"Depression is a highly prevalent mood disorder which affects up to 20% of the population. While women are twice as likely as men to be diagnosed with a mood disorder, the neurophysiological contributions to this disparity are unclear. One brain region implicated in depression-like symptoms in both humans and rodents is the hippocampus (HPC). The HPC is uniquely susceptible to stress, has distinct patterns of information flow, and functional segregation of cognitive and affective memories across the dorsoventral axis; this suggests specific hippocampal subpopulations may be involved in different aspects of learning and memory. Previously, the transcription factor Delta-FosB was shown to regulate spatial learning and cell proliferation, and was found to be induced in dHPC after stress. Herein, I elucidate Delta-FosB's contributions in hippocampal subregions among specific behavioral domains: dentate gyrus (DG) influence on spatial learning, and vHPC influence on stress-behavior in both sexes. Specifically, I show that DG SGZ FosB gene products are necessary for normal neurogenesis and learning. As the vHPC is implicated in affective learning and memory through its connectivity to limbic regions, I examined the role of vHPC Delta-FosB in stress-induced behaviors. I describe divergent patterns of behavior in males, where Delta-FosB in vHPC-NAc is necessary and sufficient for resilience to stress but Delta-FosB in vHPC-BLA is necessary for the expression of fear and anxiety. These results demonstrate that individual genes can have disparate roles within a single brain region, based not only on heterogenous cell types but on the specific projections of the neurons in which they are expressed. I also show a basal sex difference in stress susceptibility which is mediated by the vHPC-NAc circuit and adult testosterone. These data show vHPC-NAc activity is causally linked to the sex difference in susceptibility to stress-induced anhedonia. This relationship is dependent upon long-term adaptation of vHPC-NAc projections and may reflect on the biological underpinning of female vulnerability to mood disorders related to stress."--Pages ii-iii.
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