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. 2010 Oct;27(10):1875-82.
doi: 10.1089/neu.2010.1330. Epub 2010 Oct 6.

Injury-induced Regulation of Steroidogenic Gene Expression in the Cerebellum

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Free PMC article

Injury-induced Regulation of Steroidogenic Gene Expression in the Cerebellum

Anahid Mirzatoni et al. J Neurotrauma. .
Free PMC article

Abstract

Sex steroids assist adult neural tissue in the protection from and repair of damage resulting from neural injury; some steroids may be synthesized in the brain. Songbirds are especially useful models to explore steroidal neuroprotection and repair. First, the full suite of cholesterol transporters and steroidogenic enzymes are expressed in the zebra finch (ZF) brain. Second, estrogens promote recovery of behavioral function after damage to the adult ZF cerebellum. Third, the estrogen synthetic enzyme aromatase is rapidly upregulated in reactive glia following neural injury, including in the ZF cerebellum. We hypothesized that cerebellar injury would locally upregulate steroidogenic factors upstream of aromatase, providing the requisite substrate for neuroestrogen synthesis. We tested this hypothesis by lesioning the cerebellum of adult songbirds using both males and females that peripherally synthesize steroids in different amounts. We then used quantitative PCR to examine expression of mRNAs for the neurosteroidogenic factors TSPO, StAR, SCC, 3β-HSD, CYP17, and aromatase, at 2 and 8 days post-lesion. Compared to sham lesions, cerebellar lesions significantly upregulated mRNA levels of TSPO and aromatase. Sex differences in response to the lesions were detected for TSPO, StAR, and aromatase. All birds responded to experimental conditions by showing time-dependent changes in the expression of TSPO, SCC, and aromatase, suggesting that acute trauma or stress may impact neurosteroidogensis for many days. These data suggest that the cerebellum is an active site of steroid synthesis in the brain, and each steroidogenic factor likely provides neuroprotection and promotes repair.

Figures

FIG. 1.
FIG. 1.
The major steroid synthesizing enzymes (in parentheses) that catalyze the conversion of cholesterol to the sex steroids (StAR, steroidogenic acute regulatory protein; TSPO/PBR, translocator protein/peripheral benzodiazepine receptor; CYP11A1, cytochrome P450 side-chain cleavage; 3β-HSD, 3β-hydroxysteroid dehydrogenase/isomerase; CYP17, cytochrome P450 17α-hydroxylase/C17,20 lyase; 17β-HSD, 17β-hydroxysteroid dehydrogenase; CYP19, cytochrome P450 aromatase).
FIG. 2.
FIG. 2.
Levels of translocator protein (TSPO) mRNA relative to glyceraldehyde-3-phosphate dehydrogenase (GAPDH; delta CT values) in adult male and female zebra finches at 2 and 8 days post-surgery. The lesions significantly influenced levels of TSPO mRNA (p ≤ 0.05). TSPO expression was significantly higher in females than in males, and TSPO expression was higher at 2 days than at 8 days post-surgery (*p = 0.001, **p = 0.0001).
FIG. 3.
FIG. 3.
Levels of steroidogenic acute regulatory protein (StAR) mRNA relative to glyceraldehyde-3-phosphate dehydrogenase (GAPDH; delta CT value), in both male and female zebra finches at 2 and 8 days post-surgery. StAR expression was significantly higher in females than males (p = 0.0087), and STAR mRNA levels were significantly higher in females than in males at 2 days and 8 days post-surgery (*p = 0.01, **p = 0.0004).
FIG. 4.
FIG. 4.
Levels of side chain cleavage enzyme (SCC) mRNA relative to glyceraldehyde-3-phosphate dehydrogenase (GAPDH; delta CT value), in both male and female zebra finches at 2 and 8 days post-surgery. Levels of SCC mRNA were significantly greater at 2 days than at 8 days post surgery (*p = 0.03).
FIG. 5.
FIG. 5.
Levels of 3β-hydroxysteroid dehydrogenase/isomerase (3β-HSD) mRNA relative to glyceraldehyde-3-phosphate dehydrogenase (GAPDH; delta CT value) in both male and female zebra finches at 2 and 8 days post-surgery.
FIG. 6.
FIG. 6.
Levels of cytochrome P450 17α-hydroxylase/C17,20 lyase (CYP17) mRNA relative to glyceraldehyde-3-phosphate dehydrogenase (GAPDH; delta CT value) in both male and female zebra finches at 2 and 8 days post-surgery. Levels of CYP17 mRNA were significantly greater at 8 days than at 2 days post-surgery (*p = 0.0004).
FIG. 7.
FIG. 7.
Levels of aromatase mRNA relative to glyceraldehyde-3-phosphate dehydrogenase (GAPDH; delta CT value) in both male and female zebra finches at 2 and 8 days post-surgery. Lesions significantly upregulated aromatase mRNA in both males (at 2 days), and females (at 2 and 8 days; **p < 0.001). There were significantly higher levels of aromatase mRNA at 2 days than at 8 days post-surgery (*p = 0.002). Finally, there was an overall effect of sex, with mRNA upregulated more in females than in males (p < 0.0001).

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