Orbitofrontal-hypothalamic projections are disrupted in hypermetabolic murine ALS model and human patients

Abstract

Increased catabolism is a new clinical manifestation of Amyotrophic Lateral Sclerosis. A dysfunction of lateral hypothalamus may drive hypermetabolism in ALS; however, Its causes and anatomical substrates are unknown. We hypothesize that disruption cortico-hypothalamic circuits may impair energy homeostasis in ALS. We used rAAV2 for large-scale projection mapping and image analysis pipeline based on Wholebrain and Ilastik to quantify projections from the forebrain to the latera hypothalamus of the SOD1(G93A) ALS mouse model as well as of the FusΔNLS ALS mouse model. Expanded projections from agranular Insula, ventrolateral orbitofrontal and secondary motor cortex to lateral hypothalamus were found in two independent cohorts of the hypermetabolic SOD1(G93A) ALS model. The non-hypermetabolic FusΔNLS ALS mouse model display a loss of projections from motor cortex but no change in projections from insula and orbitofronal cortex. 3T DTI-MRI data on 83 ALS patients and 65 controls confirmed the disruption of the orbitofrontal-hypothalamic tract in ALS patients. Converging murine and human data demonstrate the selective disruption of hypothalamic inputs in ALS as a factor contributing to the origin of hypermetabolism.

Effect of the Minor C Allele of CNTN4 rs2619566 on Medial Hypothalamic Connectivity in Early-Stage Patients of Chinese Han Ancestry with Sporadic Amyotrophic Lateral Sclerosis

“…Amyotrophic lateral sclerosis (ALS) is a neuromuscular disorder characterized by progressive muscle atrophy and paralysis, in which the affected individual eventually dies of breathing failure. ALS is characterized by both upper and lower motor neuron dysfunction, but is not limited to these regions, eg, structural or functional impairment in the middle temporal gyrus, 1 insula, 2 , 3 anterior cingulate gyrus 4 and some regions within the occipital and parietal lobes. 5 …”

“… 6 Neuroimaging studies have observed that hypothalamus atrophy in ALS in the premorbid stage and correlates with body mass index (BMI). 8 Furthermore, a diffusion tensor imaging study demonstrated the selective involvement of orbitofrontal, insular, and motor cortex projections to the hypothalamus in murine ALS models and human patients, 3 and some studies showed that neurons of the hypothalamus innervate various subcortical motor structures such as the cerebellum, vestibular nuclei 9 and even spinal cord, 10 which may be associated with motor dysfunction in ALS.…”