TY - JOUR
T1 - Long-term ovariectomy decreases serotonin neuron number and gene expression in free ranging macaques
AU - Bethea, C. L.
AU - Smith, A. W.
AU - Centeno, M. L.
AU - Reddy, A. P.
N1 - Funding Information:
We are deeply grateful to the technicians of the Division of Animal Resources, including surgery personnel, for their help with all aspects of this study. We especially thank Dr. Kris Coleman, Head of Behavioral Sciences, who provided expert knowledge and advice on the Japanese macaque troop, on Japanese macaque behavior and what it means to other monkeys. We also are especially grateful to Dr. Coleman's assistant, Nicola Roberts, who was intimately involved in monitoring the behavior and well being of the animals in this study. This study was supported by NIH grants MH62677 to C.L.B. and P51-RR000163 for the operation of ONPRC.
PY - 2011/9/29
Y1 - 2011/9/29
N2 - The serotonin system responds to the ovarian steroids, estradiol (E) and progesterone (P), in women and female animal models. In macaques, ovarian steroid administration to ovariectomized (Ovx) individuals improves serotonin neural function through actions on pivotal serotonin-related genes and proteins, such as TPH2 (tryptophan hydroxylase 2), SERT (serotonin reuptake transporter), and the 5HT1A autoreceptor. In addition, ovarian steroid administration reduces gene and protein expression in the caspase-independent pathway and reduces DNA fragmentation in serotonin neurons. This study examines the hypothesis that long-term ovariectomy will lead to a loss of serotonin neurons and compromised gene expression in serotonin neurons. Female Japanese macaques were ovariectomized or tubal ligated (n=5/group) at 3 years of age and returned to their natal troop. After 3 years, the animals were collected, administered a fenfluramine challenge to determine global serotonin availability, and then euthanized. Fev, TPH2, SERT, and 5HT1A expression were examined with digoxigenin in situ hybridization (ISH) and quantitative image analysis. Cell number, positive pixel area, and average pixel density were determined. In the Ovx group, Fev, TPH2, SERT, and 5HT1A showed a significant decease in average and total cell number and positive pixel area. The reduction in Fev-positive neurons suggests that there were fewer serotonin neurons in Ovx animals compared to ovary-intact animals. The decrease in TPH2 in the Ovx animals was consistent with earlier results in 5-month Ovx animals, but it may be due to the decrease in cell number rather than a decrease in expression on an individual cell basis. The decrease in SERT and 5HT1A in long-term Ovx differed from previous studies in short-term Ovx. In summary, long-term ovarian steroid loss resulted in fewer serotonin neurons and overall lower Fev, TPH2, SERT, and 5HT1A gene expression. This may be due to serotonin cell death or to a negative impact on a long-term developmental process in young female macaques.
AB - The serotonin system responds to the ovarian steroids, estradiol (E) and progesterone (P), in women and female animal models. In macaques, ovarian steroid administration to ovariectomized (Ovx) individuals improves serotonin neural function through actions on pivotal serotonin-related genes and proteins, such as TPH2 (tryptophan hydroxylase 2), SERT (serotonin reuptake transporter), and the 5HT1A autoreceptor. In addition, ovarian steroid administration reduces gene and protein expression in the caspase-independent pathway and reduces DNA fragmentation in serotonin neurons. This study examines the hypothesis that long-term ovariectomy will lead to a loss of serotonin neurons and compromised gene expression in serotonin neurons. Female Japanese macaques were ovariectomized or tubal ligated (n=5/group) at 3 years of age and returned to their natal troop. After 3 years, the animals were collected, administered a fenfluramine challenge to determine global serotonin availability, and then euthanized. Fev, TPH2, SERT, and 5HT1A expression were examined with digoxigenin in situ hybridization (ISH) and quantitative image analysis. Cell number, positive pixel area, and average pixel density were determined. In the Ovx group, Fev, TPH2, SERT, and 5HT1A showed a significant decease in average and total cell number and positive pixel area. The reduction in Fev-positive neurons suggests that there were fewer serotonin neurons in Ovx animals compared to ovary-intact animals. The decrease in TPH2 in the Ovx animals was consistent with earlier results in 5-month Ovx animals, but it may be due to the decrease in cell number rather than a decrease in expression on an individual cell basis. The decrease in SERT and 5HT1A in long-term Ovx differed from previous studies in short-term Ovx. In summary, long-term ovarian steroid loss resulted in fewer serotonin neurons and overall lower Fev, TPH2, SERT, and 5HT1A gene expression. This may be due to serotonin cell death or to a negative impact on a long-term developmental process in young female macaques.
KW - 5HT1A autoreceptor
KW - Estrogen
KW - Fenfluramine
KW - Fev
KW - Progesterone
KW - Serotonin reuptake transporter
KW - TPH2
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UR - http://www.scopus.com/inward/citedby.url?scp=80052265975&partnerID=8YFLogxK
U2 - 10.1016/j.neuroscience.2011.06.003
DO - 10.1016/j.neuroscience.2011.06.003
M3 - Article
C2 - 21763405
AN - SCOPUS:80052265975
SN - 0306-4522
VL - 192
SP - 675
EP - 688
JO - Neuroscience
JF - Neuroscience
ER -