Friday, November 22, 2024
11/22/2024
PROJECT SUMMARY The supraspinal connectome refers to the full set of neurons that reside in the brain and project axons to the spinal cord. The sheer complexity of this connectome, both anatomical and functional, has presented stubborn challenges to understanding and treating the highly variable disruption that accompanies spinal injury. Anatomically, the wide distribution of the cell bodies has made it very difficult to trace and quantify all populations simultaneously, leading most studies to focus on just one or several main supraspinal cell types. Functionally, descending control is distributed across multiple populations with outputs that can be complementary, antagonistic, or potentially compensatory after injury. These functional relationships strongly affect outcomes after spinal injury but are difficult to capture in single- or several-tract approaches. This project aims to advance the field though an approach that yields a comprehensive understanding of spinal injury at a whole-connectome level and by providing new viral tools to selectively manipulate subtypes of brain-spinal neurons. First, we will use 3D whole-brain and -spinal imaging to visualize and precisely quantify the number and activity level of spared neurons in all supraspinal cell types across cohorts of animals that receive graded contusion injuries, while simultaneously measuring both spontaneous and rehabilitation-induced recovery of function. With whole-brain data and advanced statistical techniques we can take advantage of the natural variability between individual animals to identify the elements of the connectome that are most predictive of recovery. Next, we will systematically test these predicted functional relationships by targeted, reversible chemogenetic silencing of selected supraspinal populations before injury, after injury, and after rehabilitation. Importantly, these silencing experiments will employ both direct targeting of brain regions and newly developed viral tools that enable selective manipulation of defined subtypes of spinally projecting neurons. Collectively, these connectome-level data and new subtype-specific tools are needed to 1) help resolve lurking variability that currently challenges the field, 2) provide a comprehensive, rational framework that prioritizes interest in the full sets of supraspinal populations of highest relevance to functional recovery, and 3) provide a pipeline and data resources that extracts maximal, brain-wide information from pre-clinical models of spinal injury to more fully align them with the complex needs of individuals living with SCI.
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