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.