Neuroprotective Effects of Estrogen in Serotonin Neurons

Oregon Health & Science University, Portland OR

Investigators

Abstract

[unreadable] DESCRIPTION (provided by applicant): Understanding estrogen's neuroprotective actions in the serotonin system has relevance to many aspects of women's mental health. Women have 2-3 times higher lifetime frequency of depression than men and depressive episodes often correlate with reproductive life events such as menstruation, post-partum, and the onset of menopause. We want to understand how fluctuations in hormones during reproductive life events may alter the serotonin system and underlie changes in women's mental health. Our long-term goal is to expand our knowledge of the neuroprotective mechanisms of sex steroid hormones. The objective of the proposed research is to determine the effects of estrogen administration after ovariectomy on the kynurenine pathway. We hypothesize that estrogen down regulates kynurenine mono-oxygenase (KMO), the enzyme responsible for shifting tryptophan metabolism away from pathways in which tryptophan is converted to serotonin or the neuroprotective kynurenic acid, towards pathways in which tryptophan is converted to several neurotoxic metabolites. This down regulation and subsequent metabolic shift may be a mechanism for estrogen neuroprotection in the serotonin system. In order to test this hypothesis I intend to conduct experiments in placebo and hormonally-treated ovariectomized monkeys to: determine if KMO is localized to serotonin neurons, determine the effect of estrogen treatment on KMO mRNA and protein expression in the dorsal raphe nuclei, and investigate the effect of estrogen treatment on kynurenic acid/ quinolinic acid ratios in serotonin neurons of the dorsal raphe nucleus, serum, CSF and urine. Serotonin function has been linked to a wide variety of psychological and behavioral disorders including aggressive disorders, depression, stress sensitivity (anxiety), sleep disorders, and obesity. A vast amount of research has shown this system is profoundly altered by changes in the hormonal balance in both men and women. Understanding how changes in hormonal balance may alter the serotonin system and underlie changes in mental health is extremely important. [unreadable] [unreadable] [unreadable]