetic changes. Epigenetic regulation of BDNF, as one of the most characterized gene loci in epigenetics, has recently emerged as a target in research on memory and psychiatric disorders. Specifically, epigenetic alterations of BDNF exons are heavily involved in mediating memory functions and antidepressant effects. In this review, we discuss key research on stress-induced depression from both preclinical and clinical studies, which revealed that differential epigenetic regulation of specific BDNF exons is associated with depression pathophysiology. Considering that BDNF has a central role in depression, we argue that memory extinction, an adaptive response to fear exposure, is dependent on BDNF modulation and holds promise as a prospective target for alleviating or treating depression and anxiety disorders.

Keywords: DNA methylation; brain-derived neurotrophic factor; depression; histone modification; memory extinction.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Anxiety Disorders / genetics
  • Anxiety Disorders / physiopathology
  • Brain-Derived Neurotrophic Factor / genetics*
  • Depression / genetics*
  • Depression / physiopathology
  • Epigenesis, Genetic / genetics*
  • Fear / physiology
  • Humans
  • Memory / physiology
  • Memory Disorders / genetics*
  • Memory Disorders / physiopathology
  • Promoter Regions, Genetic / genetics


  • Brain-Derived Neurotrophic Factor
  • BDNF protein, human