Research reportLevels of trkA and BDNF mRNA, but not NGF mRNA, fluctuate across the estrous cycle and increase in response to acute hormone replacement
Introduction
Alzheimer's disease is an age-related neurodegenerative disease characterized by a progressive loss of cognitive functions with corresponding memory loss and dementia. Studies have shown that after the age of 65, the prevalence of dementia and Alzheimer's disease doubles every five years [19]and that women are at greater risk than men (see Ref. [14]for review). However, recent clinical studies suggest that estrogen replacement may help to reduce the risk and severity of Alzheimer's-related dementia in postmenopausal women 15, 16, 34, 33, 36, 43.
Recently, we and others have shown that, in rats, cholinergic neurons located within specific regions of the basal forebrain are significantly affected by changes in circulating estrogens. These neurons are the major source of cholinergic innervation to the hippocampal formation and cortex and have been shown by numerous studies to play an important role in learning and memory processes 5, 27, 35. Loss of these neurons is also thought to contribute significantly to cognitive decline associated with aging and Alzheimer's disease 5, 44. We have recently shown that, in rats, long-term loss of ovarian function results in decreases in specific measures of basal forebrain cholinergic function over and above those associated with normal aging [6], suggesting that the long-term loss of circulating estrogens in postmenopausal women may contribute to an age-related decline in basal forebrain cholinergic function. This is consistent with other recent studies showing that estrogen replacement in young adult rats produces increases in basal forebrain cholinergic function 7, 10, 13, 24, 40, and suggests that one mechanism by which estrogen replacement may help to reduce the risk and severity of Alzheimer's-related dementia in women is by enhancing the functional status of cholinergic projections emanating from the MS and NBM.
Cholinergic neurons in the MS and NBM are significantly affected by nerve growth factor (NGF), a polypeptide growth factor produced in the hippocampus and cortex [23]. Effects of NGF are mediated by binding with trkA, a membrane-bound, tyrosine kinase receptor [1], and studies suggest that over 90% of the trkA-expressing cells detected in the MS and NBM are cholinergic neurons projecting to the hippocampus and cortex 4, 12. Brain-derived neurotrophic factor (BDNF) is an NGF-related polypeptide which, like NGF, is expressed in the hippocampal formation and cortex and is thought to play an important role in learning and memory processes [23]. Like NGF, BDNF can enhance the functional status of cholinergic neurons in the basal forebrain 31, 32. BDNF has also been shown to play an important role in the formation of long-term potentiation in the hippocampus 21, 37, the promotion of activity-dependent dendritic growth [26], and protection from apoptotic cell death [3], all of which are relevant to age-related changes in learning and memory processes.
Decreases in both trkA and BDNF mRNA 30, 39, as well as TrkA protein [29]have been detected in association with Alzheimer's disease, suggesting that decreases in the expression of, and/or responsiveness to, specific neurotrophins may contribute to the functional decline associated with the disease. Significant decreases in trkA expression in the MS have also been observed as a function of aging and ovariectomy in female rats 2, 6, suggesting that the combination of aging and long-term hormone deprivation may contribute to decreases in basal forebrain cholinergic survival and function by decreasing the responsiveness of the cholinergic neurons to endogenous NGF.
The purpose of the present study was to determine whether the expression of trkA mRNA in the basal forebrain, as well as NGF mRNA and BDNF mRNA in the hippocampus, are significantly affected by physiological changes in circulating gonadal steroids as assessed by fluctuations across the estrous cycle, as well as by the response to acute replacement with physiological levels of estrogen or estrogen plus progesterone.
Section snippets
Materials and methods
Gonadally intact and ovariectomized female Sprague–Dawley rats (180–200 g) were purchased from Charles River Laboratories, and maintained on a 12 h light/12 h dark cycle with lights on at 6.00 h and with food and water available ad libitum. All animals were housed for a minimum of 2 weeks prior to use. Daily vaginal smears were obtained from gonadally intact animals for a period of 2 weeks and these animals were then killed on the morning of diestrus 2 (n=7), the morning of proestrus (n=6), the
Hormone levels
The levels of circulating estradiol detected by radioimmunoassay have been presented previously [9]. In gonadally intact animals, mean serum levels of estradiol were 28.6±5.6 pg/ml on the morning of proestrus, 47.9±8.5 pg/ml on the afternoon of proestrus, and were less than 5 pg/ml at all other time-points. Mean serum levels of progesterone were 10.2±3.4 ng/ml on the morning of diestrus 2, 7.0±1.0 ng/ml on the morning of proestrus, 18.3±5.0 ng/ml on the afternoon of proestrus, 7.4±1.5 ng/ml on
Discussion
The data demonstrate that the levels of both trkA and BDNF mRNA within specific regions of the brain are significantly affected by physiological changes in the levels of circulating gonadal hormones. Specifically, the data show that acute estradiol administration produces a significant increase in trkA mRNA in the MS, but not the NBM, and that the increase in trkA mRNA peaks at 24 h post-injection and then rapidly declines to control levels. Administration of progesterone 48 h after receiving
Acknowledgements
I wish to acknowledge Douglas Nelson and Denise Gillen-Caralli for their excellent technical assistance, Dr. Paul Isackson for providing the cDNA for making the NGF and BDNF riboprobes, and the Assay Core of the Center for Reproductive Physiology for performing the hormone assays. This work was supported by NSF Grant No. IBN-9630851.
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2022, Hormones and BehaviorCitation Excerpt :In fact, ovariectomy, which also disrupts the hypothalamic-pituitary-ovarian axis, decreased hippocampal BDNF mRNA expression in female rats, an effect prevented by hormone replacement (Berchtold et al., 2001; Gibbs, 1999; Singh et al., 1995). However, ovariectomy did not affect BDNF protein (Gibbs, 1999), leading to the hypothesis that different mechanisms might regulate BDNF mRNA and protein, including an uncoupling of transcriptional and translational mechanisms, or an increase in protein degradation from the hippocampus (Gibbs, 1998). Transcriptional (Nibuya et al., 1996) and epigenetic mechanisms (Tsankova et al., 2006) contribute most to regulate BDNF expression.