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In the clinical setting, repeated exposures (10–30) to low-doses of ionizing radiation (≤ 200 cGy), as seen in radiotherapy for cancer, causes fatigue. Almost nothing is known, however, about the fatigue inducing effects of a single exposure to environmental low-dose ionizing radiation that might occur during high-altitude commercial air flight, a nuclear reactor accident or a solar particle event (SPE). To investigate the short-term impact of low-dose ionizing radiation on mouse biobehaviors and neuroimmunity, male CD-1 mice were whole body irradiated with 50 cGy or 200 cGy of gamma or proton radiation. Gamma radiation was found to reduce spontaneous locomotor activity by 35% and 36%, respectively, 6 h post irradiation. In contrast, the motivated behavior of social exploration was un-impacted by gamma radiation. Examination of pro-inflammatory cytokine gene transcripts in the brain demonstrated that gamma radiation increased hippocampal TNF-α expression as early as 4 h post-irradiation. This was coupled to subsequent increases in IL-1RA (8 h and 12 h post irradiation) in the cortex and hippocampus and reductions in activity-regulated cytoskeleton-associated protein (Arc) (24 h post irradiation) in the cortex. Finally, restraint stress was a significant modulator of the neuroimmune response to radiation blocking the ability of 200 cGy gamma radiation from impairing locomotor activity and altering the brain-based inflammatory response to irradiation. Taken together, these findings indicate that low-dose ionizing radiation rapidly activates the neuroimmune system potentially causing early onset fatigue-like symptoms in mice.

Prostate cancer (PCa) is prevalent in older men, and the second leading cause of mortality. Aging and psychosocial stress affect tumor progression in other reproductive cancers, but interactions between age, stress and tumor progression in PCa remain unexplored. Since inflammation is a key player in tumor progression, we evaluated the effects of age and psychosocial stress on pro- and anti-inflammatory mediators in an orthotopic PCa model. Young (2 M) or old (18 M) male C57BL/6 mice with orthotopic RM-9 tumors were subjected to 14 days of combined social isolation and 2-h restraint (stressed) or remained group-housed in home cages (nonstressed). Twenty-five cytokines were quantified in tumor homogenates using multiplexed ELISAs. Age effects were evident for six proinflammatory cytokines ( p p

In previous experiments, we have shown that spaceflight can alter leukocyte and lymphocyte population distributions and mitogen-induced cytokine expression. We hypothesize that these changes are a result of flight-induced physiological and psychological stress. On July 8, 2011, age- and weight-matched, female C57BL/6J mice were placed into Animal Enclosure Modules (AEMs) and flown on the Space Shuttle Atlantis (STS-135) for 13 days ( N = 6–7). Ground controls were housed at the Space Life Science Laboratory (SLSL) at Kennedy Space Center (KSC). Ground AEM control mice were placed into the same hardware used in flight and environmental parameters such as temperature and CO2 levels were matched as closely as possible based on 48 h delayed telemetry data ( N = 12–13). Vivarium control mice were housed in regular shoebox cages ( N = 4). Mice were euthanized and dissected within 3–5 h of landing. Adrenals were removed, snap frozen in liquid N2, and shipped on ice back to Loma Linda University via overnight courier for analysis. Although corticosterone levels were slightly elevated in spaceflight mice, with a corresponding decrease in phosphorylated adrenocorticotropic hormone (ACTH) levels, these changes were not enough to reach significance. Similarly, there were no significant changes in catecholamine levels. This suggests that there is no significant impact of spaceflight on stress pathways. However, closer examination of the data indicates that the circadian rhythm may have masked the overall effect of spaceflight.

Previous studies in mice have shown that total body irradiation (TBI) leads to splenic atrophy, acute reductions in splenic leukocyte populations, and changes in phagocytic function. We also reported that many TBI-induced changes in splenic phagocytic populations were mitigated by chlorisondamine, a non-selective nicotinic blocker, suggesting sympathetic control. To characterize the long-term effects associated with TBI on the noradrenergic sympathetic innervation of the spleen, female, 9–10 week-old C57BL/6J mice were irradiated with Co-60 gamma-rays (0–2 Gy) and euthanized 6 months later. Sucrose–potassium phosphate–glyoxylic acid (SPG) histofluorescence staining and HPLC were used to examine splenic noradrenergic innervation and neurochemical concentration of catecholamines, respectively. All samples of the spleen were taken distal to the hilus. Fluorescence histochemistry for catecholamines revealed no change in the distribution of fluorescent nerves in the splenic white pulp in irradiated mice compared with controls. However, the density of sympathetic nerves coursing along the central arterioles and extending into the periarteriolar lymphatic sheath was greater in mice irradiated at 2 Gy compared with non-irradiated controls. The white pulps also appeared to be reduced in spleens from this group. While norepinephrine concentrations did not differ from control values, dopamine concentrations were reduced. Collectively, these findings suggest maintained nerve distribution in a reduced volume of white pulp in irradiated mice, and increased norepinephrine release and availability for target cells of the immune system.

