Abstract
Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of motoneurons in the primary motor cortex (pMO) and in spinal cord. However, the pathogenic process involves multiple subnetworks in the brain and functional MRI studies demonstrate an increase in functional connectivity in areas connected to pMO despite the ongoing neurodegeneration. The extent and the structural basis of the motor subnetwork remodeling in experimentally tractable models remain unclear. We have developed a new retrograde AAV9 to quantitatively map the projections to pMO in the SOD1(G93A) ALS mouse model. We show an increase in the number of neurons projecting from somatosensory cortex to pMO at presymptomatic stages, followed by an increase in projections from thalamus, auditory cortex and contralateral MO (inputs from 20 other structures remains unchanged) as disease advances. The stage- and structure-dependent remodeling of projection to pMO in ALS may provide insights into the hyperconnectivity observed in ALS patients.
Highlights
Amyotrophic lateral sclerosis (ALS) is classically described as a disease of upper and lower motor neurons (Ravits et al, 2007)
We consistently identified a small contingent of neurons projecting to pMO located in hypothalamus (HY 0.6 ± 0.2% of the total pool of neurons projecting to pMO in the forebrain); out of these hypothalamic neurons, not previously reported, the majority was located in the lateral zone of hypothalamus (zona incerta 23 ± 10% of the total of hypothalamic neurons projecting to pMO; lateral preoptic area 23 ± 19% of the total of hypothalamic neurons projecting to pMO; lateral hypothalamic area 14 ± 18% of the total of hypothalamic neurons projecting to Figure 2 continued provided by thalamus (TH), followed by somatosensory (SS), contralateral secondary motor cortex and contralateral primary motor cortex
We have demonstrated, using viral-tracing approaches, that the motor subnetwork in an ALS mouse model undergoes distinct remodeling during disease progression with stage and structure-dependent effects: projection from somatosensory cortex (SS) is increased already in presymptomatic mice and remains stable, whereas projections from AUD and cMOs and cMOp either appear or increase further in the symptomatic stage
Summary
Amyotrophic lateral sclerosis (ALS) is classically described as a disease of upper and lower motor neurons (Ravits et al, 2007). ALS has been growingly conceptualized as a disease of the motor subnetwork or, in more advanced stages, a multi-network disease affecting motor, premotor and sensory areas To which extent these networks are damaged by the neurodegeneration and remodel themselves during the disease progression, it is a subject of active investigation. An increase in functional connectivity in the motor subnetwork was already detectable in presymptomatic and early-stage ALS patients (Schulthess et al, 2016). These data indicate that a significant architectural remodeling of the motor subnetwork takes place in ALS patients in the face of ongoing neurodegeneration, the extent of such remodeling and the structural changes underlying this effect in the motor network are unclear. We have identified one structural component of the early and selective remodeling of the large-scale architecture of the motor subnetwork, which may contribute to explain the functional connectivity changes observed in patients
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