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Item Bisphosphonates suppress periosteal osteoblast activity independently of resorption in rat femur and tibia(2006-05) Iwata, Ken; Li, Jiliang; Follet, Helene; Phipps, Roger J; Burr, David B.Recent studies demonstrate that bisphosphonates suppress bone resorption by leading to apoptosis of the osteoclast and inhibiting the differentiation to mature osteoclasts. The influence of bisphosphonates on bone formation is unknown, although it has been hypothesized that bisphosphonates inhibit osteoblast apoptosis and stimulate osteoblast proliferation and differentiation in vitro, leading to increased bone formation. The purpose of this study was to investigate the effect of bisphosphonates on bone formation. We administered risedronate at 0.05, 0.5 or 5.0 μg/kg/day or alendronate at 0.1, 1.0 or 10 μg/kg/day subcutaneously for 17 days to 6-month-old female Sprague–Dawley rats. Control rats were given a daily subcutaneous injection of saline. Following sacrifice, the femoral and tibial mid-diaphyses were harvested and mineralizing surface (MS/BS), mineral apposition rate (MAR) and bone formation rate (BFR/BS) were measured on periosteal and endocortical surfaces. In the femur, periosteal MAR was significantly lower in all treatment groups (22–29% for risedronate, 26–36% for alendronate) than in control. In the tibia, periosteal MAR and BFR of all treatment groups were significantly lower (41–50% for risedronate, 43–52% for alendronate) than in the control group. Because the periosteal surfaces of these bones are only undergoing bone formation in modeling mode, our results show that bisphosphonates suppress bone formation independently of bone resorption. Because this effect is seen on periosteal MAR rather than on periosteal MS/BS, we hypothesize that bisphosphonates affect the activity of individual osteoblasts at the cell level. This may help to explain the reason that the anabolic effects of teriparatide are blunted when administered concurrently with or following a course of bisphosphonates in humans.Item Exploring the Effects of a Corticotropin Releasing Factor (CRF) Receptor Antagonist on Habit Expression(2020-12) Haines, Kari; Czachowski, Cristine L.; Grahame, Nicholas J.; Logrip, Marian L.Some individuals with alcohol use disorder (AUD) continue to drink because they have developed a habit in which they are not considering the consequences of their actions. Habitual actions persist despite changes in reward and are often studied using devaluation procedures. Stress hormones, such as corticotropin releasing factor (CRF), have been linked to AUD when examining binge-like drinking and withdrawal in rodents. Stress has been examined in the switch from goal-directed to habitual behavior, and CRF has often mimicked the effects of stress exposure. This study looked at the possible direct effects of CRF on habit expression in rats using an operant paradigm. Finding possible novel mechanisms of habit could create an avenue for future novel treatment options. Female and male Long Evans rats were trained on a variable interval schedule using sucrose as a reward. Rats then underwent devaluation procedures including both sensory-specific satiety and conditioned taste aversion (CTA) to test for habitual behaviors. Prior to an extinction session post-CTA, animals were treated with either 20 mg/kg R121919, a CRF1 receptor antagonist, or vehicle. A second extinction session was conducted where animals received the alternative treatment. Lever presses were recorded as a measure of goal-directed or habitual behavior. Sensory-specific satiety devaluation tests revealed that animals were not sensitive to devaluation. This was further supported by both post-CTA extinction sessions. R121919 had no effect on lever pressing in either devalued or valued groups. Further research is needed to explore how a CRF receptor antagonist may affect habit formation or the transition from goal-directed to habit behaviors. Future studies should also examine any possible interaction effects CRF may have with alcohol or stress on habitual behaviors.Item Iron deficiency and high-intensity running interval training do not impact femoral or tibial bone in young female rats(Cambridge University Press, 2022-10-28) Scott, Jonathan M.; Swallow, Elizabeth A.; Metzger, Corinne E.; Kohler, Rachel; Wallace, Joseph M.; Stacy, Alexander J.; Allen, Matthew R.; Gasier, Heath G.; Anatomy, Cell Biology and Physiology, School of MedicineIn the US, as many as 20% of recruits sustain stress fractures during basic training. In addition, approximately one-third of female recruits develop iron deficiency upon completion of training. Iron is a cofactor in bone collagen formation and vitamin D activation, thus we hypothesized iron deficiency may be contributing to altered bone microarchitecture and mechanics during 12-weeks of increased mechanical loading. Three-week old female Sprague Dawley rats were assigned to one of four groups: iron adequate sedentary, iron deficient sedentary, iron adequate exercise, and iron deficient exercise. Exercise consisted of high-intensity treadmill running (54 min 3×/week). After 12-weeks, serum bone turnover markers, femoral geometry and microarchitecture, mechanical properties and fracture toughness, and tibiae mineral composition and morphometry were measured. Iron deficiency increased the bone resorption markers C-terminal telopeptide type I collagen and tartate-resistant acid phosphatase 5b (TRAcP 5b). In exercised rats, iron deficiency further increased bone TRAcP 5b, while in iron adequate rats, exercise increased the bone formation marker procollagen type I N-terminal propeptide. In the femur, exercise increased cortical thickness and maximum load. In the tibia, iron deficiency increased the rate of bone formation, mineral apposition, and zinc content. These data show that the femur and tibia structure and mechanical properties are not negatively impacted by iron deficiency despite a decrease in tibiae iron content and increase in serum bone resorption markers during 12-weeks of high-intensity running in young growing female rats.Item The Need for Speed in Rodent Locomotion Analyses.(Wiley, 2014-10) Batka, Richard J.; Brown, Todd J.; Mcmillan, Kathryn P.; Meadows, Rena M.; Jones, Kathryn J.; Haulcomb, Melissa M.; Department of Anatomy & Cell Biology, IU School of MedicineLocomotion analysis is now widely used across many animal species to understand the motor defects in disease, functional recovery following neural injury, and the effectiveness of various treatments. More recently, rodent locomotion analysis has become an increasingly popular method in a diverse range of research. Speed is an inseparable aspect of locomotion that is still not fully understood, and its effects are often not properly incorporated while analyzing data. In this hybrid manuscript, we accomplish three things: (1) review the interaction between speed and locomotion variables in rodent studies, (2) comprehensively analyze the relationship between speed and 162 locomotion variables in a group of 16 wild-type mice using the CatWalk gait analysis system, and (3) develop and test a statistical method in which locomotion variables are analyzed and reported in the context of speed. Notable results include the following: (1) over 90% of variables, reported by CatWalk, were dependent on speed with an average R2 value of 0.624, (2) most variables were related to speed in a nonlinear manner, (3) current methods of controlling for speed are insufficient, and (4) the linear mixed model is an appropriate and effective statistical method for locomotion analyses that is inclusive of speed-dependent relationships. Given the pervasive dependency of locomotion variables on speed, we maintain that valid conclusions from locomotion analyses cannot be made unless they are analyzed and reported within the context of speed.