Targeting synapse turnover to enhance stroke rehabilitation

Strokes result in a period of remodeling of remaining brain circuitry which is shaped by behavioral experience. Pro-growth signaling cascades cause surviving neurons in regions near and previously connected to damaged regions to grow new connections, i.e., reactive synaptogenesis. The patterns of connections grown and maintained are neural activity-dependent and therefore sensitive to the effects of behavioral experiences that activate remodeling circuits. This has long been thought to create an opportunity to shape brain reorganization with behavioral interventions in a manner that improves outcome, as well as to create sensitive time windows for that opportunity. There is ample support for both general possibilities, though it continues to be unclear exactly when and how to intervene to optimize outcomes, and there continues to be a relatively superficial understanding of the nature of the interaction between the behavioral interventions and remodeling responses that supports improved function. This project is focused on obtaining a more detailed basic understanding of the synaptic structural plasticity involved, including how it changes over time after stroke and its potential to be targeted to further improve function. This will be studied in a well-established mouse model of motor rehabilitative training (RT) for post-stroke upper limb impairments after subtotal ischemic infarcts of the forelimb region of primary motor cortex (M1). Repeated in vivo imaging of synaptogenesis as visualized by dendritic spine turnover will be used to examine interactions between stroke-instigated and RT-driven synaptic changes in a region of remaining M1 that is known to mediate RT-driven functional improvements. We previously found in the same region that RT starting 5 days after stroke promoted much greater persistence of new spines and synaptic structural characteristics of enhanced efficacy by magnitudes predictive of functional improvements. We think these effects are likely to reflect cooperative synaptic plasticity, between synapses formed in response to stroke damage and activated by RT. If so, they seem likely to decline with time after stroke to help explain time-sensitivity in RT efficacy, but they also suggest a potential strategy for improving it. Aim 1 is to determine whether RT effects on new spine persistence and maturation wanes with time after stroke in association with diminished RT efficacy for improving forelimb function and maintaining forelimb motor map territory. Aim 2 is to test the relevance of synapse turnover to RT effects on synapses and behavior by re-instigating it in peri-infarct M1 late after stroke. Aim 3 will test the possibility that other behavioral experiences that drive synaptic plasticity in M1 cooperatively enhance synaptic changes in response to RT to improve its efficacy both within and beyond the early post-stroke period. In addition to advancing basic understanding and possibly revealing the general potential of a novel intervention strategy, these studies will set the stage for investigating synapse turnover as a mediator and intervention target of age-dependencies in RT efficacy. Project Number: 1R01NS144898-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Theresa Jones | Institution: UNIVERSITY OF TEXAS AT AUSTIN, AUSTIN, TX | Award Amount: $393,284 | Activity Code: R01 | Study Section: Brain Injury and Neurovascular Pathologies Study Section[BINP] View on NIH RePORTER: https://reporter.nih.gov/project-details/11368400