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A study with adult male mice demonstrated that castration increased cell proliferation within the SVZ , suggesting that testosterone suppresses cell proliferation in this region. Estradiol treatment had no effect on cell proliferation in the SVZ of female mice , suggesting that it is not the cause of the sex difference in cell proliferation. Compared to the dentate gyrus, relatively little work has been done testing the effects of testosterone upon neurogenesis in the mammalian olfactory bulbs (Table 1) .These neuroactive steroids (S) either derived from the systemic circulation or produced locally in the brain, bind and dissociate nuclear receptors (SR) from HSPs (heat shock proteins). Pharmacological tools, able to increase neuroactive steroid levels, are able to exert protective effects in sciatic nerve of diabetic animals. For instance, treatment of STZ-induced diabetic neuropathy in rats with the TSPO ligand, Ro5–4864, increased the levels of PREG, PROG and DHT, and counteracted the impairment of NCV and thermal threshold, restored skin innervation density and P0 gene expression, and improved Na+,K+-ATPase activity . Interestingly, DHEA exerts sex-depending neuroprotective actions, with more potent effects in female animals . These physiological effects are mediated by activation of classical or non-classical steroid receptors. Neuroactive steroids may exert their effects by classical steroid receptors as well as non-classical steroid receptors.
The experiments summarized here clearly demonstrate that testosterone influences adult neurogenesis, as specifically demonstrated within the HVC of birds and within the olfactory bulbs and dentate gyrus of rodents. In general, acute and chronic stress cause a decrease in adult neurogenesis , and this effect is likely mediated through elevated glucocorticoid levels caused by stress 218,219. Furthermore, a male advantage in a water maze task was eliminated when rats were given preliminary trials to reduce stress 216,217. For example, testosterone replacement in castrated rats reduced anxiety and enhanced cognitive performance on an inhibitory avoidance task . This occurs because testosterone inhibits arginine vasopressin synthesis in the hypothalamus, which reduces basal adrenocorticotropic hormone (ACTH) levels, which, in turn, maintains relatively low corticosterone levels .
These transgenic animals showed a significant increase in neurogenesis within the accessory olfactory bulbs in response to exposure to male urine , a response not observed in wild type males but typical of wild type female mice. As one relevant example, transgenic mice (Sema7A knockout) that have reduced GnRH release from the hypothalamus, and therefore reduced testosterone levels from birth, showed no preference for female odors over male odors in adulthood (i.e., they lacked typical male sex preferences) . Assuming no species difference, one would conclude that testosterone enhances cell proliferation in the SVZ of males via an estrogen-dependent pathway prior to adolescence, while in the SVZ of adult males testosterone suppresses cell proliferation.
Androgens are known to have protein anabolic effects on general skeletal muscle tissue, but these effects are small (Kochakian, 1975). The possibility that confounds arising from SCI could affect retrograde transport is also an important consideration, as such an artifact could potentially result in apparent alterations in dendritic morphology. Such sprouting could potentially maintain motor activation, leading to protection of the target musculature from disuse atrophy (see below) and could support exercise training effects on locomotor function after SCI (Raineteau and Schwab, 2001; Gazula et al., 2004). Because both reticulospinal and propriospinal projections are concentrated in this area, the extensive lesions present after SCI could have produced a major denervation of dendrites in this area, resulting in the pronounced dendritic atrophy we observed. Propriospinal projections into the lumbar levels also terminate ventromedially, extending into both laminae VII and VIII (Menétey et al., 1985). In contrast, reticular formation projections to lumbar levels of the spinal cord, especially from the reticularis pontis oralis, terminate ventromedially, principally in lamina VIII (Motorina, 1977; Jones and Yang, 1985). In rats, the majority of corticospinal tract axons terminate dorsomedially, principally in laminae III–VI (Brown, 1971; Brösamle and Schwab, 1997), whereas those of the rubrospinal tract terminate in laminae V and VI (Waldron and Gwyn, 1969; Brown, 1974).
Four weeks after saporin injection, animals were reanesthetized, and the left vastus lateralis muscle (ipsilateral to the saporin-injected vastus medialis muscle in saporin animals) was exposed and injected with horseradish peroxidase (HRP) conjugated to the cholera toxin B subunit (BHRP; 2μL, 0.2%; List Biological Laboratories, Campbell CA). The dosage of tamoxifen was determined in pilot studies to be sufficient to reduce uterine weight in gonadally intact females to levels comparable to those of ovariectomized females. Saporin is a ribosome-inactivating protein; it kills cells by irreversibly inactivating ribosomes and thereby halting protein synthesis (Stirpe et al., 1983, 1992). In rats, the quadriceps muscle of the thigh comprises the vastus lateralis, the vastus medialis, the vastus intermedialis, and the rectus femoris (Hebel and Stromberg, 1986). Motoneurons display remarkable plasticity in adulthood and are capable of remodeling their cellular morphology; this propensity for change may allow for the development of treatment regimens in neural disease and injuries (Edgerton et al., 2004).
However, the decline in GABAA receptor subunit expression may actually be a consequence of declining neurosteroid levels. The expression of some known neurosteroid-sensitive GABAA receptor subunits–α1, α2, α4, δ—have been shown to decrease in the prefrontal cortex of AD patients (Luchetti et al., 2011b), concurrent with declines in allopregnanolone levels (Bernardi et al., 2000; Marx et al., 2006; Smith et al., 2006; Naylor et al., 2010). However, both DHT and 3α-diol were significantly reduced 2 weeks following injury compared to intact controls, while 3α-diol levels were positively correlated with the degree of brain edema, suggesting that a compensatory response may have occurred to increase local neuroprotective activity (Lopez-Rodriguez et al., 2016). The authors reported that progesterone levels were unaffected at time points from 24 h up to 2 weeks following TBI, while testosterone, DHT and 3α-diol exhibited more complex temporal changes. Other studies have investigated changes in neurosteroid levels in rodent models of induced neurological deficits, as opposed to models of disease that occur spontaneously or due to genetic factors. It is important to note that age was not considered as a factor in this study, which could further compound the interactions between sex- and disease-related effects on neurosteroid levels. In the cerebellum, allopregnanolone decreased in EAE females but not males, while progesterone decreased in both male and female EAE rats, and DHP was unaffected (Giatti et al., 2010).
