An unbiased approach to identify network disruptions and remodeling in the motor system of ALS rodents


Scientific Other

Poster Number: 235


Christi Kolarcik, PhD, Peter Strick, PhD


1. University of Pittsburgh, 2. University of Pittsburgh

Amyotrophic lateral sclerosis (ALS) is a progressive, fatal motor neuron disease characterized by the degeneration and death of motor neurons in the brain, brainstem, and spinal cord. Considering this system-wide degeneration, it is critical to understand the underlying motor network, how it is disrupted by the degenerative process, and what remodeling occurs with disease progression. It is equally important to determine how the disease progresses through the motor network and why certain muscles may be affected differently. Our objective was to define the anatomical connectivity patterns from the cortex to two hindlimb muscles using a neuroanatomical tracing technique to characterize the chain of synaptically-linked neurons that control their function. The normal state of these pathways was characterized in control animals and then the G93A SOD1 mouse model of ALS was evaluated at pre-symptomatic, denervation, symptom onset, and end-stage disease phases. We hypothesized that connectivity within the motor network and projection specificity to fast- versus slow-twitch muscles would impact neural vulnerability to the degenerative process. Anatomical locations associated with each order of transport were characterized as well as the rabies virus-infected neurons located in each node. Density-based analysis of the cortical representation of each muscle indicate that rabies-positive cells are observed in locations consistent with those associated with hindlimb muscles in stimulation studies. Our results outline the time course of retrograde transneuronal transport from hindlimb muscles affected in ALS and suggest differences based on muscle fiber type and alterations that occur with disease progression. Ongoing studies are aimed at quantifying and further characterizing changes in connectivity and transneuronal transport to provide insight into the mechanisms underlying motor neuron degeneration and to aid in the development of targeted therapies.