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

作　　者：David Bayer Stefano Antonucci Hans-Peter Muller Rami Saad Luc Dupuis Volker Rasche Tobias M.Bockers Albert C.Ludolph Jan Kassubek Francesco Roselli 

机构地区：[1]Department of Neurology,Ulm University,Ulm,Germany [2]CEMMA(Cellular and Molecular Mechanisms in Aging)Research Training Group,Ulm,Germany [3]University of Strasbourg,Strasbourg,France [4]Department of Internal Medicine II,Ulm University Medical Centre,Ulm,Germany [5]Institute of Anatomy and Cell Biology,Ulm University,Ulm,Germany [6]German Center for Neurodegenerative Diseases-DZNE,Ulm,Germany

出　　处：《Translational Neurodegeneration》2021年第2期213-229,共17页转化神经变性病（英文）

基　　金：FR is supported by the Thierry Latran Foundation(projects“Trials”and“Hypothals”),the Radala Foundation,the Deutsche Forschungsgemeinschaft(German Research Foundation)-Project-ID 251293561-Collaborative Research Center(CRC)1149 and individual grants 431995586(RO-5004/8-1)and 443642953(RO5004/9-1);the Cellular and Molecular Mechanisms in Aging(CEMMA)Research Training Group,and BMBF(FKZ 01EW1705A,as member of the ERANET-NEURON consortium“MICRONET”);SA and DB are members of the International Graduate School in Molecular Medicine at Ulm University;DB is part of the Graduate School in Cellular and Molecular Mechanisms in Aging at Ulm University.Open Access funding enabled and organized by Projekt DEAL.

摘　　要：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.

关 键 词：RAAV2 Agranular insula Orbitofrontal cortex Lateral hypothalamus HYPERMETABOLISM Amyotrophic lateral sclerosis 

分 类 号：R746.4[医药卫生—神经病学与精神病学]