 The research plan calls for the recruitment of adult human subjects with major depressive disorder MDD or healthy control HC volunteers over the 5-year grant period. All participants are required to be medically healthy as determined by medical history, physical examination, ECG, screening blood laboratory tests, urine analysis, and urine toxicology drug screen. Participants with MDD must have demonstrated inadequate therapeutic response to a minimum of one adequate antidepressant trial e.g. TRD. MDD participants who meet this minimum TRD threshold will be eligible for the experiments in Aim 1. 