This project will rely on mouse genetic tools in order to dissect, at the molecular level, the role of specific genes in determining differences in emotionality. We plan to manipulate the levels of expression of the two corticosteroid receptor genes the glucocorticoid receptor, GR, and the mineralocorticoid receptor, MR to create animals that either over- or under-express them. We plan to use a promoter that exhibits region- specific differences in activity to obtain altered gene expression in a region-specific manner within the brain. The targeted regions include structures that typically express these genes and regulate reactivity to stress and anxiety, including the hippocampus and the cortex. Finally, we plan to use inducible constructs in order to gain control over the timing and duration of over- or under-expression of these receptors, and to do so in a brain regions-specific manner. In these animal models, we will ascertain the behavioral and neuroendocrine profiles of the mice, and examine the consequences of the genetic manipulation on learning and memory. We will also study the effect of a chronic social stress (social defeat) on both behavior and gene expression in the brain. We will determine whether this single manipulation leads to patterns of gene expression in specific brain circuits that resemble what we observe in the context of spontaneous differences in emotionality in the rat. This would begin to point to certain genes, such as the corticosteroid receptors, as key triggers or """"""""switches"""""""" in the modulation of emotional reactivity. These studies should not only yield novel animal models with altered emotional reactivity, they should also shed light on the mechanisms that might control spontaneous differences in emotionality as studied in the other projects.
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