The development and function of the nervous system is regulated not only by electrical and biochemical signals, but also by mechanical inputs. For instance, most if not all neurons generate mechanical stress and experience strain during migration, axon outgrowth, and dendritic spine remodeling. With a few notable exceptions, however, the study of cell mechanics has been neglected in neuroscience. We seek to fill this knowledge gap by investigating the genetic and physical basis of how neurons withstand mechanical stress focusing on C. elegans touch receptor neurons as a model. Key entry points for this investigation are the findings that loss of unc-70 spectrin function makes C. elegans neurons vulnerable to damage induced by normal movement and the well-known function for actin-spectrin networks in protecting red blood cells from the mechanical strains generated as they transit through tiny capillaries. In new work, we establish a simple visible assay for loss of spectrin function in the ventral touch receptor neurons and create transgenic animals expressing a genetically-encoded strain sensor that enables us to visualize how body bending and touch sensation affects stress in neural actin-spectrin networks. The proposed research combines genetic dissection, high-speed quantitative confocal microscopy, and in vitro biochemistry to investigate the role of spectrin networks in mechanical neuroprotection and sensory mechanoelectrical transduction. This work has the potential to transform understanding of neuronal cell mechanics and the contribution of actin-spectrin networks in this process. The new knowledge we seek to acquire could provide insight into the genetic basis of mechanical neuroprotection and potential risk factors related to traumatic brain injury.
All neurons experience mechanical stress during development and traumatic brain injury (TBI). While intensive study of TBI has uncovered spectrin breakdown products fragments as potential biomarkers, spectrin's function in the nervous system is not well understood. The proposed research exploits simple animal models to develop a comprehensive understanding of how conserved actin-spectrin networks regulate responses to mechanical stress in the nervous system and has the potential to reveal novel mechanisms of mechanical neuroprotection that could inform understanding of sensory neuron function and its dysregulation.
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