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The relevance of depression in the clinical realm is well known, as it is one of the most common mental disorders in the United States. Clinical depression is the leading cause of disease for women worldwide. The sex difference in depression and anxiety has guided the research of not just recent studies but older studies as well, supporting the theory that gonadal hormones are associated with the mechanisms of emotional cognition. The scientific literature points towards a clear correlative relationship between gonadal hormones, especially estrogens, and emotion regulation. This thesis investigates the neural pathways that have been indicated to regulate mood and anxiety. Currently, the research points to the hypothalamic-pituitary-adrenal axis, which regulates the stress response through its ultimate secretion of cortisol through the adrenal cortex, and its modulated response when exposed to higher levels of estrogen. Another mechanism that has been investigated is the interaction of estrogen and the serotonergic system, which is noteworthy because the serotonergic system is known for its importance in mood regulation. However, it is important to note that the research seeking to determine the neurobiological underpinnings of estrogen and the serotonergic system is not expansive. Future research should focus on determining the direct relationship between cortisol hypersecretion and estrogens, the specific neurobiological effects of serotonergic receptor subtypes on the antidepressant actions of estrogens, and the simultaneous effects of the stress and serotonergic systems on depressive symptoms.
receptor (RAR) and vitamin D receptor (VDR). The RXR/RAR dimer is activated by ligand all
trans retinoic acid (ATRA), which culminates in gut-specific effector T cell migration. Similarly,
the VDR/RXR dimer binds 1,25(OH)2D3 to cause skin-specific effector T cell migration.
Targeted migration is a potent addition to current vaccines, as it would induce activated T cell
trafficking to appropriate areas of the immune system and ensure optimal stimulation (40).
ATRA, while in use clinically, is limited by toxicity and chemical instability. Rexinoids
are stable, synthetically developed ligands specific for the RXR. We have previously shown that
select rexinoids can enhance upregulation of gut tropic CCR9 receptors on effector T cells.
However, it is important to establish whether these cells can actually migrate, to show the
potential of rexinoids as vaccine adjuvants that can cause gut specific T cell migration.
Additionally, since the RXR is a major contributor to VDR-mediated transcription and
epidermotropism (15), it is worth investigating whether these compounds can also function as
adjuvants that promote migration by increasing expression of skin tropic CCR10 receptors on T
cells.
Prior experiments have demonstrated that select rexinoids can induce gut tropic migration
of CD8+ T cells in an in vitro assay and are comparable in effectiveness to ATRA (7). The effect
of rexinoids on CD4+ T cells is unknown however, so the aim of this project was to determine if
rexinoids can cause gut tropic migration in CD4+ T cells to a similar extent. A secondary aim
was to investigate whether varying concentrations in 1,25-Dihydroxyvitamin D3 can be linked to
increasing CCR10 upregulation on Jurkat CD4+ T cells, with the future aim to combine 1,25
Dihydroxyvitamin D3 with rexinoids.
These hypotheses were tested using murine splenocytes for the migration experiment, and
human Jurkat CD4+ T cells for the vitamin D experiment. Migration was assessed using a
Transwell chemotaxis assay. Our findings support the potential of rexinoids as compounds
capable of causing gut-tropic migration in murine CD4+ T cells in vitro, like ATRA. We did not
observe conclusive evidence that vitamin D3 causes upregulated CCR10 expression, but this
experiment must be repeated with a human primary T cell line.