OHSU

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Cynthia L. Bethea, Ph.D.

Senior Scientist
Oregon National Primate Research Center
Admin Unit: -- None --
Phone: 503-690-5327
Lab Phone: 503-690-5348
Fax: 503-690-5384
Office: west campus, Cooley building
Programs:
Behavioral Neuroscience
Neuroscience Graduate Program
Research Interests:
Serotonin, Estrogen, Progesterone, Neuroprotection, Molecular » Click here for more about Dr. Bethea's research » PubMed Listing
Preceptor Rotations
Dr. Bethea has not indicated availability for preceptor rotations at this time.
Faculty Mentorship
Dr. Bethea has not indicated availability as a mentor at this time.
Profile

The dorsal and medial raphe nuclei contain the serotonergic neurons that project to all areas of the forebrain. These neurons are critical for proper regulation of mood, affect, integrated cognition and other autonomic neural functions. This laboratory has devoted effort toward understanding the actions of ovarian hormones in serotonin neurons and their terminal fields with a macaque model of surgical menopause. We showed that serotonin neurons express estrogen receptor beta (ERb) and progestin receptors (PR). Thus, they are direct targets of the ovarian hormones estrogen (E) and progesterone (P).  We found that E, plus or minus P supplementation, regulates the expression of pivotal serotonin-related genes and proteins in the monkey dorsal raphe in a pattern suggestive of increased serotonin production, increased serotonin turnover, increased neural firing and decreased degradation.

In another paradigm, we observed that stress-sensitive cynomolgus monkeys have fewer serotonin neurons than stress-resilient companions. Moreover, the lower serotonin cell number was strongly correlated to lower levels of E and P during their menstrual cycles. The stress-sensitive macaques also had overall lower expression of serotonin-related genes than stress-resilient counterparts reflecting the serotonin cell number.

These correlations raised the question of whether E and P could be neuroprotective for serotonin neurons.

This issue may be extremely important for menopausal women grappling with issues surrounding hormone therapy (HT). Women experience premature ovarian failure and loss of ovarian steroid production around 50 years of age. Thus, with extended life spans, a woman may live 35-40 years without ovarian steroids.   If serotonin neurons are gradually dying due to lack of steroid supported gene expression, then geriatric depression, anxiety, fretfulness, decreased coping skills and increased vulnerability to stress can be predicted outcomes.

We have recently conducted Affymetrix cDNA array analysis on laser captured serotonin neurons from spayed monkeys treated with placebo, E or E+P. In hormone-treated (HT) monkeys, a significant number of genes that are involved in neuroprotection were altered. Overall, it appears that HT is neuroprotective of serotonin neurons and probably other neurons in the midbrain by several major mechanisms. HT induces a decrease in gene expression in the TNF/cytokine signaling pathway and in Smac/Diablo, a mediator of apoptosis by this pathway, but it increases calpain that blocks TNF signaling; HT induces a decrease in expression of genes that encode pivotal proteins in the caspase dependent and independent pathways; HT increases gene expression of pivotal survival factors; and HT alters gene expression governing cell cycle initiation and progression. Thus, HT provides trophic support and inhibits the expression of genes that increase vulnerability to cytokines and stress in serotonin neurons and the surrounding neuropile. We are now determining whether the changes in gene expression are manifested at the protein level.

Education

Ph.D., Emory University, 1978