Disruption of orbitofrontal-hypothalamic projections in a murine ALS model and in human patients.

BACKGROUND: Increased catabolism has recently been recognized as a clinical manifestation of amyotrophic lateral sclerosis (ALS). The hypothalamic systems have been shown to be involved in the metabolic dysfunction in ALS, but the exact extent of hypothalamic circuit alterations in ALS is yet to be determined. Here we explored the integrity of large-scale cortico-hypothalamic circuits involved in energy homeostasis in murine models and in ALS patients. METHODS: The rAAV2-based large-scale projection mapping and image analysis pipeline based on Wholebrain and Ilastik software suites were used to identify and quantify projections from the forebrain to the lateral hypothalamus in the SOD1(G93A) ALS mouse model (hypermetabolic) and the FusΔNLS ALS mouse model (normo-metabolic). 3 T diffusion tensor imaging (DTI)-magnetic resonance imaging (MRI) was performed on 83 ALS and 65 control cases to investigate cortical projections to the lateral hypothalamus (LHA) in ALS. RESULTS: Symptomatic SOD1(G93A) mice displayed an expansion of projections from agranular insula, ventrolateral orbitofrontal and secondary motor cortex to the LHA. These findings were reproduced in an independent cohort by using a different analytic approach. In contrast, in the FusΔNLS ALS mouse model hypothalamic inputs from insula and orbitofrontal cortex were maintained while the projections from motor cortex were lost. The DTI-MRI data confirmed the disruption of the orbitofrontal-hypothalamic tract in ALS patients. CONCLUSION: This study provides converging murine and human data demonstrating the selective structural disruption of hypothalamic inputs in ALS as a promising factor contributing to the origin of the hypermetabolic phenotype.

Linking nighttime outdoor lighting attributes to pedestrians' feeling of safety: An interactive survey approach.

Public space lighting (PSL) contributes to pedestrians' feeling of safety (FoS) in urban areas after natural dark. However, little is known how different PSL attributes, such as illuminance, light temperature, uniformity and glare, affect people's FoS in different contextual settings. The present study aims to bridge this knowledge gap by developing a model linking different PSL attributes with FoS, while controlling for individual, locational, environmental and temporal factors. To develop such model, the study employs a novel interactive user-oriented method, based on a specially-designed mobile phone application-CityLightsTM. Using this app, a representative sample of observers reported their impressions of PSL attributes and FoS in three cities in Israel, following a set of predetermined routes and points. As the study shows, higher levels of illumination and uniformity positively affect FoS, while lights perceived as warm tend to generate higher FoS than lights perceived as cold. These findings may guide future illumination polices aimed at promoting energy efficiency while ensuring urban sustainability.