The Brain-Derived Neurotrophic Factor: Missing Link Between Sleep Deprivation, Insomnia, and Depression.

The brain-derived neurotrophic factor (BDNF) mediates the plasticity-related changes that associate with memory processing during sleep. Sleep deprivation and chronic stress are associated with propensity to depression, anxiety, and insomnia. We propose a model by which explain alterations in the CNS and serum expression of BDNF associated with chronic sleep deprivation, depression, and insomnia. Mild sleep deprivation activates the cerebral cortex and brainstem to generate the physiologic drive for non-rapid eye movement (NREM) and rapid eye movement (REM) sleep drive respectively, associated with BDNF upregulation in these regions. This physiological response loses effectiveness with longer episodes or during chronic of total or selective REM sleep loss, which are associated with impaired hippocampal BDNF expression, impaired memory and cognition. Chronic sleep deprivation and insomnia can act as an external stressors and result in depression, characterized by hippocampal BDNF downregulation along with disrupted frontal cortical BDNF expression, as well as reduced levels and impaired diurnal alterations in serum BDNF expression. Acute REM sleep deprivation breaks the cycle by restoration of hippocampal, and possibly restoration of cortical and serum expression of BDNF. The BDNF Val66Met polymorphism alters susceptibility to depression, anxiety, and insomnia by altering availability and expression of BDNF in brain and blood. The proposed model is testable and implies that low levels and low variability in serum BDNF are associated with poor response to anti-depressive medications, electroconvulsive therapy, and REM sleep deprivation, in patients with depression. Our mode is also backed up by the existing clinical evidence but is yet to be investigated.