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

Translational Neurodegeneration

Volker Rasche¹  Hans-Peter Müller²  Rami Saad²  Stefano Antonucci²  David Bayer³  Jan Kassubek⁴  Albert C. Ludolph⁴  Francesco Roselli⁴  Tobias M. Böckers⁵  Luc Dupuis⁶ 

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

关键词: rAAV2;    Agranular insula;    Orbitofrontal cortex;    Lateral hypothalamus;    Hypermetabolism;    Amyotrophic lateral sclerosis;   

DOI  :  10.1186/s40035-021-00241-6

来源: Springer

【 摘 要 】

BackgroundIncreased 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.MethodsThe 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.ResultsSymptomatic 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.ConclusionThis 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.

【 授权许可】

CC BY