Abstract
The hindlimb unloading (HU) model has been used extensively to simulate the cephalad fluid shift and musculoskeletal disuse observed in spaceflight with its application expanding to study immune, cardiovascular and central nervous system responses, among others. Most HU studies are performed with singly housed animals, although social isolation also can substantially impact behavior and physiology, and therefore may confound HU experimental results. Other HU variants that allow for paired housing have been developed although no systematic assessment has been made to understand the effects of social isolation on HU outcomes. Hence, we aimed to determine the contribution of social isolation to tissue responses to HU. To accomplish this, we developed a refinement to the traditional NASA Ames single housing HU system to accommodate social housing in pairs, retaining desirable features of the original design. We conducted a 30-day HU experiment with adult, female mice that were either singly or socially housed. HU animals in both single and social housing displayed expected musculoskeletal deficits versus housing matched, normally loaded (NL) controls. However, select immune and hypothalamic-pituitary-adrenal (HPA) axis responses were differentially impacted by the HU social environment relative to matched NL controls. HU led to a reduction in % CD4+ T cells in singly housed, but not in socially housed mice. Unexpectedly, HU increased adrenal gland mass in socially housed but not singly housed mice, while social isolation increased adrenal gland mass in NL controls. HU also led to elevated plasma corticosterone levels at day 30 in both singly and socially housed mice. Thus, musculoskeletal responses to simulated weightlessness are similar regardless of social environment with a few differences in adrenal and immune responses. Our findings show that combined stressors can mask, not only exacerbate, select responses to HU. These findings further expand the utility of the HU model for studying possible combined effects of spaceflight stressors.
Highlights
The spaceflight environment poses significant challenges to multiple organ systems
To test the hypothesis that social isolation impacts tissue responses to hindlimb unloading (HU), we developed a refinement of the traditional NASA Ames HU cage design that allows paired housing of animals (Figure 2)
Animals selected for this study were female C57BL/6NJ mice shown previously to be sensitive to bone loss caused by HU (Sankaran et al, 2017)
Summary
The spaceflight environment poses significant challenges to multiple organ systems. Microgravity exposure leads to a cephalad fluid shift (Foux et al, 1976; Thornton et al, 1987) as well as osteopenia (Lang et al, 2004) and sarcopenia (LeBlanc et al, 2000). Immune system dysregulation occurs, characterized by altered immune cell function and reactivation of viruses (Crucian et al, 2015, 2018; Mehta et al, 2017). These findings from astronauts are the main motivation to study rodents flown into space with the rationale that rodents are used extensively to model human conditions on Earth and may prove useful for understanding mechanisms and anticipating human responses to spaceflight. Limited opportunities for rodent spaceflight studies, along with other challenges of conducting microgravity experiments, stimulated interest in using ground-based rodent models of weightlessness
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