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Such studies hold promise for building long-term effective treatment solutions in the near future. Here, we will review recent developments and current applications of novel strategies that reveal the cellular and molecular basis of CSMN health and vulnerability. However, visualizing and identifying these vulnerable neuron populations in the complex and heterogeneous environment of the cerebral cortex have proved challenging. Detailed cellular analyses are crucial to gain a better understanding of the pathologies underlying CSMN degeneration. In addition, CSMN death results in long-term paralysis in spinal cord injury patients. CSMN degeneration has an immense impact on motor neuron circuitry and is one of the underlying causes of numerous neurodegenerative diseases, such as primary lateral sclerosis (PLS), hereditary spastic paraplegia (HSP), and amyotrophic lateral sclerosis (ALS).