Abstract
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.
Highlights
Increased catabolism has recently been recognized as a clinical manifestation of amyotrophic lateral sclerosis (ALS)
Simple foreground/background segmentations were generated by resorting to the pixel classification workflow, which allowed automatic clearance of most of the brain autofluorescence background in Fiji (Fig. 1a, 4.6)
This step improved the discrimination of few ZsGreen+ neurons in region of interest (ROI) containing many more dendrite stretches and artifacts, minimizing the chance of generating artifactual counts and reducing the computational burden placed on ilastik cell density classifier
Summary
Increased catabolism has recently been recognized as a clinical manifestation of amyotrophic lateral sclerosis (ALS). We explored the integrity of large-scale cortico-hypothalamic circuits involved in energy homeostasis in murine models and in ALS patients. Amyotrophic lateral sclerosis (ALS) is traditionally conceptualized as a neurodegenerative condition primarily affecting the upper motoneurons located in the primary motor cortex, and lower motoneurons located in the spinal cord, whose dysfunction and loss result in a relentless, progressive and fatal motor impairment [1]. Hypermetabolism has been recognized as an important, nonmotor clinical feature of ALS [2]. The increased catabolism may be a result of intrinsic hypermetabolism, as demonstrated in both ALS patients (in about 50–60% of cases [9,10,11,12,13]) and mutant SOD1 ALS mice [14,15,16]. Metabolism and energy balance seem to be promising targets for intervention, since increasing caloric intake is beneficial for survival, in fastprogressing ALS patients [17, 18]
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