The differentiation of pluripotent stem cells in three-dimensional cultures can recapitulate key aspects of brain development, but protocols are prone to variable results. Here we differentiated multiple human pluripotent stem cell lines for over 100 d using our previously developed approach to generate brain-region-specific organoids called cortical spheroids and, using several assays, found that spheroid generation was highly reliable and consistent. We anticipate the use of this approach for large-scale differentiation experiments and disease modeling.

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Populations with obesity are more likely to fall and exhibit balance instability. The reason for this is likely multifactorial, but there is some evidence that sensory function is impaired during obesity. We tested the hypothesis that muscle proprioceptor function is compromised in a mouse model of diet induced obesity. An in vitro muscle-nerve preparation was used to record muscle spindle afferent responses to physiological stretch and sinusoidal vibration. We compared the responses of C57/Bl6 male and female mice on a control diet (10% kcal fat) with those eating a high fat diet (HFD; 60% kcal fat) for 10 weeks (final age 14–15 weeks old). Following HFD feeding, adult mice of both sexes exhibited decreased muscle spindle afferent responses to muscle movement. Muscle spindle afferent firing rates during the plateau phase of stretch were significantly lower in both male and female HFD animals as were two measures of dynamic sensitivity (dynamic peak and dynamic index). Muscle spindle afferents in male mice on a HFD were also significantly less likely to entrain to vibration. Due to the importance of muscle spindle afferents to proprioception and motor control, decreased muscle spindle afferent responsiveness may contribute to balance instability during obesity.

Individuals with obesity are more likely to fall and exhibit balance instability. The reason for this is likely multifactorial, but there is some evidence that sensory function is impaired during obesity. We tested the hypothesis that muscle proprioceptor function is compromised in a mouse model of diet induced obesity. We used an in vitro musclenerve preparation to record muscle spindle afferent responses to physiological stretch and sinusoidal vibration. We compared the responses of mice on a control diet (10% kcal fat) with those eating a high fat diet (60% kcal fat) alone or in combination with either aspirin (120mg/kg/day in drinking water) or rosiglitazone (0.01% in chow) for 10 weeks. Following high fat diet feeding, adult mice exhibited decreased muscle spindle afferent responses to stretch and lower dynamic sensitivity. Treatment with aspirin or rosiglitazone did not completely rescue muscle spindle afferent responsiveness. Due to the importance of muscle spindle afferents to proprioception and motor control, decreased muscle spindle afferent responsiveness may contribute to balance instability during obesity. Future studies should test this hypothesis in the human population. v ACKNOWLEDGMENTS First, I would like to thank members of the Wilkinson lab who assisted with running experiments and analyzing data. I would like to thank Shreejit Padmanabhan for analyzing muscle tension data, and Adam Abtahie and Adam Cai for assisting with vibration data analysis and crosschecking of data analysis. Second, I would like to thank Larry Young and Nelia Medeiros for providing essential animal training and continuous assistance with animal work. Third, I would like to thank my thesis committee members Dr. Michael Sneary and Dr. Rachael French for providing valuable criticisms. Finally, I would like to thank my amazing mentor Dr. Katherine Wilkinson for believing in me and giving me the opportunity to conduct research in her laboratory. Her encouragement and guidance helped me all throughout my research, writing of the thesis, and helped me become a better scientist. vi