The overall purpose of this Program Project application is to understand the molecular and neuronal mechanisms that lead to individual differences in emotional responsiveness, and to apply this understanding to uncovering the biological basis of vulnerability to major depressive disorder (MDD). Like many common disorders, MDD is a heterogeneous illness with a complex genetic nature, involving interacting genes An essential element in the vulnerability to the illness is how one reacts and copes with stress and anxiety provoking situations. This is determined at the level of the brain, and involves critical neuronal circuits that control emotional responsiveness. Thus it is important to characterize the biological basis of differences in emotional reactivity in animal models, and use this knowledge in our efforts to understand vulnerability to mood disorders in humans. To this end, we plan to focus on a particular set of known candidate systems-the stress system and the serotonergic and noradrenergic systems that closely interact with it. But, we also plan to search for novel candidate genes using microarray technology and to begin to explore their relationship to differences in emotional reactivity. We plan to study the known and the novel candidate molecules under both basal to define the neuronal phenotypes (patterns of gene expression in the brain) that accompany the behavioral differences in emotional responsiveness. Project 1 (Subproject 0013) is concerned with stress-serotonin interactions, as well as the discovery of novel candidates that are differentially expressed in animals with different emotional responsiveness. Project 2 (Subproject 0010) focuses on stress- noradrenaregic interactions in rats. In addition, it involves the study of these interactions in human postmortem brain tissue from depressed individuals and matched controls. Project 3 (Subproject 0011) uses a developmental approach to uncover the unfolding of the behavioral differences in emotional responsiveness and their neuronal correlates in the rat. Project 4 (Subproject 0012) uses mouse genetic approaches to over- or under-express the corticosteroid receptors in a tissue specific and inducible manner and study the effects on emotionality Project 5 (Subproject 0013) will involve the study of depressed individual using a combination of neuroendocrine and neuroimaging approaches to investigate individual differences in the interaction between the stress and serotonin system and its relevance to treatment response. The components of this project are highly complementary and synergistic. It is hoped that their completion will shed light on the molecular, neurobiological and environmental factors that lead to increased vulnerability to depression and affect the individual's response to the treatment of this illness.
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