Spinal cord injury (SCI) is a devastating neurologic insult that can disrupt ascending and descending neural circuits necessary for walking, somatosensation, urination and other vital autonomic functions. The majority of SCI patients suffer from anatomically and functionally incomplete spinal cord injury (I-SCI) that results in varying degrees of neurological dysfunction. Although long-distance regeneration of central nervous system (CNS) axons does not occur in mammals, clinical and experimental studies demonstrate considerable spontaneous recovery of neurological function after I-SCI. Experimental studies in rodents and non-human primates indicate that synaptic reorganization between supraspinal motor tracts and spared intraspinal relay circuits that bypass a spinal lesion can re-establish brain-cord communication, and give rise to remarkable motor recovery after I-SCI. Unfortunately, a limited understanding of the cellular and molecular mechanisms governing this functionally meaningful intraspinal circuit plasticity has precluded development of therapeutics to augment this spontaneously occurring recovery process. Astrocytes are critical regulators of synaptogenesis and circuit development during development, and moderate synaptic strength and structural synaptic plasticity following changes in neural activity. In response to diverse CNS injuries, astrocytes undergo graded and regionally distinct changes in structure and function collectively referred to as reactive astrogliosis. After SCI, scar-forming, reactive astrocytes surrounding lesions are indispensible regulators of inflammation. The functions of non-scar-forming, reactive perineuronal astrocytes in spinal cord regions undergoing functionally meaningful circuit remodeling after SCI are not clear, but potential roles include regulation of synapse recovery and neuroprotection. The objective of the current study is to delineate fundamental molecular mechanisms through which astrocytes modulate intraspinal synaptic reorganization and spontaneous locomotor recovery after SCI. This research will test the overriding hypothesis that after I-SCI, intraspinal perineuronal astrocytes in spared tissue undergo changes in transcriptional profile that modulate and promote intraspinal synaptic plasticity and circuit remodeling underlying spontaneous locomotor recovery.
In Aim 1, I will use astrocyte-specific transcriptomics to delineate changes in perineuronal astrocyte gene expression that underlie supraspinal-intraspinal synaptic plasticity within key spinal circuit reorganizing zones rostral to an I-SCI lesion.
In Aim 2, I will assess the relevance of perineuronal astrocyte reactivity for supraspinal-intraspinal synaptic remodeling and motor recovery.
In Aim 3, I will compare mechanisms through which astrocytes regulate supraspinal-intraspinal plasticity in reorganizing zones above an I-SCI lesion, with those regulating sensorimotor circuit reorganization within the denervated motor centers below. Together, these studies will serve as a critical first step towards identifying astrocyte molecular pathways that may be therapeutically targeted to enhance functionally relevant plasticity and promote recovery of neurological function after I-SCI.

Public Health Relevance

In the US, nearly 13,000 people each year experience a debilitating spinal cord injury, which results in disability that prevents them from being able to perform essential daily functions, including walking, reaching, grasping and urination. Although many patients experience varying degrees of spontaneous recovery after injury, a lack of understanding of this remarkable process has prohibited the development of therapies for treating spinal cord injury patients with enduring neurological dysfunction. The proposed research will provide critical insight into the biochemical and cellular mechanisms that regulate spontaneous recovery after spinal cord injury, and aid in the discovery of new therapeutic targets for treating neurological disability that occurs after, traumatic brain or spinal cord injury, stroke, as well as that brought on by neurodegenerative diseases such as multiple sclerosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Transition Award (R00)
Project #
5R00NS105915-04
Application #
10004175
Study Section
NST-2 Subcommittee (NST)
Program Officer
Bambrick, Linda Louise
Project Start
2018-04-01
Project End
2022-05-31
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048