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.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
E-Mail: david.bayer{at}uni-ulm.de, stefano.antonucci{at}uni-ulm.de, hans-peter.mueller{at}uni-ulm.de, ldupuis{at}neuro-cnrs.unistra.fr, tobias.boeckers{at}uni-ulm.de, albert.ludolph{at}rku.de, jan.kassubek{at}uni-ulm.de, francesco.roselli{at}uni-ulm.de
- Abbreviations
- ABA
- Allen brain atlas, version 2011
- ACA
- Anterior cingulate area
- aco
- anterior commissure olfactory limb
- act
- anterior commissure temporal limb
- AI
- Agranular insular area
- ALS
- Amyotrophic lateral sclerosis
- ALS-FRS-R
- ALS functional rating scale revised
- AOB
- Accessory olfactory bulb
- AP
- Anteroposterior
- AUD
- Auditory areas
- BLA
- Basolateral amygdalar nucleus
- BMA
- Basolateral amygdalar nucleus
- BSA
- Bovine serum albumin
- CA3so
- Field CA3 stratum oriens
- ccg
- genu of corpus callosum
- CLA
- Claustrum
- COA
- Cortical amygdalar area
- DG
- Dentate gyrus
- DP
- Dorsal peduncular area
- DPBS
- Dulbecco’s phosphate buffered saline
- DTI
- Diffusion-tensor-imaging
- DV
- Dorsoventral
- EP
- Endopiriform nucleus
- fa
- corpus callosum anterior forceps
- FA
- Fractional anisotropy
- FUS
- B6.FUSΔNLS/+
- HSB
- Hue-saturation-brightness color model
- GU
- Gustatory areas
- HY
- Hypothalamus
- ILA
- Infralimbic area
- int
- internal capsule
- kiFUS
- FUS-/ZsGreen+/-
- LA
- Lateral amygdalar nucleus
- LHA
- Lateral hypothalamic area
- ME
- Median eminence
- ML
- Mediolateral
- MM
- Medial mammillary nucleus
- MOp
- Primary motor area
- MOs
- Secondary motor area
- MRI
- Magnetic resonance imaging
- mSOD1
- mSOD+/ZsGreen+/-
- mSOD
- B6SJL73 Tg(SOD1*G93A)1Gur/J (high-copy)
- NLOT
- Nucleus of the lateral olfactory tract
- OCT
- Optimal cutting temperature compound
- opt
- optic tract
- ORBl/vl
- Orbital area, lateral/ventrolateral part
- ORBl/vl+ AI
- Group of Orbital area, lateral/ventrolateral part and Agranular insular area
- ORBm
- Orbital area, medial part
- OT
- Olfactory tubercle
- P110
- Post-natal day 110
- PA
- Posterior amygdalar nucleus
- PAA
- Piriform-amygdalar area
- PBS
- Phosphate buffered saline
- PFA
- Paraformaldehyde
- PIR
- Piriform area
- PL
- Prelimbic area
- PL+ ORBm
- Group of Prelimbic area and Orbital area, medial part
- PTL
- Posterior parietal association areas
- rAAV
- recombinant adeno-associated virus
- rAAV2-retro
- retrograde recombinant adeno-associated virus 2
- RAM
- Random-access memory
- RGB
- Red-green-blue color model
- Rhinal CTX
- Group of Perirhinal area, Ectorhinal area and Entorhinal area, lateral part
- ROI
- Region of Interest
- RSP
- Retrosplenial area
- rt
- room temperature
- SCH
- Suprachiasmatic nucleus
- SS
- Somatosensory areas
- Tea
- Temporal association areas
- TFAS
- Tractwise fractional anisotropy statistics
- tiff
- Tagged image file format
- TOI
- Tract-of-interest
- TT
- Taenia tecta
- VIS
- Visual areas
- VISC
- Visceral area