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Pharmacology and Neuroscience

The process of aging leads to reductions in steroid hormone production. This is perhaps best exemplified by the menopause that occurs in human females, yet the male sex hormone also changes with aging, as do adrenal hormones. A mitochondrial phosphoprotein, designated the steroidogenic acute regulatory protein (StAR), was identified and shown to play a key role in the acute induction of steroid synthesis. Compelling evidence for its essential role in steroidogenesis came from genetic analyses of StAR in patients with congenital lipoid adrenal hyperplasia (lipoid CAH), a potentially fatal autosomal recessive disorder characterized by severely impaired adrenal and gonadal steroidogenesis coupled with characteristic lipid deposits in steroidogenic tissues. Therefore, it is reasonable to surmise that changes in StAR activity may be responsible for age-related declines in steroidogenesis, which impact the health and quality of life of the elderly. The brain has the ability to produce steroids from cholesterol yielding newly synthesized neurosteroids. At the same time, brain tissue also converts steroids not produced in the brain, such as deoxycorticosterone, into so-called neuroactive steroids. Very little is known about the process of neurosteroid synthesis, as opposed to neuroactive steroid synthesis. We recently reported the presence of StAR in the brain, consistent with neurosteroidogenesis being a regulated event. The focus of this seed grant is to test the hypothesis that regulation of neurosteroid production changes during aging, that is, that the regulated activity of brain tissue to convert cholesterol to pregnenolone and other steroids changes with age. This is a subject that has not been previously studied, in contrast to other studies that examined aging and neuroactive steroid levels or activity. Therefore, the specific aims of this grant are: 1) to determine neurosteroidogenesis in the aging rat brain. This will be accomplished by measuring basal and stimulated pregnenolone synthesis in tissue from different brain areas (cortex, cerebellum, hypothalamus and hippocampus); 2) to determine how gender affects age-dependent changes in neurosteroid production. This will be accomplished by performing measurements on brain tissue from both male and female rats of different ages; 3) to quantify changes in brain levels of StAR-expressing and cytochrome P450 side-chain cleavage (P450scc) enzyme-expressing cells. This will be done with stereological cell counting techniques on brain sections stained with specific antibodies to StAR and P450scc. Because circulating precursors for neuroactive steroids decline during aging, brain cells with the ability to synthesize neurosteroids may become more and more important in maintaining cognition, and physical and mental health, as the human body ages. Therefore, it is important to understand how aging affects those brain cells that synthesize neurosteroids de novo.

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