In Vivo Synaptic Dynamics During Post-Stroke Motor Rehabilitation

Lay Summary

Imaging Structural Changes Following Stroke to Define Optimal Strategies for Motor Rehabilitation

The researchers will use cellular imaging in a mouse model of stroke to understand the structural basis and timing of new synapse formation that underlies motor rehabilitation, and will use this information to guide the design of combined training and medications to maximize rehabilitation outcomes.

Stroke destroys about 14 billion brain synapses a minute. Following a stroke, the brain promotes structural and functional reorganization of the surviving tissue in surrounding areas. The nature and timing of synapse remodeling, and how closely it relates to regaining motor function in the affected limbs, is not yet understood. There seems to be a narrow window of opportunity during which the brain is more receptive to changes induced by rehabilitation. The investigators hypothesize that both an increase in synaptic dynamics and a consolidation of new synapses formed in the regions surrounding the stroke are crucial for functional recovery of motion. They further hypothesize that deliberately exercising affected limbs accelerates this recovery by selectively stabilizing newly formed synapses, and that, by using certain drugs in combination with training, functional outcomes can be improved.

They will use fluorescent two-photon microscopy to repeatedly view neurons and their synapses in the animals’ sensorimotor cortex, where a focal stroke has been induced. Over days and months, the investigators will image the same neurons’ “dendritic spines.” These are a neuron’s branches that form a synapse with a neighboring brain cell’s axon to receive the neighbor’s electrochemical signals.  They will image synapse formation as the mice receive limb training and an enzyme called chondroitinase ABC, which reduces glial scarring.

Their preliminary data indicate that dendritic spines turn over quickly in the sensorimotor cortex immediately after stroke, with more spines forming than being eliminated (in contrast to healthy mice).  The investigators anticipate that dendritic spines, initially dynamic immediately following stroke, will then slow down their turnover, but be less stable. They further anticipate that persistent training of affected limbs will stabilize newly formed synapses while the enzyme will gradually reduce glial scarring, to optimize motor recovery.

Significance:  If limb training and enzyme use are shown to enhance synapse formation and motor outcomes in the animal model, the research should help to guide new approaches to maximizing stroke rehabilitation outcomes in patients.

Abstract

In Vivo Synaptic Dynamics During Post-Stroke Motor Rehabilitation

The synapse is the site of information exchange in the nervous system.  Its structure and function are constantly modified in living animals and closely associated with development, learning experience, and neuropathologies.  Stroke is the third greatest killer in the United States.  About 14 billion synapses are lost in every minute of stroke.  To compensate for this traumatic loss, the brain promotes dramatic structural and functional reorganization of the surviving tissue.  However, the dynamic nature of this remodeling and how it is related to behavior recovery remain unclear. 

The goal of this proposal is to reveal the structural basis of motor rehabilitation in the post-stroke living brain, to determine the best motor training paradigm, and to identify a potential pharmacological treatment that will enhance such structural remodeling.  We will take advantage of both transgenic mice expressing yellow fluorescent protein in a subset neurons and a newly developed transcranial two-photon in vivo imaging technique to achieve this goal.  We will follow the turnover of postsynaptic dendritic spines in the peri-infarct region of the post-stroke living brain (this region is known to have maximum structural remodeling after stroke).  We will next determine whether and how motor training of affected limbs increases spine formation in this region, and see if drugs that increase structural plasticity of synapse also improve behavior recovery. 

Such studies will provide valuable information on the structural changes underlying behavior recovery after stroke, and assist in further designing physical therapy protocols and drug treatment to maximize its benefit.