Testosterone and Corticosterone in the Mesocorticolimbic System of Male Rats: Effects of Gonadectomy and Caloric Restriction.

Steroid hormones can modulate motivated behaviors through the mesocorticolimbic system. Gonadectomy (GDX) is a common method to determine how steroids influence the mesocorticolimbic system, and caloric restriction (CR) is often used to invigorate motivated behaviors. A common assumption is that the effects of these manipulations on brain steroid levels reflects circulating steroid levels. We now know that the brain regulates local steroid levels in a region-specific manner; however, previous studies have low spatial resolution. Using ultrasensitive liquid chromatography tandem mass spectrometry, we examined steroids in microdissected regions of the mesocorticolimbic system (ventral tegmental area, nucleus accumbens, medial prefrontal cortex). We examined whether GDX or CR influences systemic and local steroids, particularly testosterone (T) and steroidogenic enzyme transcripts. Adult male rats underwent a GDX surgery and/or CR for either 2 or 6 weeks. Levels of T, the primary steroid of interest, were higher in all brain regions than in the blood, whereas corticosterone (CORT) was lower in the brain than in the blood. Importantly, GDX completely eliminated T in the blood and lowered T in the brain. Yet, T remained present in the brain, even 6 weeks after GDX. CR decreased both T and CORT in the blood and brain. Steroidogenic enzyme (Cyp17a1, 3ß-hydroxysteroid dehydrogenase, aromatase) transcripts and androgen receptor transcripts were expressed in the mesocorticolimbic system and differentially affected by GDX and CR. Together, these results suggest that T is synthesized within the mesocorticolimbic system. These results provide a foundation for future studies examining how neurosteroids influence behaviors mediated by the mesocorticolimbic system.

Lymphoid organs of neonatal and adult mice preferentially produce active glucocorticoids from metabolites, not precursors.

Glucocorticoids (GCs) are circulating adrenal steroid hormones that coordinate physiology, especially the counter-regulatory response to stressors. While systemic GCs are often considered immunosuppressive, GCs in the thymus play a critical role in antigen-specific immunity by ensuring the selection of competent T cells. Elevated thymus-specific GC levels are thought to occur by local synthesis, but the mechanism of such tissue-specific GC production remains unknown. Here, we found metyrapone-blockable GC production in neonatal and adult bone marrow, spleen, and thymus of C57BL/6 mice. This production was primarily via regeneration of adrenal metabolites, rather than de novo synthesis from cholesterol, as we found high levels of gene expression and activity of the GC-regenerating enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), but not the GC-synthetic enzyme CYP11B1. Furthermore, incubation with physiological concentrations of GC metabolites (11-dehydrocorticosterone, prednisone) induced 11ß-HSD1- and GC receptor-dependent apoptosis (caspase activation) in both T and B cells, showing the functional relevance of local GC regeneration in lymphocyte GC signaling. Local GC production in bone marrow and spleen raises the possibility that GCs play a key role in B cell selection similar to their role in T cell selection. Our results also indicate that local GC production may amplify changes in adrenal GC signaling, rather than buffering against such changes, in the immune system.