Gonadal hormones, such as testosterone and estradiol, modulate muscle size and strength in males and females. However, the influence of sex hormones on muscle strength in micro- and partial-gravity environments (e.g., the Moon or Mars) is not fully understood. Purpose: To determine the influence of gonadectomy (castration/ovariectomy) on progression of muscle atrophy in both micro- and partial- gravity environments in male and female rats. Methods: Male and female Fischer rats (n=120) underwent castration/ovariectomy (CAST/OVX) or sham surgery (SHAM) at 11 weeks of age. After 2 weeks of recovery, rats were exposed to hindlimb unloading (0g), partial weight bearing at 40% of normal loading (0.4g, Martian gravity) or normal loading (1.0g) for 28 days. Results: In males, CAST did not exacerbate bodyweight loss or other metrics of musculoskeletal health. In females, OVX animals tended to have greater bodyweight loss and greater gastrocnemius loss. Within seven days of exposure to either micro- or partial-gravity, females had detectable changes to estrous cycle, with greater time spent in low-estradiol phases, diestrus and metestrus (~47% in 1g vs 58% in 0g and 72% in 0.4g animals, p=0.005). Conclusion: In males, testosterone deficiency at the initiation of unloading has little effect on the trajectory of muscle loss. In females, initial low estradiol status may result in greater musculoskeletal losses.

No abstract

Epidemiologic studies have demonstrated that infections during pregnancy increase the risk of offspring developing Schizophrenia, Autism, Depression and Bipolar Disorder and have implicated interleukin-6 (IL-6) as a causal agent. However, other cytokines have been associated with psychiatric disorders; therefore, it remains to be established whether elevating IL-6 is sufficient to alter the trajectory of neural development. Furthermore, most rodent studies have manipulated the maternal immune system at mid-gestation, which affects the stem cells and progenitors in both the primary and secondary germinal matrices. Therefore, a question that remains to be addressed is whether elevating IL-6 when the secondary germinal matrices are most active will affect brain development. Here, we have increased IL-6 from postnatal days 3-6, when the secondary germinal matrices are rapidly expanding. Using Nestin-CreERT2 fate mapping we show that this transient increase in IL-6 decreased neurogenesis in the dentate gyrus of the dorsal hippocampus, reduced astrogliogenesis in the prefrontal cortex and amygdala and decreased oligodendrogenesis in the body and splenium of the corpus callosum all by ∼50%. Moreover, the IL-6 treatment elicited behavioral changes classically associated with neurodevelopmental disorders. As adults, IL-6 injected male mice lost social preference in the social approach test, spent ∼30% less time socially engaging with sexually receptive females and produced ∼50% fewer ultrasonic vocalizations during mating. They also engaged ∼50% more time in self-grooming behavior and had an increase in inhibitory avoidance. Altogether, these data provide new insights into the biological mechanisms linking perinatal immune activation to complex neurodevelopmental brain disorders.Significance statementIn these studies, we doubled circulating IL-6 levels in mice from postnatal days 3-6 to test the hypothesis that this would be sufficient to disturb neural development. More specifically, we hypothesized that IL-6 would affect postnatal neural stem cell and progenitor expansion and specification. We show that this transient increase in IL-6 decreases the numbers of granule neurons in the dorsal hippocampus, astrocytes in the prefrontal cortex and amygdala and oligodendrocytes in the corpus callosum. Importantly, this transient increase in IL-6 changes the sociability, communication and repetitive behaviors of the treated mice as adults, which are core symptoms pertinent to several neurodevelopmental psychiatric disorders.