Original articleInfluence of estradiol, stress, and 5-HT2A agonist treatment on Brain-Derived Neurotrophic Factor expression in female rats
Introduction
Estrogens have profound effects on the brain, including modulation of neuronal proliferation, survival, and plasticity (reviewed in Behl 2002, McEwen 2001, and can influence cognition and mood in several rodent behavioral models Gibbs and Aggarwal 1998, Luine et al 1998, Galea et al 2001a, Galea et al 2001b. Moreover, the twofold higher incidence of mood disorders in women has been attributed to changes in the ovarian hormones (Kessler et al 1994). The fluctuation in estrogen levels during the menstrual cycle as well as their steep decline at postpartum and perimenopause could trigger depressive, manic, or psychotic illness in vulnerable female populations (reviewed in Joffe and Cohen 1998, Young and Korszun 1998. In such patients, estrogen treatment is reported to decrease the psychotic symptoms and to improve mood and the performance in selected cognitive tasks Zweifel and O’Brien 1997, Ahokas et al 2000, Ahokas et al 2001. Estrogen replacement therapy may also improve cognitive function in postmenopausal women and Alzheimer’s disease patients, although the results are mixed (reviewed in Hogervorst et al 2000, LeBlanc et al 2001, Mulnard et al 2000.
The influence of estrogen on cognition and mood could occur via regulation of the neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), which affects neuronal survival, differentiation, and synaptic plasticity Lu and Chow 1999, Thoenen 2000. Brain-derived neurotrophic factor has been implicated in learning and memory (Yamada et al 2002), Alzheimer’s disease (Murer et al 2001), the pathophysiology and treatment of depression Nibuya et al 1995, Siuciak et al 1998, Duman 1998; Duman et al Duman et al 2000, Chen et al 2001, Shirayama et al 2002, and psychosis Angelucci et al 2000, Takahashi et al 2000. In male rats, immobilization stress or glucocorticoid administration results in a dramatic decrease in BDNF expression Smith et al 1995, Vaidya et al 1997, Vaidya et al 1999. This stress-induced decrease in BDNF levels may be detrimental, since BDNF is protective against glucocorticoid-induced cell death (Nitta et al 1999) and has antidepressant effects Siuciak et al 1998, Shirayama et al 2002. It is not known whether stress and BDNF have similar effects in female rats.
Several studies have examined the effect of estradiol on BDNF messenger RNA (mRNA) expression in female rats. Long-term (25 weeks) estradiol replacement in aged female ovariectomized (OVX) rats restored BDNF mRNA levels in some hippocampal subfields (Singh et al 1995). Another study reports that long-term (5 weeks), but not short-term (5 days), estradiol treatment also restored hippocampal BDNF mRNA levels following a prolonged estrogen deprivation (Berchtold et al 2001); however, other studies of short-term estradiol treatment have reported decreased BDNF protein Murphy et al 1998b, Gibbs 1999, no change (Gibbs 1998), or increased BDNF mRNA (Gibbs 1999). In the cortex, estradiol both increased (Sohrabji et al 1995) and decreased BDNF mRNA (Jezierski and Sohrabji 2000). The direction in which short-term estradiol treatment regulates BDNF appears to be important for neuronal connectivity. Relatively short-term (24 to 48 hours) estradiol administration increases the dendritic spine density in the hippocampus by suppressing the BDNF levels (Murphy et al 1998b). In vivo, both the hippocampal BDNF mRNA levels (Gibbs 1998) and the dendritic spine density (Woolley et al 1990a) fluctuate over the short estrous cycle of female rats.
Brain-derived neurotrophic factor Altar 1999, Duman 1998, Duman et al 2000 and estradiol (Joffe and Cohen 1998) may have antidepressant effects, in part, through regulation of the serotoninergic system. Brain-derived neurotrophic factor enhances serotonin synthesis (Siuciak et al 1998) and promotes the survival and sprouting of serotoninergic fibers Mamounas et al 1995, Mamounas et al 2000. Estradiol stimulates the synthesis of tryptophan hydroxylase Bethea et al 2000, Pecins-Thompson et al 1996 and the serotonin transporter (McQueen et al 1997), down-regulates 5-hydroxytryptamine type 1A (5-HT1A) receptors Biegon and McEwen 1982, Osterlund et al 2000 and up-regulates 5-hydroxytryptamine type 2A (5-HT2A) receptors in the cortex Cyr et al 1998, Cyr et al 2000a, Sumner and Fink 1995, Sumner and Fink 1998. The 5-HT2A receptors are targets of hallucinogens, as well as atypical antipsychotics and antidepressants Titeler et al 1988, Levy and Van de Kar 1992, Berendsen 1995, Gellman and Aghajanian 1994. The 5-HT2A receptor activation causes a dramatic increase in BDNF mRNA in the frontal and parietal cortex but a decrease in the hippocampal dentate gyrus (DG) in male rats Vaidya et al 1997, Vaidya et al 1999.
Together, these studies suggest that estradiol and BDNF may influence neuronal plasticity, cognition, and mood through interacting cellular mechanisms. Given the conflicting results with different estradiol treatment paradigms (discussed above), the present study examined the effect of acute and chronic estradiol treatment on BDNF mRNA expression in OVX female rats. In addition, the influence of estradiol treatment on BDNF response to 5-HT2A and stress were examined.
Section snippets
Animal treatment paradigms
Female Sprague Dawley rats (200 to 250 g, Charles-River Laboratories, Wilmington, Massachusetts) were group housed and maintained on a 12-hour light/dark cycle with access to food and water ad libitum. For the estrous cycle experiments, daily vaginal smears were obtained from intact animals for over 2 weeks and only those with regular 5-day cycle were used. Rats were classified as 1) proestrus if the vaginal smear on the morning of the experiment showed predominantly nucleated cells and 2)
BDNF mRNA levels in intact cycling female rats
During proestrus, when estrogen levels are highest, BDNF mRNA levels were significantly reduced in the hippocampal DG granular cell layer (70% ± 3%, p < .02) and in the medial prefrontal cortex (84% ± 2%, p < .01) (Figure 1). Brain-derived neurotrophic factor mRNA levels in CA1 pyramidal cell layer were also reduced but did not reach significance (87% ± 7%, p > .05).
Time-course of estradiol-mediated BDNF mRNA expression in acute OVX rats
Acute estradiol treatment of acute OVX rats led to a time-dependent decline in the hippocampal BDNF mRNA expression (Figure 2A).
Discussion
Acute and subacute elevations of estradiol in the young adult female rats were associated with an overall time-dependent down-regulation of BDNF mRNA in distinct hippocampal and neocortical areas. In the intact cycling female rats, BDNF mRNA levels were decreased by 30% in the DG and by 16% in the medial prefrontal cortex during proestrus, when the estradiol levels are highest, compared to estrus, when the estradiol levels are lowest. Gibbs (1998) also reported lowest BDNF mRNA levels during
Acknowledgements
This work was supported by NARSAD Young Investigator Award and BIRCWH 1K12DA14038-01 (IC) and by USPHS Grants MH45481 and 2 PO1 MH25642, a Veterans Administration National Center Grant for PTSD, and by the Connecticut Mental Health Center (RSD). The authors thank George Anderson, Ph.D. for measuring the plasma estradiol levels and Michael Cassaday for assistance with editing.
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