Hematopoietic stem cell transplant (HSCT) is an established treatment for many hematological disorders including lymphomas and leukemias. Although the prognosis after HSCT has historically been poor, associated with high mortality rates, advances in treatment have led to increases in long-term survival and, consequently, an increased risk for neuropsychological dysfunction. Roughly 40% of all allogeneic HSCTs performed in 2006–2010 involved total body irradiation (TBI) conditioning. Previously, we reported that many TBI-induced changes in splenic phagocytic populations were mitigated by chlorisondamine (CHL), a non-selective nicotinic blocker that crosses the blood–brain barrier. In this study, we characterized the effects of body-only proton irradiation (excluding brain) and CHL on the response to a bacterial challenge in 8- to 10-week-old female C57BL/6 mice. Mice were given CHL (1 mg/kg, i.p.) and irradiated (0 or 3 Gy) 60–90 min later. Ten days post-irradiation, mice were inoculated with 5e7 CFU of Escherichia coli (i.p.) and euthanized 90–120 min later. We characterized blood and splenic leukocyte population distributions (flow cytometry and hematology), cytokine levels (multiplexed cytokine analysis) and oxidative burst capacity. Radiation decreased virtually all splenic leukocyte counts while increasing oxidative burst capacity. In the blood, radiation decreased lymphocytes but increased innate subsets. Sympathetic blockade did not counter most of these radiation effects. This suggests that the disruptive effect of TBI on brain–immune communication is dependent on direct exposure to the brain.

Interactions between age, psychosocial stress and prostate cancer (PCa) progression are critically understudied. Therefore, we characterized the effects of aging and psychosocial stress on anxiety/depression-like behavior, tumor growth and host defense using the immunocompetent, orthotopic, RM-9 murine PCa reconstitution model (MPR 3 ). Two- and 18-month-old tumor-bearing C57BL/6 mice were exposed to isolation and restraint stress (2 h/day) for 14 days post-tumor inoculation and compared with group-housed, non-stressed, tumor-bearing controls. Zero maze testing revealed age-related differences before tumor induction, and increased anxiety-like behavior. Open field testing showed that old non-stressed tumor-bearing mice were less active throughout the 30-min test period than young non-stressed and stressed, and old stressed tumor-bearing mice. Old mice demonstrated more depressed-like behavior than young mice with tail suspension testing, without effects of isolation/restraint stress. Old mice developed larger tumors, despite no age-related differences in tumor TGF-beta1 or VEGF levels. Tumor in young mice had more macrophages, the predominant immunocyte in tumors, and more CD4+ and CD4+FoxP3+ T-cells than old mice. Stress increased macrophage infiltration in old mice, but reduced CD4+ and CD4+FoxP3+ T-cell infiltration in young mice. CD8+ T cell infiltration was similar across treatment groups. Survival rate for old, stressed mice was 20% lower than all other groups. These findings suggest age- and stress-related differences in behavioral and immune responses in prostate tumor-bearing mice that can affect disease outcome.

Roughly 50% of adult and 100% of pediatric cancer survivors who receive whole-brain irradiation for metastatic disease will develop cognitive dysfunction. Patients who are subjected to cranial radiotherapy for management of primary and metastatic tumors (∼200,000/year) are at the highest risk for neuropsychological deficits. Radiation induces a neuroinflammatory milieu of reactive oxygen species and pro-inflammatory cytokines such as tumor necrosis factor (TNF)-a and interleukin (IL)-1b, which are responsible for the pathogenesis of radiation-induced brain injury. Minocycline (MC), a second-generation tetracycline derivative, has anti-inflammatory, free radical scavenging and antiapoptotic properties. To characterize the neuroprotective effect of MC on radiation-induced inflammation in the brain, female C57BL/6 mice were treated with MC (i.p.) for 5 days beginning immediately before whole-body irradiation with 3 Gy Co-60 γ-rays. Brains were collected 32 days post-irradiation and analyzed for gene expression and cytokine levels. Although there were few detectable changes in cytokines at the protein level, radiation exposure up-regulated gene expression of the IL-1 family (Il1f6, Il1f8 and Il1f10), TNF super family (Tnfsf11b and Tnfsf12), growth differentiating factors (Gdf1, 2, 10 and 15) and bone morphogenetic proteins (Bmp4, 5, 6, 7 and 10). With MC treatment, the expression of many of these genes was no longer significantly different from 0 Gy controls. This suggests that MC may be useful as a neuroprotective agent and may reduce the risk for neurocognitive deficits.