Presenting Author:
Principal Investigator:
Department:
Neurology, Ken and Ruth Davee Department
Keywords:
Neuroinflammation, ALS, mild cortical injury, CSMN, corticospinal motor neurons, neurodegenerative disease, neurodegeneration
Location:
Third Floor, Feinberg Pavilion, Northwestern Memorial Hospital
B110 - Basic Science
Understanding the link between cortical injury and ALS
Background Traumatic brain injury (TBI) is linked to the development of neurodegenerative diseases in which motor neuron circuitry is impaired. In particular, professional athletes with concussion history [1] and military veterans are in greater risk of developing motor neuron diseases. Corticospinal motor neurons (CSMN) are located in the cerebral cortex and therefore more susceptible to TBI. CSMN are a key component of the motor neuron circuitry and play a role in ALS pathology. CSMN can be studied using UCHL1-eGFP (U-eGFP) transgenic line, in which CSMN are genetically labeled with eGFP. By crossing U-eGFP mice with ALS mouse models a distinct vacuolation pattern in the CSMN apical dendrite is observed. The immune response also plays a role in CSMN degeneration. Microglia activation correlates with CSMN deficits in patients and is present in the vicinity of diseased CSMN. Among the neuroinflammatory components observed, MCP1/CCR2 is a cytokine/receptor system critically involved in both in ALS and TBI [2,3]. Objectives Modeling TBI using mild cortical injury (CI) to study its effect on CSMN degeneration and assessing related neuroinflammation. Methods To visualize CSMN we use U-eGFP mice. Apical dendrite pattern, CSMN body size, and markers of apoptosis serve as a read-out to determine CSMN degeneration. To study neuroinflammation we use the MCP1-CCR2 reporter mouse in which cells that express MCP1 or CCR2 are labeled with red or green fluorescence, respectively. A unilateral mild CI is produced over the motor cortex using controlled cortical impact method. Results A mild CI that produces a small contusion cavity after 48 hrs. was successfully performed in both U-eGFP and MCP1-CCR2 mice. Preliminary results show CSMN with vacuolated apical dendrites underneath the contusion cavity and decreased numbers in layer V of the motor cortex. CSMN in the contralateral side of the cortex do not present vacuoles. Microgliosis and astrogliosis is increased after 48hrs. throughout the motor cortex and MCP1+ and CCR2+ cells are identified as microglia and infiltrating monocytes, respectively. Discussion and conclusions The mechanisms that lead to CSMN degeneration are not completely understood. This study allows for the development of a mild CI model in which CSMN have a common pattern of degeneration with CSMN from ALS mouse models. Moreover, the fact that immune response is increasingly present after TBI and during ALS pathology opens a venue for exploration to understand the basis of common neuroinflammation mechanisms in both contexts.
