Determinants of central nervous system adult neurogenesis are sex, hormones, mouse strain, age, and brain region

Abstract

Multiple sclerosis is a sexually dimorphic (SD) disease that causes oligodendrocyte death, but SD of glial cells is poorly studied. Here, we analyze SD of neural progenitors in 6-8 weeks and 6-8 months normal C57BL/6, SJL/J, and BALB/c mice in the subventricular zone (SVZ), dorsolateral horn (DLC), corpus callosum (CC), and parenchyma. With a short 2-h bromodeoxyuridine (BrdU) pulse, no gender and strain differences are present at 6-8 weeks. At 6-8 months, the number of BrdU(+) cells decreases twofold in each sex, strain, and region, indicating that a common aging mechanism regulates BrdU incorporation. Strikingly, 2× more BrdU(+) cells are found in all brain regions in 6-8 months C57BL/6 females versus males, no gender differences in 6-8 months SJL/J, and fewer BrdU(+) cells in females versus males in BALB/cs. The number of BrdU(+) cells modestly fluctuates throughout the estrous cycle in C57BL/6 and SJLs. Castration causes a dramatic increase in BrdU(+) cells in SVZ and DLC. These findings indicate that testosterone is a major regulator of adult neural proliferation. At 6-8 months, the ratio of PDGFRα(+) cells in the CC to BrdU(+) cells in the DLC of both strains, sexes, estrous cycle, and castrated mice was essentially the same, suggesting that BrdU(+) cells in the DLC differentiate into CC oligodendrocytes. The ratio of TUNEL(+) to BrdU(+) cells does not match proliferation, indicating that these events are differentially regulated. Differential regulation of these two processes leads to the variation in glial numbers between gender and strain. Explanations of neural proliferation based upon data from one sex or strain may be very misleading.

Testosterone and estradiol differentially affect cell proliferation in the subventricular zone of young adult gonadectomized male and female rats

“…It has been reported that gonadectomy affects adult neurogenesis also in mice, but with an opposite effect, that is, increasing cell proliferation in SVZ, however these effects are strainand sex-dependent (Tatar et al, 2013). Finally, in the Sprague Dawley rat, androgens enhance adult neurogenesis in DG, promoting cell survival rather than proliferation Galea, 2007, Hamson et al, 2013).…”

“…Gonadal hormones have been indicated as important intrinsic regulative factors of adult neurogenesis (Galea, 2008. The vast majority of the studies which have investigated the role of these hormones on adult neurogenesis has been performed in the DG of hippocampus (Galea, 2008, whereas only a few of them have addressed this issue in the SVZ neurogenic niche (Smith et al, 2001, Hoyk et al, 2006, Brock et al, 2010, Veyrac and Bakker, 2011, Tatar et al, 2013.…”

“…Only indirect evidences indicate that other gonadal hormones, such as progesterone and T can regulate neurogenesis in the adult SVZ niche (Peretto et al, 2001, Giachino et al, 2004, Zhang et al, 2010, Tatar et al, 2013. Similarly to the DG, the modulatory effect of gonadal hormones, particularly of E 2 , on SVZ neurogenesis appears highly variable depending on type of treatment/dose (chronic vs. acute), sex, species, and (in mouse) strain considered (Smith et al, 2001, Hoyk et al, 2006, Brock et al, 2010, Veyrac and Bakker, 2011, Tatar et al, 2013. In addition, such modulation differentially impacts the neurogenic process influencing progenitor cells proliferation and/or integration of newborn neurons in both the main and the accessory OB (Hoyk et al, 2006, Brock et al, 2010, Veyrac and Bakker, 2011.…”

Behavioral experiences as drivers of oligodendrocyte lineage dynamics and myelin plasticity

“…A further point of difference is that OPC generation has been found to differ depending on gender in C57BL/6 mice (Tatar et al, 2013), and Ehninger and colleagues assessed female mice while Okuda and associates assessed male mice.…”

Activity Dependency and Aging in the Regulation of Adult Neurogenesis

“…Sex hormones, both female and male, can influence adult neurogenesis (Galea et al 2006;Tatar et al 2013). In the hippocampus of female rodents, cell proliferation peaks during the estrogen-high-proestrous phase .…”