Yoshida Lab
News & Impact

You are here

Corticospinal Neuron Dysfunction and Degeneration in Als: Testing the Role of Corticomotor Connectivity in Motor Neuron Disease

December 1, 2020 to November 30, 2025
Funding Status: 
Active Project
Funding Agency: 
National Institutes of Health (NIH)
Funding Institute: 
National Institute of Neurological Disorders and Stroke (NINDS)
Grant Number: 
Published Grant: 


In patients with amyotrophic lateral sclerosis (ALS) and the related motor neuron disease (MND) primary lateral sclerosis (PLS), deficits in motor control occur as a consequence of the degeneration of corticospinal neurons (CSNs). ALS is more common than PLS, and genetically more complex, with familial forms associated with causal mutations in over 30 ALS-related genes. In these ALS mice, however, dysfunction and degeneration of CSNs have not been carefully examined, and data implicating corticospinal (CS) circuits in these model systems of ALS is surprisingly limited. One reason for this may be the very different pattern of connectivity between CSNs and spinal MNs in humans vs. mice. In humans, CS axons located in the ventral and lateral funiculi form direct connections with both MNs (cortico-motoneuronal (CM) connections) and interneurons. In contrast, CS axons in mice are located mainly in the dorsal funiculus and only form indirect connections with MNs through pre-motor interneurons. Therefore, we will use PlexinA1 mutant mice which have CM connections together with ALS mouse models to analyze CS circuits. Our central hypothesis is that progressive defects in CS circuitry in ALS mice will be exacerbated by the establishment of CM connections. In Aim 1, we will determine formation of CS circuits in ALS mouse models with CM connections. In Aim 2, we will determine function of CS circuits in ALS mouse models with CM connections. In Aim 3, we will examine skilled movements in ALS mouse models with CM connections. These studies will provide a model system to study mechanisms of CS degeneration in ALS/PLS, and to test novel therapeutics targeting upper motor neuron dysfunction in these disorders.


Yutaka's Photo
Lab Director
Laboratory for Neural Connectivity Development in Physiology and Disease
Principal Investigator


Conditions & Recovery

Neurodegenerative Diseases icon
Worldwide, 50 million people are living with Alzheimer's and other dementias.
Motor Recovery Icon
Write and walk again.