Gene Expression Profiling Identifies Key Estradiol Targets in the Frontal Cortex of the Rat

Abstract

Estradiol modulates a wide range of neural functions in the frontal cerebral cortex where subsets of neurons express estrogen receptor-alpha and -beta. Through these receptors, estradiol contributes to the maintenance of normal operation of the frontal cortex. During the decline of gonadal hormones, the frequency of neurological and psychiatric disorders increases. To shed light on the etiology of disorders related to declining levels of estrogens, we studied the genomic responses to estradiol. Ovariectomized rats were treated with a sc injection of estradiol. Twenty-four hours later, samples from the frontal cortices were dissected, and their mRNA content was analyzed. One hundred thirty-six estradiol-regulated transcripts were identified on Rat 230 2.0 Expression Array. Of the 136 estrogen-regulated genes, 26 and 36 genes encoded proteins involved in the regulation of transcription and signal transduction, respectively. Thirteen genes were related to the calcium signaling pathway. They comprised five genes coding for neurotransmitter receptors. Transcription of three neuropeptides, including cocaine- and amphetamine-regulated transcript, were up-regulated. Fifty-two genes were selected for validation, and 12 transcriptional changes were confirmed. These results provided evidence that estradiol evokes broad transcriptional response in the cortex. Modulation of key components of the calcium signaling pathway, dopaminergic, serotonergic, and glutamatergic neurotransmission, may explain the influence of estrogens on cognitive function and behavior. Up-regulation of cocaine- and amphetamine-regulated transcript contributes to the neuroprotective effects of estradiol. Identification of estradiol-regulated genes in the frontal cortex helps to understand the pathomechanism of neurological and psychiatric disorders associated with altered levels of estrogens.

Estradiol and isotype-selective estrogen receptor agonists modulate the mesocortical dopaminergic system in gonadectomized female rats

“…Our finding that D2 expression increases in the PFC of E2 replaced animals compared to vehicle treated OVX rats may explain the enhanced BOLD response in the PFC of E2-replaced animals. Increased dopamine receptor expression in E2-treated rats are in agreement with earlier observations on the estrogen-induced upregulation of D1 and D2 expression in the frontal cortex of various rat models [4,36]. It is important to note that D2 receptors are well-established molecular targets for the treatment of neuropsychiatric disorders [61], and drugs targeting D2 are the first choice of treatments for schizophrenia, bipolar disorder and major depressive disorder.…”

“…For fMRI experiments, young (2 month old) female rats (n=20) were deeply anesthetized intraperitoneally with a mixture of xylazine (12mg/kg) and ketamine (60mg/kg), and were ovariectomized (OVX) bilaterally as described earlier [36] to minimize the levels of endogenous estrogens. Rats were housed individually after surgery, and ten days later received treatments with vehicle or one of the three estrogen receptor (ER) agonists E2, LE2, DPN.…”

“…Obvious signs of decline in PFC-associated cognitive functions appear during perimenopause [18] . Many of the symptoms also reflect a disturbed dopaminergic signaling [4,36] which seems to correlate with the reduction in the levels of E2 [20]. The neuronal assembly of the VTA is also responsive to E2 [21] as resident dopaminergic neurons express ERα and ERβ [37][38][39].…”

Neuromodulation by soy diets or equol: Anti-depressive & anti-obesity-like influences, age- & hormone-dependent effects

“…ERβ is found in four brain regions associated with behavioral and mood disorders, the frontal cortex, amygdala, hippocampus, and the hypothalamic region [38-41]. Following dietary isoflavone exposure equol levels in the frontal cortex are highest followed by hypothalamus, amygdala, and the hippocampus [42], demonstrating an ability for equol to concentrate in these regions.…”

Altered Gene Expression Profiles of the Hypothalamic Arcuate Nucleus of Male Mice Suggest Profound Developmental Changes in Peptidergic Signaling

“…To collect ARC tissues for the qPCR studies, the mice were anesthetized between 09.00 and 11.00 h with a cocktail of ketamine (25 mg/kg), Xylavet (5 mg/kg) and Pipolphen (2.5 mg/kg) in saline and then perfused transcardially with ice-cold phosphate-buffered saline (pH 7.4) containing 10% RNA later Reagent (Qiagen, Hilden, Germany) [23]. The brains were removed, snap frozen in -40°C isopentane (precooled with a mixture of dry ice and ethanol) and stored permanently at -80°C.…”