NR3C1 and major depressive disorder: When the cortisol interacts with glucocorticoid receptors in the frontal cortex and the hippocampus, these receptors operate as transcription factors, modeling the neural circuitry that regulates cognition and emotional response to stress.79 In chronic stress, excess of glucocorticoids results in shrinking of dendritic processes and impairment of hippocampal synaptic plasticity, which can impair cognitive functions and emotions, increasing the risk of depression.79