This Program Project application represents our continued efforts to understand, at a molecular, cellular and integrative level, key neurons systems which are both intrinsically important and have direct relevance to the study of two major psychiatric disorders-depression and schizophrenia. The four individual proposals represent a basic to clinical progression beginning with molecular biological studies of two neurocircuits-the brain component of the stress axis, and the dopaminergic motor and limbic pathways, moving to the study of these same systems in post-mortem human brains, and ending with neuroendocrine challenge studies in normal controls and subjects suffering from major depression. Thus, Project I investigates basic mechanisms which are critical to controlling stress responsiveness by examining its key elements at a molecular level and describing the anatomical organization of circuits which either initiate or limit the stress response. Project II studies, also at a molecular and anatomical level, two receptor systems relevant to schizophrenia and depression, specifically the dopaminergic and the serotonergic receptor families. Project III extends the study of the elements of the stress axis and of the two receptor families to post-mortem human brain, attempting to delineate their gene expression and their alterations in the brains of suicide victims and of schizophrenics. Finally, Project IV uses novel challenge paradigms to increase our understanding of the dysregulation of the stress axis in depression, both at the pituitary and the brain levels.
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