Cynthia L. Bethea

Serotonin is a neurotransmitter that is produced in discreet cell populations in the midbrain. The serotonin-producing cells send projections that release serotonin to all areas of the forebrain and the spinal cord. Correct release of serotonin is very important for integrative cognition, memory, mood and affective regulation, pituitary hormone release, satiety, sleep and pain perception. The ovarian hormones, estrogen and progesterone, act in serotonin neurons to increase neurotransmission and cell viability by a variety of mechanisms. Loss of ovarian hormones can lead to various psychiatric disorders.

Cynthia Bethea and her staff are working with primate, rodent and cell culture models to understand the mechanisms by which estrogen and progesterone act in serotonin neurons. Serotonin deficits occur in patients who are clinically depressed. Twice as many women as men suffer from depression, and many depressive episodes are associated with the withdrawal of estrogen and progesterone at the end of each menstrual cycle, following parturition and after menopause.

Researchers in this laboratory are using laser capture of serotonin neurons, microarray analysis, quantitative PCR, in situ hybridization, immunocytochemistry, ligand binding and western blotting to characterize the estrogen and progesterone regulation of gene and protein expression in serotonin neurons. They have found that serotonin neurons use a recently discovered form of the estrogen receptor called ERß. Estrogen acts through ERß on tryptophan hydroxylase, the enzyme that governs serotonin synthesis. The expression of this enzyme is increased at the mRNA and protein levels by ovarian hormones. In addition, they have found that the 5HT1A auto receptor, which acts like a brake on serotonin neurons, is decreased at the mRNA and protein levels by ovarian hormones. Thus, ovarian hormones both increase serotonin production and increase the rate at which the neurons release serotonin.

Recent studies have shown that estrogen and progesterone inhibit the expression of genes that lead to premature cell death in laser captured serotonin neurons. Protein analysis has indicated that estrogen and progesterone prevent cell death by a caspase-independent mechanism. Studies are underway to characterize DNA fragmentation by TUNEL assay in serotonin neurons. Additional studies have shown that estrogen and progesterone promote neuroplasticity by increasing the expression of genes that promote dendritic spine proliferation in laser captured serotonin neurons. Dendritic spines provide the majority of excitatory synapses in the CNS. Studies are underway to characterize the proteins involved. Together the data indicate that estrogen and progesterone increase serotonin production, increase excitatory synapses on serotonin neurons and prevent serotonin cell death.

Understanding the mechanisms by which ovarian hormones act in serotonin neurons has opened new avenues for the development of selective estrogen receptor modulators that activate ERß. Like estrogen, these drugs will act beneficially in the brain, heart and bones, but they will not have estrogen's negative peripheral effects in the breast and uterus.

BIOGRAPHY

Cynthia Bethea is a scientist in the Division of Reproductive & Developmental Sciences and an adjunct associate professor of physiology and pharmacology in the OHSU School of Medicine. After being awarded a B.S. from Winthrop University in 1972 and an M.S. in zoology at Clemson University in 1974, she earned her Ph.D. in physiology from Emory University in 1978. She conducted postdoctoral research in neuroendocrinology at the Reproductive Endocrinology Center of the University of California at San Francisco until she came to the center in 1981.

KEY PUBLICATIONS

Bethea CL. (2011) MPA: medroxy-progesterone acetate contributes to much poor advice for women. Endocrinology. 152(2):343-5. PMCID: PMC3037166.

Bethea CL, Smith AW, Centeno ML, Reddy AP. (2011) Long-term ovariectomy decreases serotonin neuron number and gene expression in free ranging macaques. Neuroscience. 29;192: 675-88. Epub 2011 Jul 2. PMCID: PMC3166449.

Coleman K, Robertson ND, Bethea CL. (2011) Long-term ovariectomy alters social and anxious behaviors in semi-free ranging Japanese macaques. Behav Brain Res. 20;225(1):317-27. Epub 2011 Aug 3. PMCID: PMC3170512.

Bogdan R, Fitzgibbon H, Woolverton WL, Bethea CL, Iyo AH, Stockmeier CA, Kyle PB, Austin MC. (2011) 5-HTTLPR genotype and gender, but not chronic fluoxetine administration, are associated with cortical TREK1 protein expression in rhesus macaques. Neurosci Lett. 3;503(2):83-6. Epub 2011 Aug 17. PMCID: PMC3178708.

Lima FB, Centeno ML, Costa ME, Reddy AP, Cameron JL, Bethea CL. (2009) Stress sensitive female macaques have decreased fifth Ewing variant (Fev) and serotonin-related gene expression that is not reversed by citalopram. Neuroscience. 2009 Dec 1;164(2):676-91. PMCID: PMC2762017. 

Weissheimer KV, Herod SM, Cameron JL, Bethea CL. (2010) Interactions of corticotropin-releasing factor, urocortin and citalopram in a primate model of stress-induced amenorrhea. Neuroendocrinology. 92(4):224-34. PMCID: PMC3025882.